👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

All reported cases are heterozygous for an FBN1 variant. De novo origin is documented in the probands where parental samples were reported (including the two in the asprosin discovery paper, the 2011 exon-64 frameshift case, and the 2023 Japanese trio); parental testing is not reported for every published case, so "invariably de novo" is an inference from the reported subset rather than an established fact. No multiplex family has been reported.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:27087445 SUPPORT Human Clinical

"Whole-exome and Sanger sequencing identified de novo, heterozygous 3′ truncating mutations in FBN1 in both patients"

Confirms heterozygous, de novo FBN1 truncating variants as the molecular basis.

PMID:21594992 SUPPORT Human Clinical

"novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene"

A second independent proband with a heterozygous de novo frameshift in the penultimate exon.

?

Discussions and Knowledge Gaps

3

Do the widely used FBN1 mouse models of Marfan syndrome say anything at all about MFLS, given that they were built on a mechanism (haploinsufficiency or dominant-negative missense) that MFLS does not use?

HUMAN MODEL MISMATCH OPEN mfls_mouse_model_mismatch

Attached to

pathophysiology#Stable Truncated Profibrillin-1 with an Altered C-Terminus

The published FBN1 knockout and dominant-negative mouse models were designed around classic Marfan biology and, by the explicit statement of the group that built the rabbit model, cannot recapitulate the MFLS genotype-phenotype relationship, because they do not produce a stable NMD-escaping C-terminally truncated profibrillin. The models that ARE informative for MFLS are the purpose-built asprosin-ablating Fbn1(NPS/+) mouse and the CRISPR rabbit. This matters for interpretation: metabolic findings from Marfan mouse models — for example that male Marfan mice are predisposed to high-fat-diet obesity, diabetes, and fatty liver — point in the opposite direction from the human MFLS metabolic phenotype and should not be transferred to this entity.

Proposed experiments

Knock-in of a specific human MFLS allele into mouse and rabbit

exp_mfls_allele_knockin

Generate models carrying an exact reported human MFLS variant (e.g. c.8226+1G>A or p.Arg2726Glufs*9) rather than an engineered truncation, and compare microfibril assembly, aortic dimensions, adipose mass, plasma asprosin, and glucose/insulin handling against both wild-type and a classic Marfan allele in the same background.

Show evidence (2 references)

PMID:29666143 SUPPORT Model Organism

"these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene"

The explicit statement that existing FBN1 mouse models do not model this entity.

PMID:35759435 SUPPORT Model Organism

"the data demonstrate that male mice of both the MFS models are susceptible to HFD-induced obesity and diabetes"

Illustrates that the metabolic phenotype of classic Marfan mouse models runs opposite to the human MFLS phenotype, reinforcing the mismatch.

How much of the congenital lipodystrophy is caused by hypophagia secondary to asprosin deficiency, and how much by a cell-autonomous failure of adipocyte differentiation in a fibrillin-1-deficient extracellular-matrix niche?

KNOWLEDGE GAP OPEN mfls_lipodystrophy_mechanism_split

Attached to

pathophysiology#Congenital Generalized Lipodystrophy and Extreme Leanness

Three routes are on the table and the literature has not separated them. The hypophagia route is well evidenced in patients and rescued in the mouse. A cell-autonomous adipogenic route rests on expression dynamics (fibrillin-1 rises as mesenchymal stem cells enter adipogenesis and declines as adipocytes mature) and on the conservation of the affected FBN1 region; the authors who proposed it state explicitly that a differentiation failure still needs to be shown experimentally. A third route proposed in review is purely mechanical — that deficient microfibrils change the mechanical properties of the adipose matrix, making it non-permissive for adipocyte expansion, independently of both appetite and TGF-beta. The distinction is therapeutically consequential: if hypophagia dominates, asprosin replacement or caloric support could restore adipose mass, whereas a cell-autonomous or matrix-mechanical block would not respond.

Proposed experiments

Patient-derived iPSC or preadipocyte adipogenic differentiation assay

exp_mfls_adipogenesis_ipsc

Differentiate MFLS patient-derived mesenchymal stem cells or preadipocytes to adipocytes in vitro, where caloric intake is not a variable, and compare lipid accumulation and adipogenic marker induction against isogenic corrected controls and against classic Marfan (NMD-degraded allele) cells.

Pair-feeding and asprosin-repletion in the Fbn1(NPS/+) mouse

exp_mfls_pairfeed_repletion

Determine what fraction of the fat-mass deficit is recovered by matching caloric intake to wild-type littermates, or by chronic asprosin repletion, versus what fraction persists — the residual being attributable to a cell-autonomous or matrix-mechanical adipogenic defect.

Show evidence (2 references)

PMID:27386756 SUPPORT In Vitro

"may fail to differentiate adipocytes and/or to accumulate adipocyte lipids, although this still needs to be shown experimentally"

The authors themselves flag the adipogenic mechanism as unproven, which is the gap.

PMID:32279186 SUPPORT Other

"Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils."

Lists the competing candidate causes of adipose dysfunction as unresolved possibilities, including the matrix-mechanical route.

Is the lifetime risk of aortic dissection in MFLS the same as, lower than, or higher than in classic Marfan syndrome?

KNOWLEDGE GAP OPEN mfls_aortic_dissection_risk

Attached to

pathophysiology#Progressive Aortic Root Dilation

Aortic root dilation is documented in MFLS and this entry conforms to the aortopathy module's dilation node, but no dissection has been reported, and at least one molecularly confirmed patient had a normal aortic root through nine years of follow-up. With fewer than a few dozen molecularly confirmed patients, most reported in childhood or early adulthood, absence of reported dissection carries almost no information. Because the allelic mechanism differs from classic Marfan syndrome (NMD-escaping neomorphic protein rather than haploinsufficiency), the aortic risk cannot simply be assumed equal, in either direction. This is why the entry deliberately does not conform to the module's dissection node.

Proposed experiments

International MFLS registry with prospective aortic imaging

exp_mfls_aortic_registry

Assemble all molecularly confirmed 3'-FBN1 truncation patients into a registry with standardized serial aortic root z-score imaging, and compare dilation trajectories against age- and sex-matched classic Marfan cohorts.

Show evidence (2 references)

PMID:26860060 SUPPORT Human Clinical

"We review six previous reports between 2000 and 2014 of seven unrelated patients"

The tiny denominator is what makes the aortic natural history unknown.

PMID:37845262 SUPPORT Human Clinical

"showing stable mild mitral regurgitation without dilation of the aortic root"

A molecularly confirmed patient with no aortic involvement, showing the variability that the registry would have to resolve.

⚙

Pathophysiology

9

FBN1 3' Truncating Variant Escaping Nonsense-Mediated Decay

The initiating lesion. A heterozygous frameshift or splice-site variant in the penultimate FBN1 exon, its donor site, or the final intron places the premature termination codon 3' of the last 50 nucleotides of the penultimate exon. This is the canonical position at which the exon-junction-complex rule that triggers nonsense-mediated mRNA decay no longer applies, so the mutant transcript is spared. This is the single molecular difference that separates MFLS from the many Marfan-causing FBN1 premature-termination alleles, which are degraded by NMD and therefore act by haploinsufficiency.

FBN1 hgnc:3603

Genetic context FBN1 hgnc:3603 allele_type: frameshift or splice-site truncating variant at the FBN1 3' terminus variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Plasma asprosin in affected individuals falls further than heterozygosity alone predicts, and overexpression of the truncated protein in wild-type cells suppresses asprosin secretion — direct evidence of a dominant-negative effect on the wild-type allele rather than simple haploinsufficiency.

nonsense-mediated decay of the mutant FBN1 transcript GO:0000184 ↓ DECREASED

Downstream

Stable Truncated Profibrillin-1 with an Altered C-Terminus Escape from NMD permits translation of a stable, C-terminally truncated profibrillin-1 protein.

Show evidence (3 references)

PMID:27087445 SUPPORT Human Clinical

"All seven mutations occur 3′ to the last 50 nt of the penultimate exon and are therefore predicted to escape mRNA nonsense-mediated decay (NMD), leading to expression of a mutant, truncated profibrillin protein"

States the NMD-escape rule and its consequence for all seven original probands.

PMID:31774634 SUPPORT Computational

"We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD."

Explicitly contrasts NMD escape in MPLS with NMD susceptibility in classic Marfan syndrome.

PMID:21594993 SUPPORT Human Clinical

"This phenotype which is different from that of classical Marfan syndrome could be caused by a truncated FBN1 protein which could escape nonsense-mediated RNA decay."

The earliest statement of the NMD-escape hypothesis, from the final-intron splice-site proband.

Stable Truncated Profibrillin-1 with an Altered C-Terminus

The neomorphic gene product. Profibrillin-1 is a 2,871-residue proprotein normally cleaved at its C-terminus by furin to yield mature fibrillin-1 plus a 140-residue C-terminal peptide. The MFLS variants cluster around that cleavage site and truncate the protein just before or within it, leaving an extremely charged terminal motif. That the mutant allele is expressed rather than degraded is not merely predicted: in one proband, cycloheximide treatment of lymphoblastoid cells failed to change the abundance of the exon-skipped transcript, experimentally confirming NMD escape in patient material. The resulting protein is the shared origin of both disease arms — it is incorporated into (and perturbs) the microfibrillar matrix, and it destroys the furin cleavage event that would have released asprosin.

FBN1 hgnc:3603

microfibril binding GO:0050436 ⚠ ABNORMAL

Downstream

Microfibril and Extracellular Matrix Assembly Defect The microfibril/TGF-beta arm shared with classic Marfan syndrome. The truncated protein with its altered charged terminus perturbs fibrillin-1 aggregation and microfibril assembly.

Loss of Furin Cleavage and Asprosin Deficiency The asprosin/adipose-metabolic arm unique to this entity. Truncation at or around the furin site ablates release of the C-terminal cleavage product.

Show evidence (4 references)

PMID:27087445 SUPPORT Human Clinical

"Profibrillin is translated as a 2,871-amino-acid long proprotein, which is cleaved at the C terminus by the protease furin"

Establishes the normal furin processing step that the truncated protein disrupts.

PMID:21594992 SUPPORT Human Clinical

"Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids."

Characterizes the shared charged C-terminal motif of the truncated product.

PMID:37845262 SUPPORT Human Clinical

"we conclude that the c.8226+5G>A variant in the FBN1 gene led to the skipping of exon 65, causing a frameshift, and that this mutant transcript escaped NMD"

Experimental confirmation in patient-derived cells that the mutant transcript is retained rather than degraded — the assumption on which the whole neomorphic-protein model rests.

+ 1 more reference

Microfibril and Extracellular Matrix Assembly Defect

The first node of the arm shared with classic Marfan syndrome. Fibrillin-1 is the principal structural component of extracellular microfibrils, and its charged, truncated form perturbs proper protein aggregation and hence incorporation into the microfibrillar matrix, with knock-on effects on the strength and elasticity of connective tissue. This node conforms to the aortopathy module's primary-lesion node because the underlying defect is the same fibrillin-1 microfibril lesion; what differs from Marfan syndrome is the allelic mechanism producing it.

fibroblast CL:0000057

microfibril assembly GO:0160054 ⚠ ABNORMAL extracellular matrix assembly GO:0085029 ⚠ ABNORMAL

Animal models

FBN1 C-terminal truncation rabbit (CRISPR/Cas9) Rabbit recapitulates Heterozygous rabbits reproduce the connective-tissue, ocular, and aortic features of the marfanoid arm.

Downstream

Congenital Generalized Lipodystrophy and Extreme Leanness The candidate congenital arm. Fibrillin-1 is a principal component of the adipose extracellular-matrix niche, and deficient microfibrils are proposed to impair adipogenesis both directly and by altering the mechanical properties of that niche. This edge, not the postnatal hypophagia edge, is what could account for lipodystrophy being present AT BIRTH. It is drawn because the entry should not assert a postnatal mechanism as the sole cause of a congenital finding — but it is unproven, and the mfls_lipodystrophy_mechanism_split discussion records exactly how unproven.

Dysregulated TGF-beta Signaling Deficient microfibrils are associated with increased TGF-beta signaling. The textbook intermediate — failure of the microfibrillar network to sequester latent TGF-beta complexes — is established for fibrillin-1 biology generally but has not been measured in MFLS tissue, which is why this edge is INDIRECT rather than DIRECT.

Show evidence (3 references)

PMID:31774634 SUPPORT In Vitro

"In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86."

Direct in vitro evidence that the MPLS allele specifically perturbs fibrillin-1 aggregation.

PMID:21594992 SUPPORT Human Clinical

"This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix."

Attributes the extracellular-matrix consequence to the altered charged C-terminus.

PMID:29666143 SUPPORT Model Organism

"FBN1 heterozygous (FBN1 Het) rabbits faithfully recapitulated the phenotypes of MFS, including muscle wasting and impaired connective tissue, ocular syndrome and aortic dilation."

A rabbit model carrying an engineered C-terminal truncation reproduces impaired connective tissue in vivo.

Dysregulated TGF-beta Signaling

Fibrillin-1 microfibrils sequester latent TGF-beta complexes in the matrix, so a defective microfibrillar network raises TGF-beta bioavailability and downstream SMAD2 phosphorylation. Both a classic Marfan allele and an MFLS allele upregulate SMAD2 phosphorylation in vitro, which is why this node is shared with the aortopathy module rather than being MFLS-specific; the causal reasoning for MFLS in the primary literature is that TGF-beta signaling is altered by, rather than untouched by, the neomorphic truncated protein.

transforming growth factor beta receptor signaling pathway GO:0007179 ↑ INCREASED

Downstream

Progressive Aortic Root Dilation TGF-beta-driven aortic wall remodeling underlies the aortic arm of the marfanoid phenotype. Marked INDIRECT because the intervening medial degeneration has been shown in classic Marfan aortopathy, not measured in MFLS aortas; the MFLS evidence is the clinical dilation endpoint plus the in vitro SMAD2 signal.

Show evidence (3 references)

PMID:31774634 SUPPORT In Vitro

"Both mutations appear to upregulate SMAD2 phosphorylation in vitro."

Direct in vitro measurement of increased TGF-beta-SMAD2 signaling for the MPLS allele.

PMID:24039054 SUPPORT Human Clinical

"this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling"

Supports altered FBN1-TGF-beta signaling as the proposed mechanism, but is an inference from genotype rather than a direct measurement, hence PARTIAL.

PMID:32279186 SUPPORT Other

"Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils."

Review linking deficient microfibrils to increased TGF-beta signaling in the fibrillinopathies including MFLS. PARTIAL because the source hedges ("potential causes") and speaks of adipose rather than aortic tissue.

Progressive Aortic Root Dilation

Dilation of the aortic bulb/root is documented in several molecularly confirmed MFLS patients and is reproduced in the rabbit model, so the marfanoid arm does reach the aorta. It is not, however, universal: at least one molecularly confirmed child had stable mild mitral regurgitation with a normal aortic root through nine years of follow-up, so aortic involvement is less uniform than in classic Marfan syndrome. Conformance is asserted only to this dilation node of the aortopathy module — aortic dissection or rupture, the module's terminal node, has not been reported in MFLS, and the reported case total is far too small to establish or exclude that risk. MFLS should nonetheless be managed with the aortic surveillance appropriate to a fibrillinopathy.

extracellular matrix organization in the aortic wall GO:0030198 ⚠ ABNORMAL

Show evidence (4 references)

PMID:20979188 SUPPORT Human Clinical

"who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia"

Documents aortic bulb dilation in the index MFLS proband.

PMID:24613577 SUPPORT Human Clinical

"The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome."

A second independent patient with aortic bulb dilatation.

PMID:29666143 SUPPORT Model Organism

"ocular syndrome and aortic dilation"

The C-terminal-truncation rabbit model reproduces aortic dilation in vivo.

+ 1 more reference

Loss of Furin Cleavage and Asprosin Deficiency

The first node of the arm unique to MFLS. Furin cleavage of profibrillin-1 normally releases a 140-residue C-terminal peptide — asprosin — encoded by the final two FBN1 exons. Every MFLS variant clusters around that cleavage site, so the truncated allele cannot yield asprosin. Crucially, circulating asprosin falls further than the 50% a heterozygous null would predict, because the expressed truncated profibrillin also suppresses secretion of asprosin from the wild-type allele. This node is the mechanistic hinge of the entry: it is where MFLS departs from classic Marfan syndrome, whose alleles are degraded by NMD and therefore leave asprosin production largely intact.

white adipocyte CL:0000448

FBN1 hgnc:3603

protein processing (furin cleavage of profibrillin-1) GO:0016485 ↓ DECREASED peptide hormone secretion (asprosin) GO:0030072 ↓ DECREASED

Animal models

Fbn1(NPS/+) mouse (CRISPR/Cas9 exon 65 skip) Mouse recapitulates The mouse reproduces the human asprosin deficit, including the greater-than-heterozygous reduction attributed to a dominant-negative effect.

Downstream

Reduced Hepatic Glucose Release with Preserved Insulin Sensitivity Asprosin normally acts on the liver to drive glucose release; its deficiency lowers hepatic glucose output.

Reduced Central Orexigenic Drive Asprosin normally crosses the blood-brain barrier to activate hypothalamic AgRP neurons; its deficiency blunts appetite.

Show evidence (4 references)

PMID:27087445 SUPPORT Human Clinical

"All seven NPS mutations are clustered around the cleavage site, resulting in heterozygous ablation of the C-terminal cleavage product (asprosin)"

Establishes ablation of the asprosin cleavage product as the direct consequence of the MFLS variant cluster.

PMID:27087445 SUPPORT Human Clinical

"NPS patients displayed a greater reduction in circulating asprosin level than predicted from their heterozygous genotype"

Measured plasma asprosin deficit exceeding the heterozygous prediction, the basis of the dominant-negative claim.

PMID:24613577 SUPPORT Human Clinical

"the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered"

Independent case demonstrating that the causal allele alters the C-terminal furin cleavage site.

+ 1 more reference

Reduced Hepatic Glucose Release with Preserved Insulin Sensitivity

Asprosin is recruited to the liver, where it activates a G-protein-cAMP-PKA pathway and drives hepatic glucose release; loss of function lowers glucose and insulin secondary to reduced hepatic glucose production. This is the node that explains the single most counterintuitive feature of MFLS: unlike generalized lipodystrophies in general — which characteristically cause severe insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes — MFLS patients have low fasting insulin and remain euglycemic and insulin-sensitive despite near-absent adipose tissue.

hepatocyte CL:0000182

hepatic glucose release GO:0006006 ↓ DECREASED glucose homeostasis GO:0042593 ⚠ ABNORMAL

Show evidence (4 references)

PMID:27087445 SUPPORT Human Clinical

"Contrary to this notion, overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"

Direct human measurement of low fasting insulin with euglycemia in MFLS patients.

PMID:27087445 SUPPORT Human Clinical

"Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation."

Establishes the normal hepatic action of asprosin whose loss produces this node.

PMID:20979188 SUPPORT Human Clinical

"She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes."

Clinical confirmation that the metabolic complications typical of generalized lipodystrophy are absent.

+ 1 more reference

Reduced Central Orexigenic Drive

Circulating asprosin crosses the blood-brain barrier and directly activates orexigenic AgRP-positive arcuate neurons through a cAMP-dependent pathway, which in turn inhibits anorexigenic POMC neurons via GABA. Asprosin-deficient patients are hypophagic, consuming fewer calories than matched peers, and the corresponding mouse model shows both hypophagia and AgRP neuron hypoactivity that is rescued by recombinant asprosin. Hypophagia, rather than adipocyte failure alone, is therefore a substantive contributor to the leanness of MFLS.

regulation of feeding behavior GO:0060259 ↓ DECREASED

Animal models

Fbn1(NPS/+) mouse (CRISPR/Cas9 exon 65 skip) Mouse recapitulates The mouse reproduces human hypophagia and demonstrates the underlying AgRP neuron hypoactivity, which is rescued by recombinant asprosin.

Downstream

Congenital Generalized Lipodystrophy and Extreme Leanness Chronically reduced caloric intake contributes to, but does not by itself account for, the congenital absence of adipose tissue. See the mfls_lipodystrophy_mechanism_split discussion for the unresolved split between this route and a cell-autonomous or matrix-mechanical adipogenic block.

Show evidence (3 references)

PMID:29106398 SUPPORT Human Clinical

"In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin."

Directly links asprosin deficiency in this syndrome to low appetite and leanness in humans.

PMID:29106398 SUPPORT Human Clinical

"We found that the two individuals examined consumed fewer calories on a daily basis than their age and sex matched peers in the lab as well as the home setting"

Quantified hypophagia measured directly in affected individuals.

PMID:29106398 SUPPORT Model Organism

"asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway"

Establishes the central mechanism by which asprosin deficiency lowers appetite.

Congenital Generalized Lipodystrophy and Extreme Leanness

The convergent clinical endpoint of the asprosin arm. Adipose tissue is profoundly reduced from birth, giving both the generalized lipodystrophy and the sunken, aged facial appearance that earned the syndrome its "progeroid" label. Two mechanisms plausibly converge here and are not fully separated in the literature: the reduced orexigenic drive above, and a direct role for fibrillin-1 in the adipose extracellular-matrix niche during adipogenesis. Fibrillin-1 is expressed as mesenchymal stem cells enter adipogenesis and declines as adipocytes mature, and the region of FBN1 affected in FBN1-associated lipodystrophy is highly conserved — but the proposal that low fibrillin-1 causes a failure to differentiate adipocytes is explicitly flagged by its authors as not yet demonstrated experimentally, and is framed for reduced fibrillin-1 rather than for the stable dysfunctional protein MFLS actually produces.

white adipocyte CL:0000448

white fat cell differentiation GO:0050872 ↓ DECREASED

Animal models

FBN1 C-terminal truncation rabbit (CRISPR/Cas9) Rabbit partially recapitulates Lipodystrophy and growth retardation appear in the heterozygous rabbits and had not been reported in prior FBN1 animal models.

Show evidence (4 references)

PMID:20979188 SUPPORT Human Clinical

"We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth"

Documents generalized lipodystrophy present from birth in the index patient.

PMID:29106398 SUPPORT Human Clinical

"display a deficiency in plasma asprosin1 associated with extreme leanness"

Links the measured asprosin deficiency to the leanness phenotype in patients.

PMID:27386756 SUPPORT In Vitro

"individuals with low fibrillin-1 (for example with FBN1 mutations associated with lipodystrophy) may fail to differentiate adipocytes and/or to accumulate adipocyte lipids, although this still needs to be shown experimentally"

Supports a candidate adipogenic mechanism but is explicitly hypothetical in the source, hence PARTIAL rather than SUPPORT.

+ 1 more reference

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

26

Cardiovascular 1

Aortic Root Dilation Aortic root aneurysm HP:0002616

Course: PROGRESSIVE

Show evidence (3 references)

PMID:20979188 SUPPORT Human Clinical

"with mild skeletal features, dilated aortic bulb, dural ectasia"

Documents aortic bulb dilation.

PMID:24613577 SUPPORT Human Clinical

"severe myopia and dilatation of the aortic bulb"

Independent report of aortic bulb dilatation.

PMID:37845262 SUPPORT Human Clinical

"showing stable mild mitral regurgitation without dilation of the aortic root"

A molecularly confirmed patient serially imaged to age nine with no aortic root dilation, establishing that aortic involvement is not universal.

Digestive 1

Poor Appetite HP:0004396

Show evidence (3 references)

PMID:29106398 SUPPORT Human Clinical

"a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness"

States low appetite as a defining feature of the asprosin-deficiency syndrome.

PMID:29106398 SUPPORT Human Clinical

"Their hypophagia was matched by subnormal daily energy expenditure when measured using indirect calorimetry"

Quantified hypophagia in the two studied patients.

PMID:37845262 SUPPORT Human Clinical

"for an undiagnosed condition and a poor appetite"

Poor appetite in an independently reported proband, here the presenting complaint.

Eye 2

Ectopia Lentis HP:0001083

Show evidence (3 references)

PMID:21594992 SUPPORT Human Clinical

"He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years"

Bilateral lens subluxation documented in a molecularly confirmed patient.

PMID:20979188 SUPPORT Human Clinical

"bilateral subluxation of the lens, and severe myopia"

Independent report of bilateral lens subluxation.

PMID:37845262 SUPPORT Human Clinical

"Ophthalmological evaluations revealed myopic astigmatism"

This proband's ophthalmological assessment found myopic astigmatism but not ectopia lentis, establishing that the feature is not universal. PARTIAL because it qualifies rather than supports the phenotype.

Myopia HP:0000545

Show evidence (3 references)

PMID:20979188 SUPPORT Human Clinical

"bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy"

Documents severe myopia.

PMID:24613577 SUPPORT Human Clinical

"marfanoid habitus, severe myopia and dilatation of the aortic bulb"

Independent report of severe myopia.

PMID:37845262 SUPPORT Human Clinical

"generalized lack of subcutaneous fat, hyperextensible joints, long fingers, and severe myopia"

Lists severe myopia among the characteristic features of the syndrome.

Head and Neck 4

Prominent Forehead HP:0011220

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"The main clinical manifestations included dolichocephaly, prominent forehead, narrow nasal ridge, mild retrognathia"

Documents prominent forehead as part of the facial gestalt.

High Palate HP:0000218

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"bilateral entropion (postoperative), high arched palate, long fingers"

Documents high-arched palate on clinical examination.

Craniosynostosis HP:0001363

Show evidence (2 references)

PMID:24039054 SUPPORT Human Clinical

"She had a characteristic facial appearance with craniosynostosis."

Documents craniosynostosis in a molecularly confirmed patient.

PMID:37845262 SUPPORT Human Clinical

"Craniosynostosis is rare in FBN1-related Marfan syndrome but is reported in several cases in MFLS"

Explicitly contrasts the rarity of craniosynostosis in classic FBN1-related Marfan syndrome with its recurrence in MFLS. Quoted for the association, not to justify a frequency band.

Macrocephaly HP:0000256

Show evidence (2 references)

PMID:21594993 SUPPORT Human Clinical

"large head circumference with corresponding hydrocephaly"

Documents large head circumference in a molecularly confirmed patient.

PMID:37845262 SUPPORT Human Clinical

"and had a head circumference of 55.3 cm (+2.2 SD)"

An independently reported proband with a head circumference above +2 SD.

Integument 1

Progeroid Facial Appearance VERY_FREQUENT HP:0005328

Show evidence (2 references)

PMID:26860060 SUPPORT Human Clinical

"a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals"

Present in all seven patients of the defining review. As with the lipodystrophy, the band is VERY_FREQUENT rather than OBLIGATE because the review selected its series on this feature, making the observed 7/7 an ascertainment artifact rather than evidence of full penetrance.

PMID:37845262 SUPPORT Human Clinical

"MFLS’s appearance of premature aging is not due to actual premature aging but rather due to low subcutaneous fat"

Establishes that the progeroid appearance is a consequence of fat loss, not accelerated aging.

Limbs 2

Arachnodactyly HP:0001166

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"high arched palate, long fingers, positive wrist and thumb signs, plain pes planus, and mild hyperextensible finger joints"

Documents long fingers with positive wrist and thumb signs on clinical examination.

Pes Planus HP:0001763

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"positive wrist and thumb signs, plain pes planus, and mild hyperextensible finger joints"

Documents pes planus on clinical examination.

Musculoskeletal 1

Joint Hypermobility HP:0001382

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"generalized lack of subcutaneous fat, hyperextensible joints, long fingers, and severe myopia"

Names hyperextensible joints among the characteristic clinical features of MFLS.

Nervous System 1

Hydrocephalus HP:0000238

Show evidence (1 reference)

PMID:21594993 SUPPORT Human Clinical

"large head circumference with corresponding hydrocephaly"

Documents hydrocephalus accompanying the enlarged head circumference in a molecularly confirmed patient.

Prenatal and Birth 1

Premature Birth HP:0001622

Show evidence (2 references)

PMID:24039054 SUPPORT Human Clinical

"(2) premature birth with an accelerated linear growth disproportionate to the weight gain"

Names premature birth as a cardinal feature.

PMID:37845262 SUPPORT Human Clinical

"The proband was born at 35 weeks and 2 days’ gestation"

Preterm delivery in an independently reported proband.

Growth 3

Marfanoid Habitus Disproportionate tall stature HP:0001519

Show evidence (2 references)

PMID:24613577 SUPPORT Human Clinical

"The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb)"

Documents marfanoid habitus in a molecularly confirmed patient.

PMID:21594993 SUPPORT Human Clinical

"and tall stature at the end of infancy"

Independent report of tall stature emerging in infancy.

Decreased Body Weight HP:0004325

Show evidence (2 references)

PMID:24039054 SUPPORT Human Clinical

"The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain."

Documents the height/weight dissociation defining this growth phenotype.

PMID:37845262 SUPPORT Human Clinical

"body mass index (BMI) was 12.6 kg/m2, and body fat percentage was 9.4%"

Quantifies the extreme leanness in a molecularly confirmed proband.

Intrauterine Growth Retardation HP:0001511

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"MFLS is characterized by clinical features including fetal growth retardation, birth before 40 weeks"

Names fetal growth retardation among the characteristic features of MFLS.

Other 9

Congenital Generalized Lipodystrophy VERY_FREQUENT HP:0009059

Temporal: CHRONIC

Show evidence (2 references)

PMID:26860060 SUPPORT Human Clinical

"A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals."

Lipodystrophy was present in all seven patients of the defining review. The band is VERY_FREQUENT rather than OBLIGATE deliberately: the review assembled its series ON the basis of this feature, so the observed 7/7 is an ascertainment artifact and an obligate claim would be circular.

PMID:24039054 SUPPORT Human Clinical

"the cardinal features of these patients include (1) congenital lipodystrophy"

Names congenital lipodystrophy as a cardinal feature of the entity.

Reduced Subcutaneous Adipose Tissue HP:0003758

Show evidence (2 references)

PMID:29106398 SUPPORT Human Clinical

"reduced subcutaneous adipose mass (Fig. 1)2 and maintenance of insulin sensitivity"

Documents reduced subcutaneous adipose mass in affected individuals.

PMID:37845262 SUPPORT Human Clinical

"generalized lack of subcutaneous fat"

Names lack of subcutaneous fat among the defining clinical features.

Entropion HP:0000621

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"the eyelid entropion seen in the present case seems to be a rare manifestation of MFLS. Only one case of eyelid entropion has previously been reported"

Two cases out of the roughly eight to nine reported, and explicitly described by the authors as a rare manifestation. Quoted to support the association and its rarity in prose, not to justify a frequency band.

Mitral Regurgitation HP:0001653

Severity: MILD

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"Mild mitral regurgitation was identified at 2 years of age."

Documents mild mitral regurgitation, with the age at detection and its stability on follow-up.

Dolichocephaly HP:0000268

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"During the early neonatal period, bilateral entropion of the upper and lower lids and dolichocephaly were noted."

Documents neonatal-onset dolichocephaly.

Narrow Nasal Ridge HP:0000418

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"dolichocephaly, prominent forehead, narrow nasal ridge, mild retrognathia, subcutaneous fat reduction"

Documents narrow nasal ridge as part of the facial gestalt.

Retrognathia HP:0000278

Severity: MILD

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"prominent forehead, narrow nasal ridge, mild retrognathia, subcutaneous fat reduction"

Documents mild retrognathia.

Dural Ectasia HP:0100775

Show evidence (1 reference)

PMID:20979188 SUPPORT Human Clinical

"dilated aortic bulb, dural ectasia, bilateral subluxation of the lens"

Documents dural ectasia in the index patient.

Hypoinsulinemia HP:0040216

Show evidence (1 reference)

PMID:27087445 SUPPORT Human Clinical

"overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"

Direct measurement of low fasting insulin with euglycemia.

🧬

Genetic Associations

1

FBN1 (Heterozygous, de novo truncating (frameshift or splice-site) variants confined to a short segment at the extreme 3' end of the FBN1 coding region — the penultimate exon, its splice donor site, and the final intron.)

Gene: FBN1 hgnc:3603 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (5 references)

PMID:27087445 SUPPORT Human Clinical

"all have truncating mutations within a 71-bp segment at the 3′ end of the FBN1 coding region, displaying tight genotype-phenotype correlation"

Establishes the tight clustering of causal variants in a 71-bp 3' segment of FBN1.

PMID:26860060 SUPPORT Human Clinical

"All mutations occurred in exon 64 of the FBN1 gene."

The naming review confirms a single shared exon across the original seven patients (numbered exon 64 in that report's convention).

PMID:27087445 SUPPORT In Vitro

"We tested this concept by overexpressing the truncated, mutant version of profibrillin in WT cells and found that this interfered with the ability of those cells to secrete asprosin into the media"

Direct in vitro support for the dominant-negative functional impact assigned to this gene-disease relationship.

+ 2 more references

💊

Medical Actions

5

Multidisciplinary supportive and surveillance care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

There is no disease-modifying therapy. Management is supportive and follows the components of the phenotype: cardiovascular surveillance for aortic root dilation as for any fibrillinopathy, ophthalmological management of ectopia lentis and myopia, and nutritional support for the very low body weight. No MFLS-specific treatment trial has been performed, and these recommendations are extrapolated from the constituent phenotypes rather than tested in this entity.

Show evidence (3 references)

PMID:20301510 SUPPORT Human Clinical

"Comprehensive management by a multidisciplinary team including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon is strongly recommended."

The GeneReviews multidisciplinary-care recommendation this entry extrapolates from. PARTIAL because it is a recommendation for classic FBN1-related Marfan syndrome, not for MFLS, and has never been evaluated in MFLS.

PMID:20301510 SUPPORT Human Clinical

"Echocardiography annually when aortic dimensions are small and the rate of aortic dilatation is slow"

The aortic surveillance schedule this entry extrapolates from. PARTIAL for the same reason: it is the classic Marfan schedule, and no MFLS-specific surveillance interval has been studied.

PMID:20301510 SUPPORT Human Clinical

"fluoroquinolone antibiotics, which may exacerbate the predisposition for aneurysm and dissection"

The GeneReviews agents-to-avoid caution, recorded because MFLS patients have documented aortic root dilation. PARTIAL: transferability to MFLS is untested.

Beta-blocker or angiotensin receptor blocker aortic protection

Action: Pharmacotherapy NCIT:C15986

Agent: beta-blocker NCIT:C29576 angiotensin receptor blocker NCIT:C66930

Pharmacologic reduction of hemodynamic stress on the aortic wall — the therapy that the aortic surveillance in the entry above exists to trigger. In FBN1-related Marfan syndrome, beta-blockers or angiotensin receptor blockers are routinely prescribed once aortic root dilation is progressive, and GeneReviews recommends initiating therapy at diagnosis at any age. This is recorded because MFLS patients have documented aortic root dilation and the entry already carries three Marfan-derived surveillance recommendations; carrying the surveillance while omitting the therapy it triggers would be internally inconsistent. It is NOT evidence that the therapy works in MFLS. No MFLS patient has been reported on either drug class, no aortic outcome has been measured in this entity, and the published series is roughly eight to nine patients — so the extrapolation is from shared FBN1 aortopathy biology, not from data. All evidence here is therefore PARTIAL, exactly as for the other GeneReviews-derived items.

Mechanism Target:

INHIBITS Progressive Aortic Root Dilation — Both drug classes act on the hemodynamic load borne by the weakened aortic wall rather than on the upstream fibrillin-1 or TGF-beta lesion, so the target is the dilation node itself, not the microfibril or TGF-beta node. (ARBs are additionally proposed to attenuate TGF-beta signaling in Marfan aortopathy, but that mechanism is contested in the Marfan literature and has never been examined in MFLS, so it is not asserted here.)

Show evidence (1 reference)

PMID:20301510 SUPPORT Human Clinical

"Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers or angiotensin receptor blockers (ARBs), are routinely prescribed."

States the mechanism by which the drug classes act on the aortic wall. PARTIAL because it is a classic FBN1-related Marfan syndrome recommendation with no MFLS-specific evidence.

Show evidence (1 reference)

PMID:20301510 SUPPORT Human Clinical

"Therapy is generally initiated at the time of diagnosis with Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis."

Gives the timing of initiation this entry extrapolates from. PARTIAL: it is the classic Marfan trigger, and no MFLS-specific threshold has been studied.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

MFLS is autosomal dominant, and every reported case with parental testing arose de novo, so recurrence risk to the parents of a proband is low. An affected individual, however, has a 50% transmission risk to each child — ordinary Mendelian arithmetic for a heterozygous autosomal dominant variant, which transfers from FBN1-related Marfan syndrome to MFLS without needing MFLS-specific data because it follows from the mode of inheritance rather than from the phenotype.

Show evidence (1 reference)

PMID:20301510 SUPPORT Human Clinical

"Each child of an individual with Marfan syndrome has a 50% chance of inheriting the pathogenic variant and the disorder"

The transmission risk for a heterozygous autosomal dominant FBN1 variant. PARTIAL because the sentence is written for Marfan syndrome, though the arithmetic follows from the inheritance mode this entry curates.

Surgical correction of entropion

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

One proband underwent surgery to correct bilateral eyelid entropion at 16 months because of severe corneal epithelial damage. This is the only surgical intervention with a reported indication and outcome in an MFLS patient.

Show evidence (1 reference)

PMID:37845262 SUPPORT Human Clinical

"Because she had severe corneal epithelial damage, she underwent surgery to correct bilateral entropion at Kawasaki Medical School Hospital at the age of 1 year 4 months."

A single reported case; the indication and timing are documented, the long-term outcome is not.

Recombinant asprosin replacement (investigational, preclinical only)

Action: Pharmacotherapy NCIT:C15986

Asprosin replacement is the mechanistically obvious therapy for the metabolic arm and fully rescues hypophagia and AgRP neuron activity in the mouse model. It has NOT been tested in humans and there is no clinical program; it is recorded here as a preclinical concept, not a recommendation. Replacement would in any case address only the asprosin arm and would not be expected to affect the microfibril/aortic arm. No therapeutic_agent is bound: asprosin is a 140-residue peptide hormone described in 2016 and has no CHEBI entry and no NCIT clinical-agent term, so per the guidance the slot is left empty rather than filled with a wrong or over-broad term.

Mechanism Target:

RESTORES Loss of Furin Cleavage and Asprosin Deficiency — Exogenous recombinant asprosin substitutes for the cleavage product that the truncated profibrillin cannot release.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin"

Establishes rescue of the asprosin-deficiency phenotype by exogenous asprosin in the model.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"A single subcutaneous dose of recombinant asprosin was sufficient to completely rescue the hypophagia of Fbn1NPS/+ mice"

Supports the preclinical rationale only; there is no human evidence, hence PARTIAL and MODEL_ORGANISM.

🔬

Biochemical Markers

2

Plasma asprosin (DECREASED)

Context: Circulating asprosin, the C-terminal cleavage product of profibrillin-1, measured by asprosin-specific sandwich ELISA. Affected individuals show a reduction greater than heterozygosity alone predicts. There is no LOINC-coded clinical assay; asprosin ELISA remains a research measurement, which is why no reference_ranges block is given.

Pathograph Readouts

Readout Of Loss of Furin Cleavage and Asprosin Deficiency Negative Diagnostic

Low plasma asprosin directly reports the failure of furin cleavage at the profibrillin C-terminus.

Show evidence (1 reference)

PMID:27087445 SUPPORT Human Clinical

"To measure circulating asprosin levels, we developed a sandwich ELISA"

Establishes the assay by which this readout is measured.

Show evidence (2 references)

PMID:27087445 SUPPORT Human Clinical

"NPS patients displayed a greater reduction in circulating asprosin level than predicted from their heterozygous genotype, compared not only with WT control subjects"

Direct measurement of reduced plasma asprosin in affected individuals.

PMID:27087445 SUPPORT Human Clinical

"Asprosin was found to be present in plasma at consistent nanomolar levels in humans, mice, and rats"

Establishes the normal circulating range against which the patient deficit is measured.

Fasting plasma insulin (DECREASED)

Context: Overnight-fasted plasma insulin, approximately two-fold below unaffected controls in the two studied patients, with normal plasma glucose.

Pathograph Readouts

Readout Of Reduced Hepatic Glucose Release with Preserved Insulin Sensitivity Negative Diagnostic

Low fasting insulin with euglycemia reports reduced hepatic glucose output rather than beta-cell failure, and is the finding that separates MFLS from other generalized lipodystrophies.

Show evidence (1 reference)

PMID:27087445 SUPPORT Human Clinical

"overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"

The direct measurement underlying this readout and its direction.

Show evidence (1 reference)

PMID:27087445 SUPPORT Human Clinical

"overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"

Reports the measured direction and magnitude of the insulin deficit.

🔬

Diagnosis

1

Molecular confirmation of a 3' FBN1 truncating variant

Diagnosis rests on identifying a heterozygous truncating FBN1 variant within the short 3'-terminal segment (the penultimate exon, its donor site, or the final intron) in an individual with congenital generalized lipodystrophy, a progeroid facial appearance, and marfanoid features. Variant position is diagnostically decisive: an FBN1 truncating variant located further 5' is subject to nonsense-mediated decay and predicts classic Marfan syndrome, not MFLS. Note that phenotype alone is not sufficient — the Marfan systemic score was only 5 in one molecularly confirmed proband.

Show evidence (3 references)

PMID:27087445 SUPPORT Human Clinical

"all have truncating mutations within a 71-bp segment at the 3′ end of the FBN1 coding region, displaying tight genotype-phenotype correlation"

The tight genotype-phenotype correlation is what makes variant position diagnostic.

PMID:26860060 SUPPORT Human Clinical

"We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy"

Establishes the genotype-phenotype relationship as the basis for recognizing the entity.

PMID:37845262 SUPPORT Human Clinical

"Since the clinical symptoms were consistent with previous cases and the genetic mutation was confirmed, we believe that this case can be definitively diagnosed as a case of MFLS."

Illustrates that definitive diagnosis rests on clinical features plus molecular confirmation.

📈

Progression

3

Prenatal and neonatal

Age: Fetal life to birth

Fetal growth restriction and preterm birth are common, and both the generalized lipodystrophy and the progeroid facial appearance are present from birth.

Show evidence (2 references)

PMID:20979188 SUPPORT Human Clinical

"We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth"

Documents the congenital onset of both defining features.

PMID:37845262 SUPPORT Human Clinical

"MFLS is characterized by clinical features including fetal growth retardation, birth before 40 weeks, generalized lack of subcutaneous fat, hyperextensible joints, long fingers, and severe myopia"

Summarizes the prenatal/perinatal onset features of the syndrome.

Infancy and childhood

Age: Infancy through childhood

A characteristic dissociation emerges between accelerated linear growth and poor weight gain, so tall stature and the marfanoid habitus develop while body weight stays very low.

Show evidence (1 reference)

PMID:24039054 SUPPORT Human Clinical

"the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features"

Defines the cardinal natural-history triad including the characteristic growth dissociation.

Adolescence and adulthood

Age: Second decade onward

Ocular and aortic manifestations of the marfanoid arm typically declare themselves later; lens subluxation was the finding that prompted FBN1 testing in one proband at age 16.

Show evidence (1 reference)

PMID:21594992 SUPPORT Human Clinical

"He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene."

Illustrates the delayed emergence of the ocular marfanoid features relative to the neonatal lipodystrophy.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Fewer than a few dozen molecularly confirmed individuals have been reported. The 2016 review that named the entity collected seven unrelated patients from six reports published between 2000 and 2014; the 2023 Japanese case report counted eight previously reported cases, and scattered single-case reports have accrued since, including the first Chinese proband in 2019.

Show evidence (2 references)

PMID:26860060 SUPPORT Human Clinical

"We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function."

Establishes the very small size of the reported case series at the time the entity was named.

PMID:37845262 SUPPORT Human Clinical

"To our knowledge, eight cases of MFLS associated with heterozygous variants near the 3’ terminus of the FBN1 gene have been reported"

An independent later count of the total published case series.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Marfanoid-Progeroid-Lipodystrophy Syndrome:

Wiedemann-Rautenstrauch (neonatal progeroid) syndrome

Overlapping Features MFLS patients were repeatedly diagnosed at birth as having neonatal progeroid syndrome / Wiedemann-Rautenstrauch syndrome, and the syndrome is still often reported under the "NPS" label in the asprosin literature. The distinguishing features are the later emergence of marfanoid and ocular signs, and the 3' FBN1 genotype.

Show evidence (2 references)

PMID:24613577 SUPPORT Human Clinical

"We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome."

Documents the initial misdiagnosis that makes this the leading differential.

PMID:20979188 SUPPORT Human Clinical

"This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features."

Describes the overlapping presentation.

Classic Marfan syndrome

Overlapping Features Classic FBN1-related Marfan syndrome shares the skeletal, ocular, and aortic features but lacks congenital generalized lipodystrophy and the progeroid facial appearance. The separating variable is FBN1 variant position and its NMD consequence. See the Marfan_Syndrome entry.

Show evidence (1 reference)

PMID:31774634 SUPPORT Human Clinical

"Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS)."

States the allelic relationship between the two entities directly.

Other congenital generalized lipodystrophies

Overlapping Features Berardinelli-Seip congenital lipodystrophy (AGPAT2, BSCL2) and other generalized lipodystrophies present with near-absent adipose tissue but are characteristically complicated by severe insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes — precisely the complications absent in MFLS. Sequencing of the classic lipodystrophy and progeria genes was negative in the index MFLS patient.

Show evidence (1 reference)

PMID:20979188 SUPPORT Human Clinical

"We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C)."

Documents exclusion of the other congenital lipodystrophy and progeria genes.

🐁

Animal Models

2

FBN1 C-terminal truncation rabbit (CRISPR/Cas9)

A CRISPR/Cas9 rabbit engineered with a C-terminal fibrillin-1 truncation, generated specifically because existing FBN1 knockout and dominant-negative mouse models do not reproduce the MFLS genotype-phenotype relationship.

Species

Rabbit

Genotype

FBN1 heterozygous C-terminal truncation

Publication

PMID:29666143

Pathograph links

Microfibril and Extracellular Matrix Assembly Defect recapitulates fidelity: moderate Heterozygous rabbits reproduce the connective-tissue, ocular, and aortic features of the marfanoid arm.

Limitations: The engineered truncation is not one of the specific human MFLS alleles, and rabbit connective-tissue involvement is reported qualitatively rather than against a quantitative microfibril-assembly assay.

Show evidence (1 reference)

PMID:29666143 SUPPORT Model Organism

"this novel rabbit model mimics the histopathological changes and functional defects of MPL syndrome, and could become a valuable model for studies of pathogenesis and drug screening for MPL syndrome"

The authors' own assessment of the model's validity for this entity.

Congenital Generalized Lipodystrophy and Extreme Leanness partially recapitulates fidelity: moderate Lipodystrophy and growth retardation appear in the heterozygous rabbits and had not been reported in prior FBN1 animal models.

Limitations: Dysglycemia accompanies the rabbit lipodystrophy, which does not match the human MFLS metabolic phenotype of low fasting insulin with preserved euglycemia and insulin sensitivity; the metabolic arm is therefore only partially reproduced.

Show evidence (1 reference)

PMID:29666143 SUPPORT Model Organism

"Moreover, skin symptoms, lipodystrophy, growth retardation and dysglycemia were also seen in these FBN1 Het rabbits, and have not been reported in other animal models."

Documents the lipodystrophy phenotype, and the accompanying dysglycemia that limits fidelity.

Show evidence (1 reference)

PMID:29666143 SUPPORT Model Organism

"we describe the generation of a rabbit MPL model with C-terminal truncation of fibrillin-1 using a CRISPR/Cas9 system"

Establishes the existence, species, and construction of the model.

Fbn1(NPS/+) mouse (CRISPR/Cas9 exon 65 skip)

A mouse engineered to carry the identical molecular event documented in a human MFLS patient — a heterozygous deletion causing exon 65 skipping and frameshift ablation of the asprosin coding region.

Species

Mouse

Genotype

Fbn1 heterozygous 10-bp deletion at the exon-65/intron-65 border (asprosin-ablating)

Publication

PMID:29106398

Pathograph links

Loss of Furin Cleavage and Asprosin Deficiency recapitulates fidelity: high The mouse reproduces the human asprosin deficit, including the greater-than-heterozygous reduction attributed to a dominant-negative effect.

Limitations: Rodent adipose and hypothalamic physiology differ from human, and the model addresses the asprosin arm only — it is not informative about the microfibril/aortic arm.

Readouts

Plasma asprosin concentration

Direction: DECREASED

Interpretation: Confirms that the engineered human-equivalent allele lowers circulating asprosin below the heterozygous prediction, as in patients.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"we found asprosin concentrations lower than 50% in these mice despite heterozygosity"

Reports the measured plasma asprosin deficit in the model.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"which harbor an identical molecular event documented in a known individual with NPS"

The allele was designed to match a real patient variant, supporting the model's relevance.

Reduced Central Orexigenic Drive recapitulates fidelity: high The mouse reproduces human hypophagia and demonstrates the underlying AgRP neuron hypoactivity, which is rescued by recombinant asprosin.

Limitations: AgRP neuron electrophysiology cannot be measured in patients, so the central mechanism remains inferred rather than demonstrated in humans.

Readouts

AgRP neuron firing frequency and resting membrane potential

Direction: DECREASED

Interpretation: Establishes hypothalamic AgRP hypoactivity as the central lesion of asprosin deficiency.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"we found that AgRP+ neuron activity was significantly lower in Fbn1NPS/+ mice compared with WT littermates, demonstrated by decreased firing frequency and resting membrane potential"

Direct electrophysiological measurement of the readout.

Daily food intake after recombinant asprosin

Direction: RESTORED

Interpretation: Rescue by a single dose establishes that the hypophagia is caused by asprosin deficiency rather than by an indirect effect of mutant fibrillin-1.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"A single subcutaneous dose of recombinant asprosin was sufficient to completely rescue the hypophagia of Fbn1NPS/+ mice, demonstrating that NPS-associated hypophagia is due to a deficiency of plasma asprosin and not due to some indirect effect of mutated fibrillin-1"

Reports the rescue experiment behind this readout.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"Like humans with NPS2, Fbn1NPS/+ mice display extreme leanness compared with sex-matched WT littermates"

The model reproduces the human leanness phenotype, supporting its relevance to this node.

Show evidence (1 reference)

PMID:29106398 SUPPORT Model Organism

"We introduced a small heterozygous deletion (10 bp) encompassing the exon-65/intron-65 border"

Establishes the exact engineered allele defining this model.

{ }

Source YAML

click to show

name: Marfanoid-Progeroid-Lipodystrophy Syndrome
creation_date: "2026-08-17T09:00:00Z"
category: Mendelian
parents:
- Progeroid syndrome
- Hereditary disorder of connective tissue
- Congenital lipodystrophy
synonyms:
- MFLS
- MPLS
- MPL syndrome
- Marfan lipodystrophy syndrome
- Marfanoid-progeroid syndrome
- Progeroid and marfanoid aspect-lipodystrophy syndrome
- Neonatal progeroid variant of Marfan syndrome
description: >-
  Marfanoid-progeroid-lipodystrophy syndrome (MFLS) is an ultra-rare, usually de
  novo autosomal dominant fibrillinopathy caused by heterozygous truncating FBN1
  variants clustered in a short segment at the extreme 3' end of the coding
  region — the penultimate exon, its splice donor site, and the final intron. It
  combines partial manifestations of Marfan syndrome — marfanoid habitus,
  arachnodactyly, ectopia lentis, severe myopia, aortic root dilation, dural
  ectasia — with two features that classic Marfan syndrome does not have:
  congenital generalized lipodystrophy present from birth, and a progeroid facial
  appearance of neonatal onset.

  What distinguishes MFLS from classic Marfan syndrome is mechanistic, not merely
  a matter of severity. Most Marfan-causing FBN1 premature termination alleles
  are degraded by nonsense-mediated mRNA decay and act through haploinsufficiency
  of the microfibrillar matrix. The MFLS alleles lie 3' of the last 50
  nucleotides of the penultimate exon, escape nonsense-mediated decay, and are
  therefore translated into a stable truncated profibrillin-1. That truncated
  protein does two things at once. Through the microfibril / TGF-beta arm shared
  with Marfan syndrome it perturbs fibrillin-1 assembly and increases
  TGF-beta-SMAD2 signaling, producing the marfanoid, ocular, and aortic features.
  Through an arm unique to this entity it disrupts the furin cleavage site at the
  profibrillin C-terminus and so ablates production of asprosin, the
  140-amino-acid C-terminal cleavage product that circulates as a fasting-induced
  glucogenic and orexigenic hormone. Asprosin deficiency explains the metabolic
  phenotype that separates MFLS from every other lipodystrophy: hypophagia,
  extreme leanness, low fasting insulin, and preserved insulin sensitivity and
  euglycemia, rather than the insulin resistance and diabetes typical of
  generalized lipodystrophies.

  This entry is deliberately kept separate from the Marfan_Syndrome entry, which
  models the classic FBN1 microfibril/TGF-beta disease; the shared arm is
  expressed here as conformance to the aortopathy_tgfbeta_dysregulation module
  rather than by duplicating that entry. Note also that the "progeroid" label is
  descriptive of facial appearance: affected individuals have not been shown to
  undergo accelerated systemic aging, and MFLS is not a laminopathy.
disease_term:
  preferred_term: progeroid and marfanoid aspect-lipodystrophy syndrome
  term:
    id: MONDO:0014831
    label: progeroid and marfanoid aspect-lipodystrophy syndrome
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    All reported cases are heterozygous for an FBN1 variant. De novo origin is
    documented in the probands where parental samples were reported (including
    the two in the asprosin discovery paper, the 2011 exon-64 frameshift case,
    and the 2023 Japanese trio); parental testing is not reported for every
    published case, so "invariably de novo" is an inference from the reported
    subset rather than an established fact. No multiplex family has been
    reported.
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome and Sanger sequencing identified de novo, heterozygous 3′ truncating mutations in FBN1 in both patients"
    explanation: Confirms heterozygous, de novo FBN1 truncating variants as the molecular basis.
  - reference: PMID:21594992
    reference_title: "Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene"
    explanation: A second independent proband with a heterozygous de novo frameshift in the penultimate exon.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than a few dozen molecularly confirmed individuals have been reported.
    The 2016 review that named the entity collected seven unrelated patients from
    six reports published between 2000 and 2014; the 2023 Japanese case report
    counted eight previously reported cases, and scattered single-case reports
    have accrued since, including the first Chinese proband in 2019.
  evidence:
  - reference: PMID:26860060
    reference_title: "Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function."
    explanation: Establishes the very small size of the reported case series at the time the entity was named.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, eight cases of MFLS associated with heterozygous variants near the 3’ terminus of the FBN1 gene have been reported"
    explanation: An independent later count of the total published case series.
progression:
- phase: Prenatal and neonatal
  age_range: Fetal life to birth
  notes: >-
    Fetal growth restriction and preterm birth are common, and both the
    generalized lipodystrophy and the progeroid facial appearance are present
    from birth.
  evidence:
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth"
    explanation: Documents the congenital onset of both defining features.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MFLS is characterized by clinical features including fetal growth retardation, birth before 40 weeks, generalized lack of subcutaneous fat, hyperextensible joints, long fingers, and severe myopia"
    explanation: Summarizes the prenatal/perinatal onset features of the syndrome.
- phase: Infancy and childhood
  age_range: Infancy through childhood
  notes: >-
    A characteristic dissociation emerges between accelerated linear growth and
    poor weight gain, so tall stature and the marfanoid habitus develop while body
    weight stays very low.
  evidence:
  - reference: PMID:24039054
    reference_title: "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features"
    explanation: Defines the cardinal natural-history triad including the characteristic growth dissociation.
- phase: Adolescence and adulthood
  age_range: Second decade onward
  notes: >-
    Ocular and aortic manifestations of the marfanoid arm typically declare
    themselves later; lens subluxation was the finding that prompted FBN1 testing
    in one proband at age 16.
  evidence:
  - reference: PMID:21594992
    reference_title: "Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene."
    explanation: Illustrates the delayed emergence of the ocular marfanoid features relative to the neonatal lipodystrophy.
genetic:
- name: FBN1
  association: >-
    Heterozygous, de novo truncating (frameshift or splice-site) variants confined
    to a short segment at the extreme 3' end of the FBN1 coding region — the
    penultimate exon, its splice donor site, and the final intron.
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  presence: Positive
  gene_term:
    preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  notes: >-
    The pathogenic mechanism is not haploinsufficiency. Because the variants lie
    3' of the last 50 nucleotides of the penultimate exon, the mutant transcript
    escapes nonsense-mediated decay and a stable truncated profibrillin-1 is
    expressed; this is captured structurally as functional_impact_category
    DOMINANT_NEGATIVE on the initiating pathophysiology node. Reported alleles
    include c.8155_8156del, c.8156_8175del (p.Lys2719Thrfs*12), c.8175_8182del8
    (p.Arg2726Glufs*9), the splice variants c.8226+1G>A, c.8226+1G>T and
    c.8226+5G>A, and p.Glu2759Cysfs*9.

    Exon numbering differs between reports and is a recurring source of
    confusion. The earlier case reports and the 2016 naming review place the
    frameshifts in "exon 64", described as the penultimate exon; the asprosin
    papers and the 2023 Japanese case report, using NM_000138.5, place the same
    region at exons 65-66 with the splice variants in intron 65. The stable
    description is positional: the penultimate exon and the final intron, i.e.
    the last 71 bp of coding sequence.

    ClinGen's Gene-Disease Validity curation for FBN1 covers Marfan syndrome
    (MONDO:0007947, Definitive) and does not separately assert MFLS, so no ClinGen
    assertion is cited here.
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all have truncating mutations within a 71-bp segment at the 3′ end of the FBN1 coding region, displaying tight genotype-phenotype correlation"
    explanation: Establishes the tight clustering of causal variants in a 71-bp 3' segment of FBN1.
  - reference: PMID:26860060
    reference_title: "Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All mutations occurred in exon 64 of the FBN1 gene."
    explanation: The naming review confirms a single shared exon across the original seven patients (numbered exon 64 in that report's convention).
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We tested this concept by overexpressing the truncated, mutant version of profibrillin in WT cells and found that this interfered with the ability of those cells to secrete asprosin into the media"
    explanation: Direct in vitro support for the dominant-negative functional impact assigned to this gene-disease relationship.
  - reference: PMID:24613577
    reference_title: "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1."
    explanation: Documents the splice-donor class of causal allele alongside the frameshift class.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, five cases had exonic insertion or deletion variants causing a frameshift in exon 65 or 66 of FBN1. The other three cases had intronic single-nucleotide substitutions"
    explanation: Enumerates the allelic spectrum across the published series, and illustrates the alternative exon-numbering convention noted above.
pathophysiology:
- name: FBN1 3' Truncating Variant Escaping Nonsense-Mediated Decay
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. A heterozygous frameshift or splice-site variant in the
    penultimate FBN1 exon, its donor site, or the final intron places the
    premature termination codon 3' of the last 50 nucleotides of the penultimate
    exon. This is the canonical position at which the exon-junction-complex rule
    that triggers nonsense-mediated mRNA decay no longer applies, so the mutant
    transcript is spared. This is the single molecular difference that separates
    MFLS from the many Marfan-causing FBN1 premature-termination alleles, which
    are degraded by NMD and therefore act by haploinsufficiency.
  genes:
  - preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  genetic_context:
    gene:
      preferred_term: FBN1
      term:
        id: hgnc:3603
        label: FBN1
    allele_type: frameshift or splice-site truncating variant at the FBN1 3' terminus
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Plasma asprosin in affected individuals falls further than heterozygosity
      alone predicts, and overexpression of the truncated protein in wild-type
      cells suppresses asprosin secretion — direct evidence of a dominant-negative
      effect on the wild-type allele rather than simple haploinsufficiency.
  biological_processes:
  - preferred_term: nonsense-mediated decay of the mutant FBN1 transcript
    modifier: DECREASED
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All seven mutations occur 3′ to the last 50 nt of the penultimate exon and are therefore predicted to escape mRNA nonsense-mediated decay (NMD), leading to expression of a mutant, truncated profibrillin protein"
    explanation: States the NMD-escape rule and its consequence for all seven original probands.
  - reference: PMID:31774634
    reference_title: "Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD."
    explanation: Explicitly contrasts NMD escape in MPLS with NMD susceptibility in classic Marfan syndrome.
  - reference: PMID:21594993
    reference_title: "Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This phenotype which is different from that of classical Marfan syndrome could be caused by a truncated FBN1 protein which could escape nonsense-mediated RNA decay."
    explanation: The earliest statement of the NMD-escape hypothesis, from the final-intron splice-site proband.
  downstream:
  - target: Stable Truncated Profibrillin-1 with an Altered C-Terminus
    causal_link_type: DIRECT
    description: >-
      Escape from NMD permits translation of a stable, C-terminally truncated
      profibrillin-1 protein.
    evidence:
    - reference: PMID:27087445
      reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "are therefore predicted to escape mRNA nonsense-mediated decay (NMD), leading to expression of a mutant, truncated profibrillin protein"
      explanation: States the NMD-escape-to-truncated-protein step that this edge asserts.
- name: Stable Truncated Profibrillin-1 with an Altered C-Terminus
  biological_scale: MOLECULAR
  description: >-
    The neomorphic gene product. Profibrillin-1 is a 2,871-residue proprotein
    normally cleaved at its C-terminus by furin to yield mature fibrillin-1 plus a
    140-residue C-terminal peptide. The MFLS variants cluster around that cleavage
    site and truncate the protein just before or within it, leaving an extremely
    charged terminal motif. That the mutant allele is expressed rather than
    degraded is not merely predicted: in one proband, cycloheximide treatment of
    lymphoblastoid cells failed to change the abundance of the exon-skipped
    transcript, experimentally confirming NMD escape in patient material. The
    resulting protein is the shared origin of both disease arms — it is
    incorporated into (and perturbs) the microfibrillar matrix, and it destroys
    the furin cleavage event that would have released asprosin.
  genes:
  - preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  molecular_functions:
  - preferred_term: microfibril binding
    modifier: ABNORMAL
    term:
      id: GO:0050436
      label: microfibril binding
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Profibrillin is translated as a 2,871-amino-acid long proprotein, which is cleaved at the C terminus by the protease furin"
    explanation: Establishes the normal furin processing step that the truncated protein disrupts.
  - reference: PMID:21594992
    reference_title: "Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids."
    explanation: Characterizes the shared charged C-terminal motif of the truncated product.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we conclude that the c.8226+5G>A variant in the FBN1 gene led to the skipping of exon 65, causing a frameshift, and that this mutant transcript escaped NMD"
    explanation: >-
      Experimental confirmation in patient-derived cells that the mutant
      transcript is retained rather than degraded — the assumption on which the
      whole neomorphic-protein model rests.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CHX treatment did not alter the patterns of the chromatogram in the proband, which suggests that the mutant RNA was not the target of NMD"
    explanation: The specific cycloheximide experiment behind that conclusion.
  downstream:
  - target: Microfibril and Extracellular Matrix Assembly Defect
    causal_link_type: DIRECT
    description: >-
      The microfibril/TGF-beta arm shared with classic Marfan syndrome. The
      truncated protein with its altered charged terminus perturbs fibrillin-1
      aggregation and microfibril assembly.
    evidence:
    - reference: PMID:31774634
      reference_title: "Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation"
      explanation: Connects the truncated MPLS protein directly to defective fibrillin-1 aggregation.
  - target: Loss of Furin Cleavage and Asprosin Deficiency
    causal_link_type: DIRECT
    description: >-
      The asprosin/adipose-metabolic arm unique to this entity. Truncation at or
      around the furin site ablates release of the C-terminal cleavage product.
    evidence:
    - reference: PMID:27087445
      reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "clustered around the cleavage site, resulting in heterozygous ablation of the C-terminal cleavage product (asprosin)"
      explanation: Connects the truncating variants directly to loss of the asprosin cleavage product.
- name: Microfibril and Extracellular Matrix Assembly Defect
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Wall ECM or Contractile Apparatus Defect"
  biological_scale: CELLULAR
  description: >-
    The first node of the arm shared with classic Marfan syndrome. Fibrillin-1 is
    the principal structural component of extracellular microfibrils, and its
    charged, truncated form perturbs proper protein aggregation and hence
    incorporation into the microfibrillar matrix, with knock-on effects on the
    strength and elasticity of connective tissue. This node conforms to the
    aortopathy module's primary-lesion node because the underlying defect is the
    same fibrillin-1 microfibril lesion; what differs from Marfan syndrome is the
    allelic mechanism producing it.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: microfibril assembly
    modifier: ABNORMAL
    term:
      id: GO:0160054
      label: microfibril assembly
  - preferred_term: extracellular matrix assembly
    modifier: ABNORMAL
    term:
      id: GO:0085029
      label: extracellular matrix assembly
  evidence:
  - reference: PMID:31774634
    reference_title: "Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86."
    explanation: Direct in vitro evidence that the MPLS allele specifically perturbs fibrillin-1 aggregation.
  - reference: PMID:21594992
    reference_title: "Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix."
    explanation: Attributes the extracellular-matrix consequence to the altered charged C-terminus.
  - reference: PMID:29666143
    reference_title: "Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "FBN1 heterozygous (FBN1 Het) rabbits faithfully recapitulated the phenotypes of MFS, including muscle wasting and impaired connective tissue, ocular syndrome and aortic dilation."
    explanation: A rabbit model carrying an engineered C-terminal truncation reproduces impaired connective tissue in vivo.
  downstream:
  - target: Congenital Generalized Lipodystrophy and Extreme Leanness
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The candidate congenital arm. Fibrillin-1 is a principal component of the
      adipose extracellular-matrix niche, and deficient microfibrils are proposed
      to impair adipogenesis both directly and by altering the mechanical
      properties of that niche. This edge, not the postnatal hypophagia edge, is
      what could account for lipodystrophy being present AT BIRTH. It is drawn
      because the entry should not assert a postnatal mechanism as the sole cause
      of a congenital finding — but it is unproven, and the
      mfls_lipodystrophy_mechanism_split discussion records exactly how unproven.
    evidence:
    - reference: PMID:32279186
      reference_title: "Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils."
      explanation: >-
        Names impaired adipogenesis and altered mechanical properties, mediated
        through deficient microfibrils, as candidate causes of adipose
        dysfunction. PARTIAL because the source explicitly calls them potential.
    - reference: PMID:27386756
      reference_title: "Expression of FBN1 during adipogenesis: Relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "may fail to differentiate adipocytes and/or to accumulate adipocyte lipids, although this still needs to be shown experimentally"
      explanation: >-
        The proposed adipogenic route, flagged by its own authors as not yet
        demonstrated, hence PARTIAL.
  - target: Dysregulated TGF-beta Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Deficient microfibrils are associated with increased TGF-beta signaling.
      The textbook intermediate — failure of the microfibrillar network to
      sequester latent TGF-beta complexes — is established for fibrillin-1
      biology generally but has not been measured in MFLS tissue, which is why
      this edge is INDIRECT rather than DIRECT.
    evidence:
    - reference: PMID:32279186
      reference_title: "Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils."
      explanation: >-
        Links increased TGF-beta signaling to deficient microfibrils, but hedged
        ("potential causes") and stated for adipose rather than aortic tissue,
        hence PARTIAL.
- name: Dysregulated TGF-beta Signaling
  conforms_to: "aortopathy_tgfbeta_dysregulation#TGF-beta Signaling Dysregulation"
  biological_scale: MOLECULAR
  description: >-
    Fibrillin-1 microfibrils sequester latent TGF-beta complexes in the matrix, so
    a defective microfibrillar network raises TGF-beta bioavailability and
    downstream SMAD2 phosphorylation. Both a classic Marfan allele and an MFLS
    allele upregulate SMAD2 phosphorylation in vitro, which is why this node is
    shared with the aortopathy module rather than being MFLS-specific; the causal
    reasoning for MFLS in the primary literature is that TGF-beta signaling is
    altered by, rather than untouched by, the neomorphic truncated protein.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:31774634
    reference_title: "Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both mutations appear to upregulate SMAD2 phosphorylation in vitro."
    explanation: Direct in vitro measurement of increased TGF-beta-SMAD2 signaling for the MPLS allele.
  - reference: PMID:24039054
    reference_title: "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling"
    explanation: >-
      Supports altered FBN1-TGF-beta signaling as the proposed mechanism, but is an
      inference from genotype rather than a direct measurement, hence PARTIAL.
  - reference: PMID:32279186
    reference_title: "Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils."
    explanation: >-
      Review linking deficient microfibrils to increased TGF-beta signaling in the
      fibrillinopathies including MFLS. PARTIAL because the source hedges
      ("potential causes") and speaks of adipose rather than aortic tissue.
  downstream:
  - target: Progressive Aortic Root Dilation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      TGF-beta-driven aortic wall remodeling underlies the aortic arm of the
      marfanoid phenotype. Marked INDIRECT because the intervening medial
      degeneration has been shown in classic Marfan aortopathy, not measured in
      MFLS aortas; the MFLS evidence is the clinical dilation endpoint plus the
      in vitro SMAD2 signal.
    evidence:
    - reference: PMID:29666143
      reference_title: "Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "FBN1 heterozygous (FBN1 Het) rabbits faithfully recapitulated the phenotypes of MFS, including muscle wasting and impaired connective tissue, ocular syndrome and aortic dilation."
      explanation: >-
        The C-terminal-truncation model links the fibrillin-1/TGF-beta lesion to
        aortic dilation in vivo; PARTIAL because the intermediate TGF-beta step
        was not measured in the rabbit aorta.
- name: Progressive Aortic Root Dilation
  conforms_to: "aortopathy_tgfbeta_dysregulation#Progressive Aortic Dilation and Aneurysm"
  biological_scale: ORGANISM
  description: >-
    Dilation of the aortic bulb/root is documented in several molecularly
    confirmed MFLS patients and is reproduced in the rabbit model, so the
    marfanoid arm does reach the aorta. It is not, however, universal: at least
    one molecularly confirmed child had stable mild mitral regurgitation with a
    normal aortic root through nine years of follow-up, so aortic involvement is
    less uniform than in classic Marfan syndrome. Conformance is asserted only to
    this dilation node of the aortopathy module — aortic dissection or rupture,
    the module's terminal node, has not been reported in MFLS, and the reported
    case total is far too small to establish or exclude that risk. MFLS should
    nonetheless be managed with the aortic surveillance appropriate to a
    fibrillinopathy.
  biological_processes:
  - preferred_term: extracellular matrix organization in the aortic wall
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia"
    explanation: Documents aortic bulb dilation in the index MFLS proband.
  - reference: PMID:24613577
    reference_title: "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome."
    explanation: A second independent patient with aortic bulb dilatation.
  - reference: PMID:29666143
    reference_title: "Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ocular syndrome and aortic dilation"
    explanation: The C-terminal-truncation rabbit model reproduces aortic dilation in vivo.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showing stable mild mitral regurgitation without dilation of the aortic root"
    explanation: >-
      A counter-example: aortic root dilation is not universal in MFLS. Recorded as
      PARTIAL because it qualifies rather than supports the node.
- name: Loss of Furin Cleavage and Asprosin Deficiency
  biological_scale: MOLECULAR
  description: >-
    The first node of the arm unique to MFLS. Furin cleavage of profibrillin-1
    normally releases a 140-residue C-terminal peptide — asprosin — encoded by the
    final two FBN1 exons. Every MFLS variant clusters around that cleavage site,
    so the truncated allele cannot yield asprosin. Crucially, circulating asprosin
    falls further than the 50% a heterozygous null would predict, because the
    expressed truncated profibrillin also suppresses secretion of asprosin from
    the wild-type allele. This node is the mechanistic hinge of the entry: it is
    where MFLS departs from classic Marfan syndrome, whose alleles are degraded by
    NMD and therefore leave asprosin production largely intact.
  genes:
  - preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  cell_types:
  - preferred_term: white adipocyte
    term:
      id: CL:0000448
      label: white adipocyte
  biological_processes:
  - preferred_term: protein processing (furin cleavage of profibrillin-1)
    modifier: DECREASED
    term:
      id: GO:0016485
      label: protein processing
  - preferred_term: peptide hormone secretion (asprosin)
    modifier: DECREASED
    term:
      id: GO:0030072
      label: peptide hormone secretion
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All seven NPS mutations are clustered around the cleavage site, resulting in heterozygous ablation of the C-terminal cleavage product (asprosin)"
    explanation: Establishes ablation of the asprosin cleavage product as the direct consequence of the MFLS variant cluster.
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NPS patients displayed a greater reduction in circulating asprosin level than predicted from their heterozygous genotype"
    explanation: Measured plasma asprosin deficit exceeding the heterozygous prediction, the basis of the dominant-negative claim.
  - reference: PMID:24613577
    reference_title: "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered"
    explanation: Independent case demonstrating that the causal allele alters the C-terminal furin cleavage site.
  - reference: PMID:32279186
    reference_title: "Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furin processing of profibrillin-1 results in mature fibrillin-1 and releases the C-terminal propeptide as a circulating hunger hormone, asprosin."
    explanation: Review statement of the normal furin/asprosin processing step.
  downstream:
  - target: Reduced Hepatic Glucose Release with Preserved Insulin Sensitivity
    causal_link_type: DIRECT
    description: >-
      Asprosin normally acts on the liver to drive glucose release; its deficiency
      lowers hepatic glucose output.
    evidence:
    - reference: PMID:27087445
      reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release"
      explanation: States the loss-of-asprosin to reduced-hepatic-glucose-release causal step directly.
  - target: Reduced Central Orexigenic Drive
    causal_link_type: DIRECT
    description: >-
      Asprosin normally crosses the blood-brain barrier to activate hypothalamic
      AgRP neurons; its deficiency blunts appetite.
    evidence:
    - reference: PMID:29106398
      reference_title: "Asprosin is a centrally acting orexigenic hormone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness"
      explanation: States the asprosin-deficiency to low-appetite causal step in humans.
- name: Reduced Hepatic Glucose Release with Preserved Insulin Sensitivity
  biological_scale: ORGANISM
  description: >-
    Asprosin is recruited to the liver, where it activates a G-protein-cAMP-PKA
    pathway and drives hepatic glucose release; loss of function lowers glucose and
    insulin secondary to reduced hepatic glucose production. This is the node that
    explains the single most counterintuitive feature of MFLS: unlike generalized
    lipodystrophies in general — which characteristically cause severe insulin
    resistance, hypertriglyceridemia, hepatic steatosis, and diabetes — MFLS
    patients have low fasting insulin and remain euglycemic and insulin-sensitive
    despite near-absent adipose tissue.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: hepatic glucose release
    modifier: DECREASED
    term:
      id: GO:0006006
      label: glucose metabolic process
  - preferred_term: glucose homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0042593
      label: glucose homeostasis
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contrary to this notion, overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"
    explanation: Direct human measurement of low fasting insulin with euglycemia in MFLS patients.
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation."
    explanation: Establishes the normal hepatic action of asprosin whose loss produces this node.
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes."
    explanation: Clinical confirmation that the metabolic complications typical of generalized lipodystrophy are absent.
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "maintenance of insulin sensitivity despite partial lipodystrophy"
    explanation: Confirms preserved insulin sensitivity in the setting of the lipodystrophy.
- name: Reduced Central Orexigenic Drive
  biological_scale: CELLULAR
  description: >-
    Circulating asprosin crosses the blood-brain barrier and directly activates
    orexigenic AgRP-positive arcuate neurons through a cAMP-dependent pathway,
    which in turn inhibits anorexigenic POMC neurons via GABA. Asprosin-deficient
    patients are hypophagic, consuming fewer calories than matched peers, and the
    corresponding mouse model shows both hypophagia and AgRP neuron hypoactivity
    that is rescued by recombinant asprosin. Hypophagia, rather than adipocyte
    failure alone, is therefore a substantive contributor to the leanness of MFLS.
  biological_processes:
  - preferred_term: regulation of feeding behavior
    modifier: DECREASED
    term:
      id: GO:0060259
      label: regulation of feeding behavior
  evidence:
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin."
    explanation: Directly links asprosin deficiency in this syndrome to low appetite and leanness in humans.
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that the two individuals examined consumed fewer calories on a daily basis than their age and sex matched peers in the lab as well as the home setting"
    explanation: Quantified hypophagia measured directly in affected individuals.
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway"
    explanation: Establishes the central mechanism by which asprosin deficiency lowers appetite.
  downstream:
  - target: Congenital Generalized Lipodystrophy and Extreme Leanness
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronically reduced caloric intake contributes to, but does not by itself
      account for, the congenital absence of adipose tissue. See the
      mfls_lipodystrophy_mechanism_split discussion for the unresolved split
      between this route and a cell-autonomous or matrix-mechanical adipogenic
      block.
    evidence:
    - reference: PMID:29106398
      reference_title: "Asprosin is a centrally acting orexigenic hormone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Based on these results we hypothesized that NPS-associated leanness could at least partially be explained by asprosin deficiency"
      explanation: >-
        The authors themselves frame hypophagia as a partial explanation for the
        leanness, which is exactly the strength of this edge.
- name: Congenital Generalized Lipodystrophy and Extreme Leanness
  biological_scale: TISSUE
  description: >-
    The convergent clinical endpoint of the asprosin arm. Adipose tissue is
    profoundly reduced from birth, giving both the generalized lipodystrophy and
    the sunken, aged facial appearance that earned the syndrome its "progeroid"
    label. Two mechanisms plausibly converge here and are not fully separated in
    the literature: the reduced orexigenic drive above, and a direct role for
    fibrillin-1 in the adipose extracellular-matrix niche during adipogenesis.
    Fibrillin-1 is expressed as mesenchymal stem cells enter adipogenesis and
    declines as adipocytes mature, and the region of FBN1 affected in
    FBN1-associated lipodystrophy is highly conserved — but the proposal that low
    fibrillin-1 causes a failure to differentiate adipocytes is explicitly flagged
    by its authors as not yet demonstrated experimentally, and is framed for
    reduced fibrillin-1 rather than for the stable dysfunctional protein MFLS
    actually produces.
  cell_types:
  - preferred_term: white adipocyte
    term:
      id: CL:0000448
      label: white adipocyte
  biological_processes:
  - preferred_term: white fat cell differentiation
    modifier: DECREASED
    term:
      id: GO:0050872
      label: white fat cell differentiation
  evidence:
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth"
    explanation: Documents generalized lipodystrophy present from birth in the index patient.
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "display a deficiency in plasma asprosin1 associated with extreme leanness"
    explanation: Links the measured asprosin deficiency to the leanness phenotype in patients.
  - reference: PMID:27386756
    reference_title: "Expression of FBN1 during adipogenesis: Relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "individuals with low fibrillin-1 (for example with FBN1 mutations associated with lipodystrophy) may fail to differentiate adipocytes and/or to accumulate adipocyte lipids, although this still needs to be shown experimentally"
    explanation: >-
      Supports a candidate adipogenic mechanism but is explicitly hypothetical in
      the source, hence PARTIAL rather than SUPPORT.
  - reference: PMID:27386756
    reference_title: "Expression of FBN1 during adipogenesis: Relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We used human mesenchymal stem cells differentiated in culture to adipocytes to show that fibrillin-1 declines after the initiation of differentiation."
    explanation: >-
      Establishes the measured expression dynamics of fibrillin-1 across
      adipogenesis in NORMAL human mesenchymal stem cells. PARTIAL because it is
      an observation about healthy adipogenesis, not about MFLS cells; it
      motivates the adipogenic hypothesis without testing it.
phenotypes:
- category: Metabolic
  name: Congenital Generalized Lipodystrophy
  description: >-
    Near-total absence of adipose tissue present from birth, the defining
    non-Marfan feature of the syndrome.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Congenital generalized lipodystrophy
    term:
      id: HP:0009059
      label: Congenital generalized lipodystrophy
    temporality: CHRONIC
  evidence:
  - reference: PMID:26860060
    reference_title: "Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals."
    explanation: >-
      Lipodystrophy was present in all seven patients of the defining review. The
      band is VERY_FREQUENT rather than OBLIGATE deliberately: the review
      assembled its series ON the basis of this feature, so the observed 7/7 is
      an ascertainment artifact and an obligate claim would be circular.
  - reference: PMID:24039054
    reference_title: "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the cardinal features of these patients include (1) congenital lipodystrophy"
    explanation: Names congenital lipodystrophy as a cardinal feature of the entity.
- category: Metabolic
  name: Reduced Subcutaneous Adipose Tissue
  description: Markedly reduced subcutaneous fat mass, contributing to the aged facial appearance.
  phenotype_term:
    preferred_term: Reduced subcutaneous adipose tissue
    term:
      id: HP:0003758
      label: Reduced subcutaneous adipose tissue
  evidence:
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduced subcutaneous adipose mass (Fig. 1)2 and maintenance of insulin sensitivity"
    explanation: Documents reduced subcutaneous adipose mass in affected individuals.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized lack of subcutaneous fat"
    explanation: Names lack of subcutaneous fat among the defining clinical features.
- category: Craniofacial
  name: Progeroid Facial Appearance
  description: >-
    A distinctive aged facial appearance of neonatal onset, driven by absent
    facial subcutaneous fat rather than by systemic accelerated aging.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Progeroid facial appearance
    term:
      id: HP:0005328
      label: Progeroid facial appearance
  evidence:
  - reference: PMID:26860060
    reference_title: "Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals"
    explanation: >-
      Present in all seven patients of the defining review. As with the
      lipodystrophy, the band is VERY_FREQUENT rather than OBLIGATE because the
      review selected its series on this feature, making the observed 7/7 an
      ascertainment artifact rather than evidence of full penetrance.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MFLS’s appearance of premature aging is not due to actual premature aging but rather due to low subcutaneous fat"
    explanation: Establishes that the progeroid appearance is a consequence of fat loss, not accelerated aging.
- category: Skeletal
  name: Marfanoid Habitus
  description: >-
    Tall, slender build with disproportionately long limbs. Tall stature emerges
    over infancy and is dissociated from weight gain.
  phenotype_term:
    preferred_term: Marfanoid habitus
    term:
      id: HP:0001519
      label: Disproportionate tall stature
  evidence:
  - reference: PMID:24613577
    reference_title: "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb)"
    explanation: Documents marfanoid habitus in a molecularly confirmed patient.
  - reference: PMID:21594993
    reference_title: "Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and tall stature at the end of infancy"
    explanation: Independent report of tall stature emerging in infancy.
- category: Growth
  name: Decreased Body Weight
  description: >-
    Severely low body weight, dissociated from accelerated linear growth — the
    characteristic MFLS growth profile. One proband had a BMI of 12.6 kg/m2 and a
    body fat percentage of 9.4% at 9 years.
  phenotype_term:
    preferred_term: Decreased body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  evidence:
  - reference: PMID:24039054
    reference_title: "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain."
    explanation: Documents the height/weight dissociation defining this growth phenotype.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "body mass index (BMI) was 12.6 kg/m2, and body fat percentage was 9.4%"
    explanation: Quantifies the extreme leanness in a molecularly confirmed proband.
- category: Growth
  name: Intrauterine Growth Retardation
  description: >-
    Fetal growth restriction, in one documented case with growth arrest around 32
    weeks attributed to placental insufficiency.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MFLS is characterized by clinical features including fetal growth retardation, birth before 40 weeks"
    explanation: Names fetal growth retardation among the characteristic features of MFLS.
- category: Growth
  name: Premature Birth
  description: Preterm delivery is listed among the cardinal features of the entity.
  phenotype_term:
    preferred_term: Premature birth
    term:
      id: HP:0001622
      label: Premature birth
  evidence:
  - reference: PMID:24039054
    reference_title: "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(2) premature birth with an accelerated linear growth disproportionate to the weight gain"
    explanation: Names premature birth as a cardinal feature.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband was born at 35 weeks and 2 days’ gestation"
    explanation: Preterm delivery in an independently reported proband.
- category: Ocular
  name: Ectopia Lentis
  description: >-
    Bilateral lens subluxation, a cardinal Marfan feature retained in some but not
    all MFLS patients; it was the finding that triggered FBN1 testing in one
    proband, and was explicitly absent in another. No frequency band is
    asserted: it is present in at least two and absent in at least one of the
    roughly eight to nine published patients, which is too small and too incompletely
    ascertained a denominator to place in a band.
  phenotype_term:
    preferred_term: Ectopia lentis
    term:
      id: HP:0001083
      label: Ectopia lentis
  evidence:
  - reference: PMID:21594992
    reference_title: "Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years"
    explanation: Bilateral lens subluxation documented in a molecularly confirmed patient.
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral subluxation of the lens, and severe myopia"
    explanation: Independent report of bilateral lens subluxation.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmological evaluations revealed myopic astigmatism"
    explanation: >-
      This proband's ophthalmological assessment found myopic astigmatism but not
      ectopia lentis, establishing that the feature is not universal. PARTIAL
      because it qualifies rather than supports the phenotype.
- category: Ocular
  name: Myopia
  description: >-
    Myopia, often severe or with astigmatism, and one of the more consistent
    ocular features.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy"
    explanation: Documents severe myopia.
  - reference: PMID:24613577
    reference_title: "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "marfanoid habitus, severe myopia and dilatation of the aortic bulb"
    explanation: Independent report of severe myopia.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized lack of subcutaneous fat, hyperextensible joints, long fingers, and severe myopia"
    explanation: Lists severe myopia among the characteristic features of the syndrome.
- category: Ocular
  name: Entropion
  description: >-
    Bilateral inward turning of the eyelids, described as a rare manifestation and
    reported in only two MFLS patients; in one it caused severe corneal epithelial
    damage requiring surgical correction. No frequency band is asserted: the
    source calls it rare, but two of roughly eight to nine published patients is ~25%,
    which the reported denominator is far too small to distinguish from a much
    lower true frequency.
  phenotype_term:
    preferred_term: Entropion
    term:
      id: HP:0000621
      label: Entropion
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the eyelid entropion seen in the present case seems to be a rare manifestation of MFLS. Only one case of eyelid entropion has previously been reported"
    explanation: >-
      Two cases out of the roughly eight to nine reported, and explicitly described by the
      authors as a rare manifestation. Quoted to support the association and its
      rarity in prose, not to justify a frequency band.
- category: Cardiovascular
  name: Aortic Root Dilation
  description: >-
    Dilation of the aortic bulb/root, reported in multiple molecularly confirmed
    patients but explicitly absent in at least one followed to age nine. No
    dissection has been reported, though the case total is too small for that to
    be reassuring. No frequency band is asserted, because the published reports
    do not systematically state whether aortic imaging was performed in every
    patient, so the denominator is unknown.

    Ontology note, on two axes a reviewer should be able to check quickly.
    SEGMENT: the sources report dilation of the aortic bulb / aortic root
    specifically ("dilated aortic bulb", "dilatation of the aortic bulb",
    "without dilation of the aortic root"), which is the sinus-of-Valsalva
    segment — so HP:0002616 is correct and HP:0004970 Ascending tubular aorta
    aneurysm, the adjacent segment, would be wrong. SEVERITY WORDING: the label
    reads "aneurysm" while the sources say "dilation", but the HPO term's own
    definition is "An abnormal localized widening (dilatation) of the aortic
    root", so the term already means dilatation and no term request is needed.
    The preferred_term records the clinical wording.
  phenotype_term:
    preferred_term: Aortic root dilation
    term:
      id: HP:0002616
      label: Aortic root aneurysm
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with mild skeletal features, dilated aortic bulb, dural ectasia"
    explanation: Documents aortic bulb dilation.
  - reference: PMID:24613577
    reference_title: "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe myopia and dilatation of the aortic bulb"
    explanation: Independent report of aortic bulb dilatation.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showing stable mild mitral regurgitation without dilation of the aortic root"
    explanation: >-
      A molecularly confirmed patient serially imaged to age nine with no aortic
      root dilation, establishing that aortic involvement is not universal.
- category: Cardiovascular
  name: Mitral Regurgitation
  description: >-
    Mild mitral regurgitation, identified at age 2 and stable on follow-up in one
    proband. No frequency band is asserted: a single report gives no usable
    denominator, since most published cases do not state whether echocardiography
    was performed.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
    severity: MILD
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild mitral regurgitation was identified at 2 years of age."
    explanation: >-
      Documents mild mitral regurgitation, with the age at detection and its
      stability on follow-up.
- category: Skeletal
  name: Arachnodactyly
  description: Long fingers with positive wrist and thumb signs, a marfanoid skeletal feature.
  phenotype_term:
    preferred_term: Arachnodactyly
    term:
      id: HP:0001166
      label: Arachnodactyly
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high arched palate, long fingers, positive wrist and thumb signs, plain pes planus, and mild hyperextensible finger joints"
    explanation: Documents long fingers with positive wrist and thumb signs on clinical examination.
- category: Skeletal
  name: Joint Hypermobility
  description: Hyperextensible joints, listed among the characteristic features of the syndrome.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized lack of subcutaneous fat, hyperextensible joints, long fingers, and severe myopia"
    explanation: Names hyperextensible joints among the characteristic clinical features of MFLS.
- category: Skeletal
  name: Pes Planus
  description: Flat feet, without hindfoot deformity in the reported case.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "positive wrist and thumb signs, plain pes planus, and mild hyperextensible finger joints"
    explanation: Documents pes planus on clinical examination.
- category: Craniofacial
  name: Dolichocephaly
  description: Elongated skull shape, noted in the neonatal period and regarded as collateral evidence of a craniosynostosis spectrum.
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the early neonatal period, bilateral entropion of the upper and lower lids and dolichocephaly were noted."
    explanation: Documents neonatal-onset dolichocephaly.
- category: Craniofacial
  name: Prominent Forehead
  description: Frontal bossing, a recurrent element of the characteristic facial gestalt.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical manifestations included dolichocephaly, prominent forehead, narrow nasal ridge, mild retrognathia"
    explanation: Documents prominent forehead as part of the facial gestalt.
- category: Craniofacial
  name: Narrow Nasal Ridge
  description: Narrow nasal bridge, part of the characteristic facial gestalt.
  phenotype_term:
    preferred_term: Narrow nasal ridge
    term:
      id: HP:0000418
      label: Narrow nasal ridge
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dolichocephaly, prominent forehead, narrow nasal ridge, mild retrognathia, subcutaneous fat reduction"
    explanation: Documents narrow nasal ridge as part of the facial gestalt.
- category: Craniofacial
  name: Retrognathia
  description: Mild posterior positioning of the mandible.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
    severity: MILD
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent forehead, narrow nasal ridge, mild retrognathia, subcutaneous fat reduction"
    explanation: Documents mild retrognathia.
- category: Craniofacial
  name: High Palate
  description: High-arched palate, a marfanoid craniofacial feature.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral entropion (postoperative), high arched palate, long fingers"
    explanation: Documents high-arched palate on clinical examination.
- category: Craniofacial
  name: Craniosynostosis
  description: >-
    Premature cranial suture fusion, rare in FBN1-related Marfan syndrome but
    reported in several MFLS cases. No frequency band is asserted: the source
    says "several cases" without a count, and CT was not performed in every
    reported patient, so the feature is under-ascertained.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:24039054
    reference_title: "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had a characteristic facial appearance with craniosynostosis."
    explanation: Documents craniosynostosis in a molecularly confirmed patient.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Craniosynostosis is rare in FBN1-related Marfan syndrome but is reported in several cases in MFLS"
    explanation: >-
      Explicitly contrasts the rarity of craniosynostosis in classic FBN1-related
      Marfan syndrome with its recurrence in MFLS. Quoted for the association, not
      to justify a frequency band.
- category: Craniofacial
  name: Macrocephaly
  description: Large head circumference, reported with associated hydrocephalus in at least one patient.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:21594993
    reference_title: "Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large head circumference with corresponding hydrocephaly"
    explanation: Documents large head circumference in a molecularly confirmed patient.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and had a head circumference of 55.3 cm (+2.2 SD)"
    explanation: An independently reported proband with a head circumference above +2 SD.
- category: Neurologic
  name: Hydrocephalus
  description: >-
    Hydrocephalus reported in association with the large head circumference in one
    patient. No frequency band is asserted; a single report gives no usable
    denominator.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:21594993
    reference_title: "Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large head circumference with corresponding hydrocephaly"
    explanation: >-
      Documents hydrocephalus accompanying the enlarged head circumference in a
      molecularly confirmed patient.
- category: Neurologic
  name: Dural Ectasia
  description: Widening of the dural sac, a recognized Marfan feature retained in MFLS.
  phenotype_term:
    preferred_term: Dural ectasia
    term:
      id: HP:0100775
      label: Dural ectasia
  evidence:
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dilated aortic bulb, dural ectasia, bilateral subluxation of the lens"
    explanation: Documents dural ectasia in the index patient.
- category: Metabolic
  name: Poor Appetite
  description: >-
    Hypophagia measured directly in affected individuals, mechanistically
    attributable to loss of the orexigenic action of asprosin, and in one case the
    presenting complaint that led to genetic referral.
  phenotype_term:
    preferred_term: Poor appetite
    term:
      id: HP:0004396
      label: Poor appetite
  evidence:
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness"
    explanation: States low appetite as a defining feature of the asprosin-deficiency syndrome.
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their hypophagia was matched by subnormal daily energy expenditure when measured using indirect calorimetry"
    explanation: Quantified hypophagia in the two studied patients.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for an undiagnosed condition and a poor appetite"
    explanation: Poor appetite in an independently reported proband, here the presenting complaint.
- category: Metabolic
  name: Hypoinsulinemia
  description: >-
    Low fasting plasma insulin with preserved euglycemia — the inverse of the
    hyperinsulinemic insulin resistance expected in generalized lipodystrophy.
  phenotype_term:
    preferred_term: Hypoinsulinemia
    term:
      id: HP:0040216
      label: Hypoinsulinemia
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"
    explanation: Direct measurement of low fasting insulin with euglycemia.
biochemical:
- name: Plasma asprosin
  presence: DECREASED
  context: >-
    Circulating asprosin, the C-terminal cleavage product of profibrillin-1,
    measured by asprosin-specific sandwich ELISA. Affected individuals show a
    reduction greater than heterozygosity alone predicts. There is no LOINC-coded
    clinical assay; asprosin ELISA remains a research measurement, which is why no
    reference_ranges block is given.
  readouts:
  - target: Loss of Furin Cleavage and Asprosin Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low plasma asprosin directly reports the failure of furin cleavage at the
      profibrillin C-terminus.
    evidence:
    - reference: PMID:27087445
      reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "To measure circulating asprosin levels, we developed a sandwich ELISA"
      explanation: Establishes the assay by which this readout is measured.
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NPS patients displayed a greater reduction in circulating asprosin level than predicted from their heterozygous genotype, compared not only with WT control subjects"
    explanation: Direct measurement of reduced plasma asprosin in affected individuals.
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asprosin was found to be present in plasma at consistent nanomolar levels in humans, mice, and rats"
    explanation: Establishes the normal circulating range against which the patient deficit is measured.
- name: Fasting plasma insulin
  presence: DECREASED
  context: >-
    Overnight-fasted plasma insulin, approximately two-fold below unaffected
    controls in the two studied patients, with normal plasma glucose.
  readouts:
  - target: Reduced Hepatic Glucose Release with Preserved Insulin Sensitivity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low fasting insulin with euglycemia reports reduced hepatic glucose output
      rather than beta-cell failure, and is the finding that separates MFLS from
      other generalized lipodystrophies.
    evidence:
    - reference: PMID:27087445
      reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"
      explanation: The direct measurement underlying this readout and its direction.
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overnight-fasted plasma insulin levels from our NPS patients were 2-fold lower than unaffected subjects, while maintaining euglycemia"
    explanation: Reports the measured direction and magnitude of the insulin deficit.
diagnosis:
- name: Molecular confirmation of a 3' FBN1 truncating variant
  description: >-
    Diagnosis rests on identifying a heterozygous truncating FBN1 variant within
    the short 3'-terminal segment (the penultimate exon, its donor site, or the
    final intron) in an individual with congenital generalized lipodystrophy, a
    progeroid facial appearance, and marfanoid features. Variant position is
    diagnostically decisive: an FBN1 truncating variant located further 5' is
    subject to nonsense-mediated decay and predicts classic Marfan syndrome, not
    MFLS. Note that phenotype alone is not sufficient — the Marfan systemic score
    was only 5 in one molecularly confirmed proband.
  evidence:
  - reference: PMID:27087445
    reference_title: "Asprosin, a Fasting-Induced Glucogenic Protein Hormone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all have truncating mutations within a 71-bp segment at the 3′ end of the FBN1 coding region, displaying tight genotype-phenotype correlation"
    explanation: The tight genotype-phenotype correlation is what makes variant position diagnostic.
  - reference: PMID:26860060
    reference_title: "Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy"
    explanation: Establishes the genotype-phenotype relationship as the basis for recognizing the entity.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since the clinical symptoms were consistent with previous cases and the genetic mutation was confirmed, we believe that this case can be definitively diagnosed as a case of MFLS."
    explanation: Illustrates that definitive diagnosis rests on clinical features plus molecular confirmation.
differential_diagnoses:
- name: Wiedemann-Rautenstrauch (neonatal progeroid) syndrome
  description: >-
    MFLS patients were repeatedly diagnosed at birth as having neonatal progeroid
    syndrome / Wiedemann-Rautenstrauch syndrome, and the syndrome is still often
    reported under the "NPS" label in the asprosin literature. The distinguishing
    features are the later emergence of marfanoid and ocular signs, and the 3' FBN1
    genotype.
  evidence:
  - reference: PMID:24613577
    reference_title: "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome."
    explanation: Documents the initial misdiagnosis that makes this the leading differential.
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features."
    explanation: Describes the overlapping presentation.
- name: Classic Marfan syndrome
  description: >-
    Classic FBN1-related Marfan syndrome shares the skeletal, ocular, and aortic
    features but lacks congenital generalized lipodystrophy and the progeroid
    facial appearance. The separating variable is FBN1 variant position and its NMD
    consequence. See the Marfan_Syndrome entry.
  evidence:
  - reference: PMID:31774634
    reference_title: "Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS)."
    explanation: States the allelic relationship between the two entities directly.
- name: Other congenital generalized lipodystrophies
  description: >-
    Berardinelli-Seip congenital lipodystrophy (AGPAT2, BSCL2) and other
    generalized lipodystrophies present with near-absent adipose tissue but are
    characteristically complicated by severe insulin resistance,
    hypertriglyceridemia, hepatic steatosis, and diabetes — precisely the
    complications absent in MFLS. Sequencing of the classic lipodystrophy and
    progeria genes was negative in the index MFLS patient.
  evidence:
  - reference: PMID:20979188
    reference_title: "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C)."
    explanation: Documents exclusion of the other congenital lipodystrophy and progeria genes.
animal_models:
- name: FBN1 C-terminal truncation rabbit (CRISPR/Cas9)
  species: Rabbit
  genotype: FBN1 heterozygous C-terminal truncation
  publication: PMID:29666143
  description: >-
    A CRISPR/Cas9 rabbit engineered with a C-terminal fibrillin-1 truncation,
    generated specifically because existing FBN1 knockout and dominant-negative
    mouse models do not reproduce the MFLS genotype-phenotype relationship.
  evidence:
  - reference: PMID:29666143
    reference_title: "Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we describe the generation of a rabbit MPL model with C-terminal truncation of fibrillin-1 using a CRISPR/Cas9 system"
    explanation: Establishes the existence, species, and construction of the model.
  modeled_mechanisms:
  - target: Microfibril and Extracellular Matrix Assembly Defect
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Heterozygous rabbits reproduce the connective-tissue, ocular, and aortic
      features of the marfanoid arm.
    limitations: >-
      The engineered truncation is not one of the specific human MFLS alleles, and
      rabbit connective-tissue involvement is reported qualitatively rather than
      against a quantitative microfibril-assembly assay.
    evidence:
    - reference: PMID:29666143
      reference_title: "Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "this novel rabbit model mimics the histopathological changes and functional defects of MPL syndrome, and could become a valuable model for studies of pathogenesis and drug screening for MPL syndrome"
      explanation: The authors' own assessment of the model's validity for this entity.
  - target: Congenital Generalized Lipodystrophy and Extreme Leanness
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Lipodystrophy and growth retardation appear in the heterozygous rabbits and
      had not been reported in prior FBN1 animal models.
    limitations: >-
      Dysglycemia accompanies the rabbit lipodystrophy, which does not match the
      human MFLS metabolic phenotype of low fasting insulin with preserved
      euglycemia and insulin sensitivity; the metabolic arm is therefore only
      partially reproduced.
    evidence:
    - reference: PMID:29666143
      reference_title: "Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, skin symptoms, lipodystrophy, growth retardation and dysglycemia were also seen in these FBN1 Het rabbits, and have not been reported in other animal models."
      explanation: Documents the lipodystrophy phenotype, and the accompanying dysglycemia that limits fidelity.
- name: Fbn1(NPS/+) mouse (CRISPR/Cas9 exon 65 skip)
  species: Mouse
  genotype: Fbn1 heterozygous 10-bp deletion at the exon-65/intron-65 border (asprosin-ablating)
  publication: PMID:29106398
  description: >-
    A mouse engineered to carry the identical molecular event documented in a human
    MFLS patient — a heterozygous deletion causing exon 65 skipping and frameshift
    ablation of the asprosin coding region.
  evidence:
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We introduced a small heterozygous deletion (10 bp) encompassing the exon-65/intron-65 border"
    explanation: Establishes the exact engineered allele defining this model.
  modeled_mechanisms:
  - target: Loss of Furin Cleavage and Asprosin Deficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The mouse reproduces the human asprosin deficit, including the
      greater-than-heterozygous reduction attributed to a dominant-negative effect.
    limitations: >-
      Rodent adipose and hypothalamic physiology differ from human, and the model
      addresses the asprosin arm only — it is not informative about the
      microfibril/aortic arm.
    readouts:
    - name: Plasma asprosin concentration
      target: Loss of Furin Cleavage and Asprosin Deficiency
      direction: DECREASED
      interpretation: >-
        Confirms that the engineered human-equivalent allele lowers circulating
        asprosin below the heterozygous prediction, as in patients.
      evidence:
      - reference: PMID:29106398
        reference_title: "Asprosin is a centrally acting orexigenic hormone."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we found asprosin concentrations lower than 50% in these mice despite heterozygosity"
        explanation: Reports the measured plasma asprosin deficit in the model.
    evidence:
    - reference: PMID:29106398
      reference_title: "Asprosin is a centrally acting orexigenic hormone."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "which harbor an identical molecular event documented in a known individual with NPS"
      explanation: The allele was designed to match a real patient variant, supporting the model's relevance.
  - target: Reduced Central Orexigenic Drive
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The mouse reproduces human hypophagia and demonstrates the underlying AgRP
      neuron hypoactivity, which is rescued by recombinant asprosin.
    limitations: >-
      AgRP neuron electrophysiology cannot be measured in patients, so the central
      mechanism remains inferred rather than demonstrated in humans.
    readouts:
    - name: AgRP neuron firing frequency and resting membrane potential
      target: Reduced Central Orexigenic Drive
      direction: DECREASED
      interpretation: >-
        Establishes hypothalamic AgRP hypoactivity as the central lesion of
        asprosin deficiency.
      evidence:
      - reference: PMID:29106398
        reference_title: "Asprosin is a centrally acting orexigenic hormone."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we found that AgRP+ neuron activity was significantly lower in Fbn1NPS/+ mice compared with WT littermates, demonstrated by decreased firing frequency and resting membrane potential"
        explanation: Direct electrophysiological measurement of the readout.
    - name: Daily food intake after recombinant asprosin
      target: Reduced Central Orexigenic Drive
      direction: RESTORED
      interpretation: >-
        Rescue by a single dose establishes that the hypophagia is caused by
        asprosin deficiency rather than by an indirect effect of mutant
        fibrillin-1.
      evidence:
      - reference: PMID:29106398
        reference_title: "Asprosin is a centrally acting orexigenic hormone."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "A single subcutaneous dose of recombinant asprosin was sufficient to completely rescue the hypophagia of Fbn1NPS/+ mice, demonstrating that NPS-associated hypophagia is due to a deficiency of plasma asprosin and not due to some indirect effect of mutated fibrillin-1"
        explanation: Reports the rescue experiment behind this readout.
    evidence:
    - reference: PMID:29106398
      reference_title: "Asprosin is a centrally acting orexigenic hormone."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Like humans with NPS2, Fbn1NPS/+ mice display extreme leanness compared with sex-matched WT littermates"
      explanation: The model reproduces the human leanness phenotype, supporting its relevance to this node.
treatments:
- name: Multidisciplinary supportive and surveillance care
  description: >-
    There is no disease-modifying therapy. Management is supportive and follows the
    components of the phenotype: cardiovascular surveillance for aortic root
    dilation as for any fibrillinopathy, ophthalmological management of ectopia
    lentis and myopia, and nutritional support for the very low body weight. No
    MFLS-specific treatment trial has been performed, and these recommendations are
    extrapolated from the constituent phenotypes rather than tested in this entity.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    No publication reports a treatment OUTCOME in MFLS, so nothing here is
    evidenced as effective in this entity. The evidence items below are the
    FBN1-Related Marfan Syndrome GeneReviews recommendations that this entry is
    explicitly extrapolating from, cited so the extrapolation is auditable rather
    than unattributed. They are marked PARTIAL for that reason.

    GeneReviews "Agents/circumstances to avoid" for FBN1-related Marfan syndrome
    includes fluoroquinolone antibiotics, which may exacerbate the predisposition
    for aneurysm and dissection, alongside contact/competitive sports and
    isometric exercise. Whether that caution transfers to MFLS is untested, but
    given the documented aortic root dilation it is recorded here rather than
    omitted.
  evidence:
  - reference: PMID:20301510
    reference_title: "FBN1-Related Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive management by a multidisciplinary team including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon is strongly recommended."
    explanation: >-
      The GeneReviews multidisciplinary-care recommendation this entry
      extrapolates from. PARTIAL because it is a recommendation for classic
      FBN1-related Marfan syndrome, not for MFLS, and has never been evaluated in
      MFLS.
  - reference: PMID:20301510
    reference_title: "FBN1-Related Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography annually when aortic dimensions are small and the rate of aortic dilatation is slow"
    explanation: >-
      The aortic surveillance schedule this entry extrapolates from. PARTIAL for
      the same reason: it is the classic Marfan schedule, and no MFLS-specific
      surveillance interval has been studied.
  - reference: PMID:20301510
    reference_title: "FBN1-Related Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fluoroquinolone antibiotics, which may exacerbate the predisposition for aneurysm and dissection"
    explanation: >-
      The GeneReviews agents-to-avoid caution, recorded because MFLS patients have
      documented aortic root dilation. PARTIAL: transferability to MFLS is
      untested.
- name: Beta-blocker or angiotensin receptor blocker aortic protection
  description: >-
    Pharmacologic reduction of hemodynamic stress on the aortic wall — the
    therapy that the aortic surveillance in the entry above exists to trigger.
    In FBN1-related Marfan syndrome, beta-blockers or angiotensin receptor
    blockers are routinely prescribed once aortic root dilation is progressive,
    and GeneReviews recommends initiating therapy at diagnosis at any age.

    This is recorded because MFLS patients have documented aortic root dilation
    and the entry already carries three Marfan-derived surveillance
    recommendations; carrying the surveillance while omitting the therapy it
    triggers would be internally inconsistent. It is NOT evidence that the
    therapy works in MFLS. No MFLS patient has been reported on either drug
    class, no aortic outcome has been measured in this entity, and the published
    series is roughly eight to nine patients — so the extrapolation is from
    shared FBN1 aortopathy biology, not from data. All evidence here is therefore
    PARTIAL, exactly as for the other GeneReviews-derived items.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: angiotensin receptor blocker
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
  target_mechanisms:
  - target: Progressive Aortic Root Dilation
    treatment_effect: INHIBITS
    description: >-
      Both drug classes act on the hemodynamic load borne by the weakened aortic
      wall rather than on the upstream fibrillin-1 or TGF-beta lesion, so the
      target is the dilation node itself, not the microfibril or TGF-beta node.
      (ARBs are additionally proposed to attenuate TGF-beta signaling in Marfan
      aortopathy, but that mechanism is contested in the Marfan literature and
      has never been examined in MFLS, so it is not asserted here.)
    evidence:
    - reference: PMID:20301510
      reference_title: "FBN1-Related Marfan Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers or angiotensin receptor blockers (ARBs), are routinely prescribed."
      explanation: >-
        States the mechanism by which the drug classes act on the aortic wall.
        PARTIAL because it is a classic FBN1-related Marfan syndrome
        recommendation with no MFLS-specific evidence.
  notes: >-
    GeneReviews cautions that some antihypertensive classes — calcium channel
    blockers and ACE inhibitors — lack direct evidence for efficacy or safety in
    Marfan syndrome, so they are deliberately not listed as therapeutic agents
    here.
  evidence:
  - reference: PMID:20301510
    reference_title: "FBN1-Related Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapy is generally initiated at the time of diagnosis with Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis."
    explanation: >-
      Gives the timing of initiation this entry extrapolates from. PARTIAL: it is
      the classic Marfan trigger, and no MFLS-specific threshold has been studied.
- name: Genetic counseling
  description: >-
    MFLS is autosomal dominant, and every reported case with parental testing
    arose de novo, so recurrence risk to the parents of a proband is low. An
    affected individual, however, has a 50% transmission risk to each child —
    ordinary Mendelian arithmetic for a heterozygous autosomal dominant variant,
    which transfers from FBN1-related Marfan syndrome to MFLS without needing
    MFLS-specific data because it follows from the mode of inheritance rather
    than from the phenotype.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  notes: >-
    This is the one GeneReviews-derived item where the extrapolation is not
    clinical: the 50% figure is a consequence of autosomal dominant inheritance,
    which this entry independently curates and evidences, not of any
    Marfan-specific observation. It is still marked PARTIAL because the quoted
    sentence names Marfan syndrome rather than MFLS.
  evidence:
  - reference: PMID:20301510
    reference_title: "FBN1-Related Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with Marfan syndrome has a 50% chance of inheriting the pathogenic variant and the disorder"
    explanation: >-
      The transmission risk for a heterozygous autosomal dominant FBN1 variant.
      PARTIAL because the sentence is written for Marfan syndrome, though the
      arithmetic follows from the inheritance mode this entry curates.
- name: Surgical correction of entropion
  description: >-
    One proband underwent surgery to correct bilateral eyelid entropion at 16
    months because of severe corneal epithelial damage. This is the only surgical
    intervention with a reported indication and outcome in an MFLS patient.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because she had severe corneal epithelial damage, she underwent surgery to correct bilateral entropion at Kawasaki Medical School Hospital at the age of 1 year 4 months."
    explanation: A single reported case; the indication and timing are documented, the long-term outcome is not.
- name: Recombinant asprosin replacement (investigational, preclinical only)
  description: >-
    Asprosin replacement is the mechanistically obvious therapy for the metabolic
    arm and fully rescues hypophagia and AgRP neuron activity in the mouse model.
    It has NOT been tested in humans and there is no clinical program; it is
    recorded here as a preclinical concept, not a recommendation. Replacement would
    in any case address only the asprosin arm and would not be expected to affect
    the microfibril/aortic arm.

    No therapeutic_agent is bound: asprosin is a 140-residue peptide hormone
    described in 2016 and has no CHEBI entry and no NCIT clinical-agent term, so
    per the guidance the slot is left empty rather than filled with a wrong or
    over-broad term.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Loss of Furin Cleavage and Asprosin Deficiency
    treatment_effect: RESTORES
    description: >-
      Exogenous recombinant asprosin substitutes for the cleavage product that the
      truncated profibrillin cannot release.
    evidence:
    - reference: PMID:29106398
      reference_title: "Asprosin is a centrally acting orexigenic hormone."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin"
      explanation: Establishes rescue of the asprosin-deficiency phenotype by exogenous asprosin in the model.
  evidence:
  - reference: PMID:29106398
    reference_title: "Asprosin is a centrally acting orexigenic hormone."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A single subcutaneous dose of recombinant asprosin was sufficient to completely rescue the hypophagia of Fbn1NPS/+ mice"
    explanation: >-
      Supports the preclinical rationale only; there is no human evidence, hence
      PARTIAL and MODEL_ORGANISM.
discussions:
- discussion_id: mfls_mouse_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Stable Truncated Profibrillin-1 with an Altered C-Terminus
  prompt: >-
    Do the widely used FBN1 mouse models of Marfan syndrome say anything at all
    about MFLS, given that they were built on a mechanism (haploinsufficiency or
    dominant-negative missense) that MFLS does not use?
  rationale: >-
    The published FBN1 knockout and dominant-negative mouse models were designed
    around classic Marfan biology and, by the explicit statement of the group that
    built the rabbit model, cannot recapitulate the MFLS genotype-phenotype
    relationship, because they do not produce a stable NMD-escaping C-terminally
    truncated profibrillin. The models that ARE informative for MFLS are the
    purpose-built asprosin-ablating Fbn1(NPS/+) mouse and the CRISPR rabbit. This
    matters for interpretation: metabolic findings from Marfan mouse models — for
    example that male Marfan mice are predisposed to high-fat-diet obesity,
    diabetes, and fatty liver — point in the opposite direction from the human MFLS
    metabolic phenotype and should not be transferred to this entity.
  proposed_experiments:
  - experiment_id: exp_mfls_allele_knockin
    name: Knock-in of a specific human MFLS allele into mouse and rabbit
    description: >-
      Generate models carrying an exact reported human MFLS variant (e.g.
      c.8226+1G>A or p.Arg2726Glufs*9) rather than an engineered truncation, and
      compare microfibril assembly, aortic dimensions, adipose mass, plasma
      asprosin, and glucose/insulin handling against both wild-type and a classic
      Marfan allele in the same background.
  evidence:
  - reference: PMID:29666143
    reference_title: "Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene"
    explanation: The explicit statement that existing FBN1 mouse models do not model this entity.
  - reference: PMID:35759435
    reference_title: "Male Marfan mice are predisposed to high-fat diet-induced obesity, diabetes, and fatty liver."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the data demonstrate that male mice of both the MFS models are susceptible to HFD-induced obesity and diabetes"
    explanation: >-
      Illustrates that the metabolic phenotype of classic Marfan mouse models runs
      opposite to the human MFLS phenotype, reinforcing the mismatch.
- discussion_id: mfls_lipodystrophy_mechanism_split
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Congenital Generalized Lipodystrophy and Extreme Leanness
  prompt: >-
    How much of the congenital lipodystrophy is caused by hypophagia secondary to
    asprosin deficiency, and how much by a cell-autonomous failure of adipocyte
    differentiation in a fibrillin-1-deficient extracellular-matrix niche?
  rationale: >-
    Three routes are on the table and the literature has not separated them. The
    hypophagia route is well evidenced in patients and rescued in the mouse. A
    cell-autonomous adipogenic route rests on expression dynamics (fibrillin-1
    rises as mesenchymal stem cells enter adipogenesis and declines as adipocytes
    mature) and on the conservation of the affected FBN1 region; the authors who
    proposed it state explicitly that a differentiation failure still needs to be
    shown experimentally. A third route proposed in review is purely mechanical —
    that deficient microfibrils change the mechanical properties of the adipose
    matrix, making it non-permissive for adipocyte expansion, independently of
    both appetite and TGF-beta. The distinction is therapeutically consequential:
    if hypophagia dominates, asprosin replacement or caloric support could restore
    adipose mass, whereas a cell-autonomous or matrix-mechanical block would not
    respond.
  proposed_experiments:
  - experiment_id: exp_mfls_adipogenesis_ipsc
    name: Patient-derived iPSC or preadipocyte adipogenic differentiation assay
    description: >-
      Differentiate MFLS patient-derived mesenchymal stem cells or preadipocytes to
      adipocytes in vitro, where caloric intake is not a variable, and compare lipid
      accumulation and adipogenic marker induction against isogenic corrected
      controls and against classic Marfan (NMD-degraded allele) cells.
  - experiment_id: exp_mfls_pairfeed_repletion
    name: Pair-feeding and asprosin-repletion in the Fbn1(NPS/+) mouse
    description: >-
      Determine what fraction of the fat-mass deficit is recovered by matching
      caloric intake to wild-type littermates, or by chronic asprosin repletion,
      versus what fraction persists — the residual being attributable to a
      cell-autonomous or matrix-mechanical adipogenic defect.
  evidence:
  - reference: PMID:27386756
    reference_title: "Expression of FBN1 during adipogenesis: Relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "may fail to differentiate adipocytes and/or to accumulate adipocyte lipids, although this still needs to be shown experimentally"
    explanation: The authors themselves flag the adipogenic mechanism as unproven, which is the gap.
  - reference: PMID:32279186
    reference_title: "Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils."
    explanation: >-
      Lists the competing candidate causes of adipose dysfunction as unresolved
      possibilities, including the matrix-mechanical route.
- discussion_id: mfls_aortic_dissection_risk
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Progressive Aortic Root Dilation
  prompt: >-
    Is the lifetime risk of aortic dissection in MFLS the same as, lower than, or
    higher than in classic Marfan syndrome?
  rationale: >-
    Aortic root dilation is documented in MFLS and this entry conforms to the
    aortopathy module's dilation node, but no dissection has been reported, and at
    least one molecularly confirmed patient had a normal aortic root through nine
    years of follow-up. With fewer than a few dozen molecularly confirmed patients,
    most reported in childhood or early adulthood, absence of reported dissection
    carries almost no information. Because the allelic mechanism differs from
    classic Marfan syndrome (NMD-escaping neomorphic protein rather than
    haploinsufficiency), the aortic risk cannot simply be assumed equal, in either
    direction. This is why the entry deliberately does not conform to the module's
    dissection node.
  proposed_experiments:
  - experiment_id: exp_mfls_aortic_registry
    name: International MFLS registry with prospective aortic imaging
    description: >-
      Assemble all molecularly confirmed 3'-FBN1 truncation patients into a
      registry with standardized serial aortic root z-score imaging, and compare
      dilation trajectories against age- and sex-matched classic Marfan cohorts.
  evidence:
  - reference: PMID:26860060
    reference_title: "Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We review six previous reports between 2000 and 2014 of seven unrelated patients"
    explanation: The tiny denominator is what makes the aortic natural history unknown.
  - reference: PMID:37845262
    reference_title: "A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showing stable mild mitral regurgitation without dilation of the aortic root"
    explanation: A molecularly confirmed patient with no aortic involvement, showing the variability that the registry would have to resolve.
notes: >-
  Nomenclature is unusually tangled for this entity and matters when searching the
  literature. The same disorder appears as marfanoid-progeroid-lipodystrophy
  syndrome (MPL/MPLS, the name proposed in the 2016 review), Marfan lipodystrophy
  syndrome (MFLS, the OMIM 616914 title), progeroid and marfanoid
  aspect-lipodystrophy syndrome (the MONDO/Orphanet label), marfanoid-progeroid
  syndrome (proposed in 2013), and — throughout the asprosin literature — simply
  "neonatal progeroid syndrome (NPS)". That last usage is a genuine hazard: NPS is
  also the name of Wiedemann-Rautenstrauch syndrome, a distinct disorder, and the
  asprosin papers cite OMIM:264090 (Wiedemann-Rautenstrauch) alongside
  OMIM:616914. Every piece of evidence in this entry drawn from a paper that says
  "NPS" was checked to be about patients with 3' FBN1 truncating variants
  specifically.

  Exon numbering is a second trap. The earlier case reports and the 2016 naming
  review put the causal frameshifts in "exon 64", the penultimate exon; the
  asprosin papers and the 2023 Japanese case report, using NM_000138.5, describe
  the same region as exons 65-66 with the splice variants in intron 65. Both refer
  to the same 71 bp of 3'-terminal coding sequence. This entry describes the
  region positionally and quotes each source in its own convention.

  "Generalized" versus "partial" lipodystrophy is a genuine and unresolved split
  in the sources, and this entry takes a side. The original case reports describe
  "pronounced generalized lipodystrophy" (PMID:20979188) and "severe congenital
  lipodystrophy" (PMID:24039054), and the entry follows them in binding
  HP:0009059 Congenital generalized lipodystrophy. But the asprosin papers
  consistently say partial: PMID:27087445 describes NPS as "congenital, partial
  lipodystrophy, predominantly affecting the face and extremities", and
  PMID:29106398's phrase "maintenance of insulin sensitivity despite partial
  lipodystrophy" is quoted verbatim as evidence in this entry — for the insulin
  claim, not the distribution claim. The generalized reading was chosen because
  the entity-defining clinical reports use it and because whole-body measures
  (BMI 12.6, body fat 9.4%) are not consistent with a purely regional deficit;
  a curator who disagrees should note that HP:0009064 Generalized lipodystrophy
  and the parent HP:0009125 Lipodystrophy are both available as hedges.

  A third point of care: "progeroid" here describes facial appearance, not
  systemic accelerated aging. Both the group that discovered asprosin and the 2023
  case report state plainly that the appearance of premature aging is a
  consequence of low subcutaneous fat. The entry therefore does not conform to any
  accelerated-aging or senescence module, and no premature-aging phenotype
  (premature greying, scleroderma-like skin, hypogonadism) is curated, because
  these were explicitly looked for and absent in the index patient.

  Frequency bands are asserted for exactly two phenotypes — congenital
  generalized lipodystrophy and the progeroid facial appearance — because the
  2016 defining review states both were present in all seven of its patients,
  which is a real count with a real denominator. Every other phenotype here
  deliberately carries NO `frequency:`. The published series is roughly seven to
  nine molecularly confirmed patients; most reports do not state which
  investigations were performed, so a feature seen in one report has an unknown
  denominator rather than a small one, and features requiring a specific test
  (echocardiography, cranial CT, slit-lamp examination) are systematically
  under-ascertained. Per docs/frequency-evidence-guidelines.md, omitting the band
  is correct here rather than converting "reported once" into an enum value the
  arithmetic does not support.

  No GeneReviews chapter exists for MFLS itself — PubMed searches for "marfanoid
  progeroid lipodystrophy GeneReviews", "Marfan lipodystrophy syndrome
  GeneReviews", and "lipodystrophy GeneReviews[TI]" all returned nothing. The
  FBN1-Related Marfan Syndrome chapter (PMID:20301510) is recorded in the
  top-level references as the nearest expert-curated baseline; it covers the
  differential rather than this entity, so its Clinical Characteristics were NOT
  used as a phenotype baseline for MFLS.
references:
- reference: PMID:20301510
  title: "FBN1-Related Marfan Syndrome."
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:20301510

FBN1-Related Marfan Syndrome.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 14 citations 2026-08-17T09:21:18.316287

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Marfanoid-Progeroid-Lipodystrophy Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Marfanoid-Progeroid-Lipodystrophy Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

COMPREHENSIVE RESEARCH REPORT: MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

1. DISEASE INFORMATION

Overview

Marfanoid-Progeroid-Lipodystrophy Syndrome (MFLS) is an extremely rare autosomal dominant genetic disorder characterized by the triad of marfanoid features, progeroid (prematurely aged) appearance, and generalized or severe partial lipodystrophy (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, toriello2019prematureageingsyndromes pages 12-13). The syndrome represents a distinct fibrillinopathy caused by specific mutations in the extreme C-terminal region of the FBN1 gene (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, moriwaki2023acaseof pages 1-2).

Key Identifiers

OMIM ID: #616914 (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33)
MONDO ID: Not explicitly provided in available evidence
Category: Mendelian disorder; Type I fibrillinopathy; Lipodystrophy-associated progeroid syndrome
ICD-10/ICD-11: Not specifically documented in available literature
MeSH: Not explicitly documented

Synonyms and Alternative Names

MFLS
Marfanoid Progeria-Lipodystrophy Syndrome (toriello2019prematureageingsyndromes pages 12-13)
Neonatal Progeroid Syndrome (when presenting in neonatal period) (muthu2020fibrillin1andfibrillin1derived pages 1-2)
Marfanoid-progeroid syndrome (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, moriwaki2023acaseof pages 2-4)

Data Source

Information is derived from aggregated disease-level resources including case reports, clinical case series, and molecular characterization studies published between 2014-2024, with approximately 8 patients documented in the literature through 2022 (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33, moriwaki2023acaseof pages 2-4).

2. ETIOLOGY

Disease Causal Factors

Genetic Cause: MFLS is caused by heterozygous pathogenic variants in the FBN1 gene (HGNC:3603; OMIM *134797), which encodes fibrillin-1, a 2,871-amino-acid glycoprotein that is an essential component of extracellular microfibrils (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22).

Specific Mutation Characteristics: - Mutations occur between exons 64 and 65 of FBN1, located in the 3' gene regions encoding the extreme C-terminal domains of fibrillin-1 (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - Variants are located in the last 50 nucleotides of the final exon boundary, typically in exons 65-66 or intron 65 (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - All documented variants produce premature termination codons that escape nonsense-mediated decay (NMD), resulting in truncated fibrillin-1 protein rather than haploinsufficiency (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, moriwaki2023acaseof pages 1-2)

Documented FBN1 Variants: | Variant type | Specific nucleotide change | Exon/intron location | Molecular consequence | NMD escape confirmed? | |---|---|---|---|---| | Exonic | Not individually specified in available evidence (5 total exonic insertion/deletion variants across reported cases) | Exon 65 or exon 66, near 3' terminus of FBN1 | Frameshift leading to premature termination codon; predicted truncated profibrillin/fibrillin-1; associated with MFLS | Predicted in silico for 5 exonic variants; not experimentally confirmed in the available evidence (moriwaki2023acaseof pages 2-4, moriwaki2023acaseof pages 1-2) | | Intronic | c.8226+1G>A | Intron 65 | Exon 65 skipping causing frameshift and premature termination codon | Exon 65 skipping experimentally confirmed in a prior case; direct NMD escape not confirmed in the available evidence for that prior case (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) | | Intronic | c.8226+1G>T | Intron 65 | Presumed splice disruption with exon 65 skipping/frameshift leading to premature termination codon | Not confirmed in the available evidence; reported in 2 cases (moriwaki2023acaseof pages 2-4) | | Intronic | c.8226+5G>A | Intron 65 | Exon 65 skipping, frameshift, mutant transcript retained | Yes; first experimental confirmation of both exon 65 skipping and escape from nonsense-mediated decay in clinical MFLS sample (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) | | Aggregate MFLS variant class | Variants between exons 64 and 65 / extreme C-terminal region | 3' region encoding extreme C-terminal domains of fibrillin-1 | Premature stop codons that escape NMD, producing truncated fibrillin-1/profibrillin and loss of normal asprosin-related C-terminal function | Supported at syndrome level; direct experimental proof available for c.8226+5G>A case (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, moriwaki2023acaseof pages 2-4) |

Table: This table summarizes the reported FBN1 variant classes and specific intronic changes associated with Marfanoid-Progeroid-Lipodystrophy Syndrome, emphasizing their 3′-terminal localization, splice/frameshift consequences, and current evidence for nonsense-mediated decay escape.

Among the 8 reported cases through 2022: - Five cases had exonic insertion or deletion variants causing frameshifts in exon 65 or 66 of FBN1 (moriwaki2023acaseof pages 2-4) - Three cases had intronic single-nucleotide substitutions: c.8226+1G>A (1 case), c.8226+1G>T (2 cases), and c.8226+5G>A (1 case with experimental confirmation of exon 65 skipping and NMD escape) (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4)

Risk Factors

Genetic Risk Factors: - De novo mutations: Most cases appear to arise from de novo mutations, as exemplified in a 2023 case report where the heterozygous c.8226+5G>A variant was confirmed as a de novo occurrence (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - Inheritance pattern: Autosomal dominant (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33) - No ethnic or sex predisposition documented: Available evidence does not indicate specific ethnic or sex-related risk factors

Environmental Risk Factors: No environmental risk factors have been identified for MFLS, consistent with its genetic etiology.

Protective Factors

No protective genetic or environmental factors have been identified in the literature.

Gene-Environment Interactions

Not applicable; MFLS is a monogenic Mendelian disorder with no documented gene-environment interactions.

3. PHENOTYPES

The clinical phenotype of MFLS combines features of three domains: marfanoid characteristics, progeroid appearance, and lipodystrophy, with variable penetrance and severity across individuals (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4).

Organ system	Specific clinical features	Onset timing	Severity / variability	Suggested HPO terms	Key evidence
Growth / anthropometric	Fetal growth retardation; intrauterine growth restriction; low birth weight; preterm birth; accelerated linear growth disproportionate to weight gain; tall stature in childhood; low BMI / reduced body fat percentage	Prenatal to neonatal; tall stature becomes evident in childhood	Core and frequent in reported cases; growth pattern appears characteristic but absolute height varies	HP:0001511 Intrauterine growth restriction; HP:0001518 Small for gestational age; HP:0001513 Obesity not applicable / reduced adiposity better captured elsewhere; HP:0004322 Short stature not typical; HP:0000098 Tall stature; HP:0004324 Abnormality of body weight; HP:0000256 Macrocephaly when present	(moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4, toriello2019prematureageingsyndromes pages 12-13)
Metabolic / adipose	Generalized lack of subcutaneous fat; severe partial lipodystrophy / generalized lipodystrophy; poor appetite; reduced facial fat producing progeroid appearance; low body fat percentage	Congenital / neonatal, persists through childhood	Hallmark feature; severity appears high, but distribution may range from generalized to severe partial lipodystrophy in reports	HP:0009125 Lipodystrophy; HP:0001012 Generalized lipodystrophy; HP:0000280 Sparse subcutaneous fat; HP:0011968 Reduced subcutaneous adipose tissue; HP:0004396 Poor appetite	(moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4, toriello2019prematureageingsyndromes pages 12-13)
Craniofacial / progeroid appearance	Progeroid facial appearance due to loss of facial fat; dolichocephaly; prominent forehead; narrow nasal ridge; mild retrognathia / micrognathia; high-arched palate; possible craniosynostosis spectrum in some cases	Neonatal to infancy	Distinctive but variable; craniosynostosis appears uncommon/rare; dolichocephaly and frontal prominence recur across reports	HP:0000268 Dolichocephaly; HP:0011220 Prominent forehead; HP:0000445 Narrow nose / narrow nasal ridge; HP:0000278 Retrognathia; HP:0000218 High palate; HP:0000347 Micrognathia; HP:0005484 Prematurely aged appearance	(moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4, toriello2019prematureageingsyndromes pages 12-13)
Skeletal / connective tissue	Long fingers / arachnodactyly; positive wrist and thumb signs; hyperextensible finger joints / joint hypermobility; joint contractures in some reports; pes planus; marfanoid habitus	Usually recognized in infancy or childhood	Common but variably expressed; some patients show hypermobility, others contractures; overlap with Marfan-spectrum features is incomplete	HP:0001166 Arachnodactyly; HP:0001382 Joint hypermobility; HP:0001371 Flexion contracture; HP:0001763 Pes planus; HP:0001519 Marfanoid habitus	(moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13)
Ocular	Severe myopia / myopic astigmatism; lens dislocation / ectopia lentis variably present or absent; bilateral entropion with corneal epithelial damage in a rare case	Early childhood; entropion recognized neonatally in one case	Ocular involvement is variable; severe myopia is recurrent; ectopia lentis not universal; entropion appears rare	HP:0000545 Myopia; HP:0001083 Ectopia lentis; HP:0001133 Astigmatism; HP:0001137 Entropion; HP:0000480 Corneal epithelial defect / corneal abnormality	(moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4, toriello2019prematureageingsyndromes pages 12-13)
Cardiovascular	Mild mitral regurgitation; aortic root dilatation variably reported; some cases have normal aortic root diameter in childhood	Childhood	Important but inconsistent; seems less uniform than in classic Marfan syndrome, so surveillance is warranted even when early imaging is normal	HP:0001653 Mitral regurgitation; HP:0002616 Aortic root dilatation	(moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4, toriello2019prematureageingsyndromes pages 12-13)
Dermatologic / external appearance	Thin appearance from lipoatrophy; aged facial appearance; reduced subcutaneous tissue rather than primary skin disease	Congenital / early infancy	Usually secondary to fat loss; explicit skin pathology less well described than in other progeroid syndromes	HP:0000986 Thin skin when present; HP:0000282 Facial skin changes secondary to lipoatrophy; HP:0005484 Prematurely aged appearance	(moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4, toriello2019prematureageingsyndromes pages 12-13)
Neurodevelopment / function	Psychomotor development within normal range; cognition/intellectual development usually normal	Infancy through childhood follow-up	Available reports suggest preserved development, but case numbers are very small	HP:0001263 Global developmental delay absent in reported case; HP:0012759 Neurodevelopmental abnormality not established	(moriwaki2023acaseof pages 1-2, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22)
Multisystem summary / syndrome-defining pattern	Combination of congenital lipodystrophy, progeroid appearance, premature birth or fetal growth restriction, and variable Marfan-like skeletal/ocular/cardiovascular manifestations	Prenatal onset with lifelong course	Extremely rare; only a small number of patients reported, so penetrance of individual features remains uncertain	HP:0009125 Lipodystrophy; HP:0005484 Prematurely aged appearance; HP:0001519 Marfanoid habitus; HP:0001511 Intrauterine growth restriction	(moriwaki2023acaseof pages 2-4, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33)

Table: This table organizes the reported clinical phenotype of Marfanoid-Progeroid-Lipodystrophy Syndrome by organ system, including timing, variability, and suggested HPO mappings. It is useful for disease knowledge base curation and structured phenotype annotation.

Core Phenotypic Features

Growth and Anthropometry: - Intrauterine growth restriction (IUGR): Fetal growth retardation with cessation around 32 weeks gestation has been documented (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - HPO: HP:0001511 (Intrauterine growth retardation) - Low birth weight: Characteristic feature; one documented case had birth weight of 1,556 g at 35 weeks gestation (-2.6 SD) (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2) - HPO: HP:0001518 (Small for gestational age) - Preterm birth: Birth before 40 weeks (moriwaki2023acaseof pages 1-2) - Tall stature in childhood: Accelerated linear growth disproportionate to weight gain; one case reached height of 151.6 cm (+2.8 SD) at age 9 years 7 months (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - HPO: HP:0000098 (Tall stature)

Metabolic/Adipose Features (Hallmark): - Generalized lipodystrophy: Severe lack of subcutaneous fat present from birth, representing the most consistent phenotypic feature (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2) - HPO: HP:0009125 (Lipodystrophy), HP:0001012 (Generalized lipodystrophy) - Reduced facial fat: Loss of facial subcutaneous tissue creates the characteristic progeroid (prematurely aged) facial appearance (toriello2019prematureageingsyndromes pages 12-13) - HPO: HP:0000280 (Sparse subcutaneous fat), HP:0011968 (Reduced subcutaneous adipose tissue) - Poor appetite: Documented in at least one case, consistent with asprosin deficiency (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - HPO: HP:0004396 (Poor appetite) - Low body fat percentage: One case documented 9.4% body fat with BMI of 12.6 kg/m² (moriwaki2023acaseof pages 1-2)

Craniofacial/Progeroid Features: - Dolichocephaly: Elongated skull shape (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - HPO: HP:0000268 (Dolichocephaly) - Prominent forehead: Recurrent feature (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - HPO: HP:0011220 (Prominent forehead) - Narrow nasal ridge: Characteristic finding (moriwaki2023acaseof pages 1-2) - HPO: HP:0000445 (Narrow nose) - Mild retrognathia/micrognathia: Variable feature (moriwaki2023acaseof pages 1-2) - HPO: HP:0000278 (Retrognathia), HP:0000347 (Micrognathia) - High-arched palate: Present in documented cases (moriwaki2023acaseof pages 1-2) - HPO: HP:0000218 (High palate) - Prematurely aged appearance: Due to lack of facial fat rather than actual accelerated aging (toriello2019prematureageingsyndromes pages 12-13) - HPO: HP:0005484 (Prematurely aged appearance) - Craniosynostosis: Rare but documented in some cases (moriwaki2023acaseof pages 2-4)

Skeletal/Connective Tissue Features (Marfanoid): - Arachnodactyly (long fingers): Consistent finding (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2) - HPO: HP:0001166 (Arachnodactyly) - Positive wrist and thumb signs: Documented in clinical examination (moriwaki2023acaseof pages 1-2) - Joint hypermobility: Mild hyperextensible finger joints described (moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13) - HPO: HP:0001382 (Joint hypermobility) - Joint contractures: Variable feature, some patients show contractures rather than hypermobility (toriello2019prematureageingsyndromes pages 12-13) - HPO: HP:0001371 (Flexion contracture) - Pes planus (flat feet): Documented (moriwaki2023acaseof pages 1-2) - HPO: HP:0001763 (Pes planus) - Marfanoid habitus: Overall body proportions suggestive of Marfan syndrome (moriwaki2023acaseof pages 1-2) - HPO: HP:0001519 (Marfanoid habitus)

Ocular Features: - Severe myopia/myopic astigmatism: Recurrent feature; one case documented -2.5 to -3.0 diopter sphere (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2) - HPO: HP:0000545 (Myopia), HP:0001133 (Astigmatism) - Lens dislocation (ectopia lentis): Variable feature, not universally present (toriello2019prematureageingsyndromes pages 12-13) - HPO: HP:0001083 (Ectopia lentis) - Bilateral entropion: Rare; one case required surgical correction for severe corneal epithelial damage (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - HPO: HP:0001137 (Entropion), HP:0000480 (Corneal epithelial defect)

Cardiovascular Features: - Mild mitral regurgitation: Documented in childhood; stable on follow-up (moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13) - HPO: HP:0001653 (Mitral regurgitation) - Aortic root dilatation: Variably reported; appears less consistent than in classic Marfan syndrome (toriello2019prematureageingsyndromes pages 12-13) - HPO: HP:0002616 (Aortic root dilatation) - Normal aortic root diameter: Some cases show no aortic involvement in childhood (moriwaki2023acaseof pages 2-4)

Neurodevelopment: - Normal psychomotor development: Documented case showed development within normal range, walking without help at 18 months (moriwaki2023acaseof pages 1-2, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - Preserved cognitive function: Available reports suggest intellectual development is typically normal (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22)

Phenotype Onset, Severity, and Progression

Age of Onset: - Prenatal/Congenital: IUGR and lipodystrophy present from birth (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2) - Neonatal recognition: Progeroid appearance and lipodystrophy typically recognized in the neonatal period - Progressive: Some features (cardiovascular, ocular) may manifest or progress during childhood

Severity: - Variable but generally severe lipodystrophy: The lipodystrophic phenotype is consistently marked - Variable marfanoid features: Skeletal and cardiovascular manifestations show incomplete penetrance and variable expressivity - Good overall functional status: Despite dramatic appearance, neurodevelopment and function appear preserved

Frequency Among Affected Individuals: Exact frequencies are difficult to establish given the small number of reported cases (n=8 through 2022), but available data suggest: - Lipodystrophy: Nearly 100% (hallmark feature) - Progeroid appearance: Nearly 100% (secondary to lipodystrophy) - Arachnodactyly: Common (>75%) - Severe myopia: Common (>50%) - Cardiovascular involvement: Variable (25-75%) - Ectopia lentis: Variable (<50%)

Quality of Life Impact

Specific quality-of-life data are not available in the literature for MFLS. However, impacts can be inferred: - Physical appearance: Progeroid appearance may cause psychosocial stress - Feeding difficulties: Poor appetite may complicate nutrition - Visual impairment: Severe myopia may require corrective lenses from early childhood - Surgical interventions: Some patients require surgery (e.g., entropion correction) - Chronic monitoring: Lifelong cardiovascular surveillance is necessary - Normal cognitive function: Preserved intellect likely supports better overall quality of life compared to other progeroid syndromes

4. GENETIC/MOLECULAR INFORMATION

Causal Gene

Gene: FBN1 (Fibrillin-1) - Chromosomal Location: 15q21.1 - OMIM Gene ID: 134797 - HGNC ID: HGNC:3603 - Gene Size: Approximately 230 kb with 65 coding exons (muthu2020fibrillin1andfibrillin1derived pages 1-2) - Encoded Protein:* Profibrillin, a 2,871-amino-acid proprotein that is proteolytically cleaved near its C-terminus by furin convertase to produce fibrillin-1 and the 140-amino-acid hormone asprosin (muthu2020fibrillin1andfibrillin1derived pages 1-2)

Pathogenic Variants

Variant Classification: All documented MFLS variants are classified as pathogenic based on: - Segregation with disease phenotype - Location in a critical functional domain (C-terminal region) - Predicted and/or experimentally confirmed molecular consequences (frameshift, NMD escape) - Consistent phenotypic manifestations across multiple unrelated cases (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4)

Variant Type/Class: - Intronic splice-site variants: c.8226+5G>A, c.8226+1G>A, c.8226+1G>T causing exon 65 skipping (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - Exonic insertions/deletions: Five reported frameshift mutations in exons 65-66 (moriwaki2023acaseof pages 2-4)

Allele Frequency: Not documented in population databases (gnomAD, 1000 Genomes); all reported variants appear to be ultra-rare or absent from control populations, consistent with severe disease phenotype and de novo occurrence.

Origin: - Germline: All documented cases involve constitutional germline variants (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - De novo: At least one documented case confirmed as de novo (moriwaki2023acaseof pages 1-2)

Functional Consequences: - Loss of normal asprosin production: C-terminal truncation disrupts the asprosin-encoding region, leading to asprosin deficiency (muthu2020fibrillin1andfibrillin1derived pages 6-8, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 12-13, muthu2020fibrillin1andfibrillin1derived pages 1-2) - Dominant-negative effect: Production of truncated fibrillin-1 may interfere with normal fibrillin-1 function in microfibrils (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 2-4) - Escape from nonsense-mediated decay: Variants in the terminal exon escape NMD, allowing production of truncated protein (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4)

Modifier Genes

No modifier genes have been identified for MFLS specifically.

Epigenetic Information

No specific epigenetic mechanisms have been documented for MFLS.

Chromosomal Abnormalities

Not applicable; MFLS results from point mutations or small insertions/deletions, not large-scale chromosomal abnormalities.

5. ENVIRONMENTAL INFORMATION

Environmental Factors

Not applicable; MFLS is a monogenic disorder with no documented environmental contributors.

Lifestyle Factors

No lifestyle factors influence disease occurrence or severity in MFLS.

Infectious Agents

Not applicable to MFLS etiology.

6. MECHANISM / PATHOPHYSIOLOGY

Molecular level	Specific mechanism/pathway	Biological process affected	Molecular consequences in MFLS	Suggested GO terms	Key evidence
Protein	C-terminal FBN1 truncation due to variants near exons/intron 65 that escape nonsense-mediated decay	Extracellular matrix structural organization; profibrillin processing	Production of truncated fibrillin-1 rather than simple haploinsufficiency; altered extreme C-terminal domain and loss/disruption of asprosin-generating region	GO:0030198 extracellular matrix organization; GO:0006508 proteolysis; GO:0005634? not applicable	Variants near the 3' terminus generate premature stop codons that escape NMD and yield truncated fibrillin-1; exon 65 skipping was experimentally confirmed for c.8226+5G>A (moriwaki2023acaseof pages 1-2, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, moriwaki2023acaseof pages 2-4)
Protein	Loss of normal fibrillin-1 microfibril function	Microfibril assembly; elastic fiber formation	Reduced functional microfibrils and compromised extracellular scaffold properties	GO:0001525 angiogenesis; GO:0030199 collagen fibril organization; GO:0072358 cardiovascular system development	Defective fibrillin-1 reduces fully functional microfibrils and disrupts connective-tissue support, contributing to marfanoid manifestations and adipose tissue abnormalities (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 2-4, muthu2020fibrillin1andfibrillin1derived pages 4-6, muthu2020fibrillin1andfibrillin1derived pages 1-2)
Protein/endocrine	Asprosin deficiency from disruption of the C-terminal profibrillin cleavage product	Hormone secretion; glucose homeostasis; appetite regulation	Reduced asprosin is inferred to contribute to poor appetite, low glucose/insulin tone, leanness, and lipodystrophic metabolic state	GO:0042593 glucose homeostasis; GO:2000253 positive regulation of feeding behavior; GO:1904179 positive regulation of gluconeogenesis	Asprosin is a C-terminal fibrillin-1-derived hormone; in MFLS/NPS-like states, loss of this region is linked to hypophagia and extreme leanness, and the 2023 case reported poor appetite (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 12-13, muthu2020fibrillin1andfibrillin1derived pages 1-2, moriwaki2023acaseof pages 1-2)
Cellular	Dysregulated TGF-β bioavailability/signaling secondary to defective fibrillin-1/LTBP interactions	Regulation of TGF-β signaling; osteoblast maturation; adipose development	Increased active TGF-β signaling, with downstream effects on adipogenesis, connective tissue biology, and skeletal development	GO:0007179 transforming growth factor beta receptor signaling pathway; GO:0001649 osteoblast differentiation; GO:0045599 negative regulation of fat cell differentiation	Fibrillin-1 normally regulates TGF-β bioavailability; defective fibrillin-1 increases active TGF-β. Reviews note this likely contributes to bone and fat phenotypes in MFLS (muthu2020fibrillin1andfibrillin1derived pages 2-4, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 1-2)
Cellular	Impaired adipogenesis in white adipose tissue	Adipocyte differentiation; lipid storage cell development	Reduced subcutaneous adipose tissue and severe partial/generalized lipodystrophy	GO:0045444 fat cell differentiation; GO:0050872 white fat cell differentiation; GO:1903444 regulation of adipose tissue development	MFLS is consistently associated with generalized/subcutaneous fat loss; mechanistic reviews link fibrillin-1 defects, altered TGF-β signaling, and asprosin disruption to impaired adipogenesis (muthu2020fibrillin1andfibrillin1derived pages 6-8, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 4-6)
Tissue	Altered extracellular matrix mechanical properties in adipose tissue	Cell-matrix interaction; tissue morphogenesis	Fibrotic/rigid ECM environment around adipocytes that may impede normal adipose expansion and signaling	GO:0031012 extracellular matrix; GO:0009653 anatomical structure morphogenesis; GO:0009611 response to wounding	Reviews suggest altered mechanical properties of fibrillin-deficient ECM may be a major driver of adipose dysfunction, possibly more important than TGF-β alone in explaining reduced body fat (muthu2020fibrillin1andfibrillin1derived pages 4-6)
Tissue	Impaired transport/signaling milieu in adipose tissue	Insulin receptor signaling; nutrient/hormone responsiveness	Mechanical barrier and ECM remodeling may impair glucose/insulin access and downstream signaling, predisposing to insulin signaling defects	GO:0046627 negative regulation of insulin receptor signaling pathway; GO:0006006 glucose metabolic process	Fibrillin-1-related adipose ECM abnormalities are proposed to impair insulin signaling and contribute to metabolic dysfunction in lipodystrophy syndromes (muthu2020fibrillin1andfibrillin1derived pages 12-13, muthu2020fibrillin1andfibrillin1derived pages 4-6)
Systemic	Combined connective tissue and adipose endocrine disorder	Growth, musculoskeletal development, ocular/cardiovascular homeostasis, energy balance	Explains the syndromic triad of marfanoid habitus, progeroid appearance from fat loss, and lipodystrophy with variable Marfan-like ocular/cardiovascular features	GO:0048731 system development; GO:0003013 circulatory system process; GO:0001654 eye development	Clinical phenotype includes fetal growth retardation/prematurity, lack of subcutaneous fat, long fingers, myopia, and variable aortic/mitral findings, consistent with a multisystem fibrillinopathy plus endocrine-metabolic disturbance (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4)
Systemic/model-supported	Asprosin-related energy balance defect demonstrated in animal models of Fbn1 exon 65 junction disruption	Feeding behavior; body weight regulation; diabetes susceptibility	Heterozygous mice show hypophagia, reduced adiposity, and resistance to diet-induced obesity/diabetes; recombinant asprosin rescues hypophagia	GO:2000253 positive regulation of feeding behavior; GO:0042593 glucose homeostasis; GO:0040018 positive regulation of multicellular organism growth	Recent model data support a causal contribution of asprosin deficiency to appetite and adiposity phenotypes relevant to MFLS (summers2024geneticmodelsof pages 6-7)

Table: This table summarizes the main molecular, cellular, tissue, and systemic mechanisms currently implicated in Marfanoid-Progeroid-Lipodystrophy Syndrome. It is useful for linking FBN1 C-terminal variants to extracellular matrix dysfunction, altered TGF-beta signaling, asprosin deficiency, impaired adipogenesis, and the resulting multisystem phenotype.

The pathophysiology of MFLS involves a multi-level cascade from protein dysfunction to systemic metabolic and connective tissue abnormalities (muthu2020fibrillin1andfibrillin1derived pages 6-8, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 12-13, muthu2020fibrillin1andfibrillin1derived pages 2-4, muthu2020fibrillin1andfibrillin1derived pages 4-6).

Molecular Pathways

Extracellular Matrix Organization: Fibrillin-1 is a core structural component of 10-12 nm microfibrils in the extracellular matrix (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22). C-terminal truncation of fibrillin-1 in MFLS: - Reduces functional microfibril assembly (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 2-4, muthu2020fibrillin1andfibrillin1derived pages 4-6) - Compromises elastic fiber formation (muthu2020fibrillin1andfibrillin1derived pages 4-6) - Alters mechanical properties of connective tissues (muthu2020fibrillin1andfibrillin1derived pages 4-6) - GO Terms: GO:0030198 (extracellular matrix organization), GO:0030199 (collagen fibril organization)

TGF-β Signaling Pathway: Fibrillin-1 normally regulates TGF-β bioavailability through interactions with latent TGF-β binding proteins (LTBP-1 and LTBP-4) (muthu2020fibrillin1andfibrillin1derived pages 2-4, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22). Defective fibrillin-1 leads to: - Increased active TGF-β signaling (muthu2020fibrillin1andfibrillin1derived pages 2-4, muthu2020fibrillin1andfibrillin1derived pages 1-2) - Effects on osteoblast maturation and bone development (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - Complex role in adipose tissue: elevated TGF-β signaling may be an unproductive secondary response rather than primary driver of lipodystrophy (muthu2020fibrillin1andfibrillin1derived pages 4-6) - GO Terms: GO:0007179 (transforming growth factor beta receptor signaling pathway)

Asprosin Hormone Pathway: Asprosin, a C-terminal cleavage product of profibrillin, acts as a glucogenic and orexigenic hormone (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 12-13, muthu2020fibrillin1andfibrillin1derived pages 1-2). Loss of asprosin in MFLS results in: - Reduced hepatic glucose production (muthu2020fibrillin1andfibrillin1derived pages 1-2) - Decreased appetite/hypophagia (muthu2020fibrillin1andfibrillin1derived pages 6-8, summers2024geneticmodelsof pages 6-7, moriwaki2023acaseof pages 1-2) - Impaired insulin secretion and signaling (muthu2020fibrillin1andfibrillin1derived pages 12-13) - Extreme leanness and lipodystrophy (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 1-2, summers2024geneticmodelsof pages 6-7) - GO Terms: GO:0042593 (glucose homeostasis), GO:2000253 (positive regulation of feeding behavior)

Cellular Processes

Impaired Adipogenesis: Multiple mechanisms contribute to failure of adipocyte differentiation and maintenance (muthu2020fibrillin1andfibrillin1derived pages 6-8, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 4-6): - Altered extracellular matrix mechanical properties create a non-permissive environment for adipocyte expansion (muthu2020fibrillin1andfibrillin1derived pages 4-6) - Dysregulated TGF-β signaling affects adipocyte differentiation (muthu2020fibrillin1andfibrillin1derived pages 2-4) - Asprosin deficiency impacts fat development (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 1-2) - GO Terms: GO:0045444 (fat cell differentiation), GO:0050872 (white fat cell differentiation)

Fibrosis and ECM Remodeling: Fibrillin-1 deficiency leads to: - Increased collagen deposition in adipose tissue (muthu2020fibrillin1andfibrillin1derived pages 4-6) - Fibrotic extracellular matrix environment (muthu2020fibrillin1andfibrillin1derived pages 4-6) - Altered angiogenesis (muthu2020fibrillin1andfibrillin1derived pages 4-6) - Mechanical barrier to insulin and nutrient transport (muthu2020fibrillin1andfibrillin1derived pages 12-13, muthu2020fibrillin1andfibrillin1derived pages 4-6) - GO Terms: GO:0009611 (response to wounding), GO:0031012 (extracellular matrix)

Insulin Signaling Defects: Abnormal ECM and asprosin deficiency contribute to: - Impaired insulin receptor signaling (muthu2020fibrillin1andfibrillin1derived pages 12-13, muthu2020fibrillin1andfibrillin1derived pages 4-6) - Reduced glucose and insulin access to adipocytes (muthu2020fibrillin1andfibrillin1derived pages 4-6) - Metabolic dysfunction despite severe lipodystrophy - GO Terms: GO:0046627 (negative regulation of insulin receptor signaling pathway)

Protein Dysfunction

Truncated Fibrillin-1: C-terminal variants produce a truncated profibrillin/fibrillin-1 protein lacking: - Normal extreme C-terminal domains (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - The asprosin peptide sequence (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 1-2) - Proper C-terminal propeptide for secretion and assembly (muthu2020fibrillin1andfibrillin1derived pages 12-13)

Escape from Nonsense-Mediated Decay: The 2023 functional study provided the first experimental proof that mutant transcripts with premature termination codons in the terminal exon escape NMD, allowing production of truncated protein rather than simple haploinsufficiency (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4).

Metabolic Changes

Energy Balance Disruption: - Reduced appetite due to asprosin deficiency (summers2024geneticmodelsof pages 6-7, moriwaki2023acaseof pages 1-2) - Altered hepatic glucose production (muthu2020fibrillin1andfibrillin1derived pages 1-2) - Extreme leanness with very low BMI and body fat percentage (moriwaki2023acaseof pages 1-2)

Lipid Metabolism: - Severe reduction in subcutaneous white adipose tissue (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 4-6) - Impaired lipid storage capacity (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - Potential for ectopic lipid deposition (inferred from general lipodystrophy mechanisms)

Tissue Damage Mechanisms

Adipose Tissue: - Loss of subcutaneous fat through impaired adipogenesis and adipocyte maintenance (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 4-6) - Fibrotic remodeling of remaining adipose tissue (muthu2020fibrillin1andfibrillin1derived pages 4-6)

Connective Tissue: - Altered mechanical properties affecting multiple organ systems (muthu2020fibrillin1andfibrillin1derived pages 4-6) - Compromised structural support in skeletal, cardiovascular, and ocular tissues

Causal Chain Summary

Primary Trigger: FBN1 C-terminal mutation → Truncated fibrillin-1 protein + Asprosin deficiency

Upstream Mechanisms: 1. Defective microfibril assembly 2. Loss of asprosin hormone 3. Dysregulated TGF-β bioavailability

Intermediate Effects: 1. Altered ECM mechanical properties 2. Increased active TGF-β signaling 3. Reduced appetite and metabolic signaling 4. Impaired adipocyte differentiation

Downstream Consequences: 1. Generalized lipodystrophy 2. Marfanoid skeletal manifestations 3. Variable ocular and cardiovascular features 4. Progeroid appearance (secondary to fat loss)

Cell Types Involved: - Adipocytes (CL:0000136): Primary target, with impaired differentiation and maintenance - Fibroblasts (CL:0000057): Produce abnormal fibrillin-1 and contribute to ECM remodeling - Osteoblasts (CL:0000062): Affected by TGF-β dysregulation - Vascular smooth muscle cells (CL:0000359): Involved in cardiovascular manifestations - Lens epithelial cells (CL:0002224): Involved in ocular manifestations

7. ANATOMICAL STRUCTURES AFFECTED

Organ Level

Primary Organs Directly Affected:

Subcutaneous Adipose Tissue (UBERON:0002190): - Severe generalized or partial lipodystrophy represents the hallmark feature (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - Facial adipose tissue prominently affected, producing progeroid appearance - White adipose tissue (UBERON:0015143) specifically impaired

Skeletal System (UBERON:0001434): - Long bones showing marfanoid proportions with tall stature and long fingers (moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13) - Joints affected with variable hypermobility or contractures (moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13) - Skull with dolichocephaly (moriwaki2023acaseof pages 1-2)

Eye (UBERON:0000970): - Severe myopia affecting vision (moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13) - Variable lens involvement with ectopia lentis in some cases (toriello2019prematureageingsyndromes pages 12-13) - Cornea (UBERON:0000964) involved in rare entropion cases (moriwaki2023acaseof pages 1-2)

Cardiovascular System (UBERON:0004535): - Heart valves, particularly mitral valve (UBERON:0002135), with regurgitation (moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13) - Aortic root (UBERON:0004145) with variable dilatation (toriello2019prematureageingsyndromes pages 12-13)

Secondary Organ Involvement: - Placenta: Suggested by fetal growth restriction and early growth cessation (moriwaki2023acaseof pages 1-2) - Skin (UBERON:0002097): Thin appearance secondary to loss of subcutaneous fat

Body Systems Involved: - Endocrine/metabolic system: Adipose tissue as an endocrine organ; asprosin hormone deficiency - Musculoskeletal system: Bone, joint, and connective tissue manifestations - Cardiovascular system: Valve and aortic involvement - Visual system: Ocular manifestations

Tissue and Cell Level

Tissue Types Affected:

Adipose Tissue (UBERON:0001013): - White adipose tissue (UBERON:0015143) severely reduced - Subcutaneous adipose tissue (UBERON:0002190) primarily affected - Cell Types: Adipocytes (CL:0000136), preadipocytes (CL:0002334)

Connective Tissue Proper (UBERON:0002384): - Extracellular matrix (GO:0031012) with defective microfibrils - Cell Types: Fibroblasts (CL:0000057) producing abnormal fibrillin-1

Bone Tissue (UBERON:0002481): - Long bones with altered growth patterns - Cell Types: Osteoblasts (CL:0000062) affected by TGF-β dysregulation

Vascular Tissue: - Arterial wall (UBERON:0002061) in aorta and other vessels - Cell Types: Vascular smooth muscle cells (CL:0000359)

Ocular Tissue: - Lens (UBERON:0000965) with variable displacement - Retina (UBERON:0000966) affected by severe myopia - Cell Types: Lens epithelial cells (CL:0002224)

Subcellular Level

Cellular Compartments Involved:

Extracellular Matrix (GO:0031012): - Primary site of fibrillin-1 function - Microfibril assembly occurs in extracellular space - GO Terms: GO:0031012 (extracellular matrix), GO:0001527 (microfibril)

Endoplasmic Reticulum (GO:0005783): - Site of fibrillin-1 synthesis and initial folding - ER stress may be involved in asprosin deficiency-related insulin signaling defects (muthu2020fibrillin1andfibrillin1derived pages 12-13) - GO Terms: GO:0005783 (endoplasmic reticulum)

Secretory Pathway (GO:0016192): - Involved in fibrillin-1 processing and secretion - Furin-mediated cleavage of profibrillin occurs in secretory pathway - GO Terms: GO:0016192 (vesicle-mediated transport)

Localization

Anatomical Sites (UBERON Terms): - Facial region (UBERON:0001456): Prominent lipodystrophy producing progeroid appearance - Upper limb (UBERON:0002102): Arachnodactyly and joint findings - Thorax (UBERON:0000915): Cardiovascular manifestations - Orbital region (UBERON:0001697): Ocular manifestations

Lateralization: - Bilateral involvement: Ocular features, skeletal features, lipodystrophy are bilaterally symmetric - No reported asymmetry: Available case reports do not describe lateralized manifestations

8. TEMPORAL DEVELOPMENT

Onset

Typical Age of Onset: - Congenital/Prenatal: Intrauterine growth restriction documented during prenatal period (moriwaki2023acaseof pages 1-2) - Neonatal recognition: Low birth weight, lipodystrophy, and progeroid appearance present at birth (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2) - Category: Congenital disorder with manifestations evident from birth

Onset Pattern: - Chronic: Lipodystrophy persists throughout life - Progressive: Some features (cardiovascular, ocular) may manifest or progress during childhood - Insidious for some features: Cardiovascular complications may develop gradually

Progression

Disease Stages: Formal staging systems do not exist for MFLS. Clinical course can be conceptualized as:

Early Stage (Prenatal-Neonatal): - IUGR and growth restriction - Low birth weight - Generalized lipodystrophy present at birth - Progeroid appearance evident

Childhood Stage: - Accelerated linear growth with tall stature - Marfanoid skeletal features become more apparent - Ocular manifestations (severe myopia) recognized - Cardiovascular findings may emerge or progress - Normal neurodevelopmental milestones achieved

Late Childhood/Adolescence/Adulthood: - Continued lipodystrophy - Cardiovascular surveillance ongoing - Long-term outcomes documented to at least age 27 (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33)

Progression Rate: - Variable: Different organ systems progress at different rates - Lipodystrophy: Persistent and non-progressive (stable severity after initial presentation) - Cardiovascular: May be progressive, requiring ongoing monitoring - Skeletal: Growth-related changes stabilize after skeletal maturity

Disease Course Pattern: - Chronic: Lifelong condition - Non-remitting: No spontaneous remissions documented - Stable neurodevelopment: Cognitive function preserved (moriwaki2023acaseof pages 1-2, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22)

Disease Duration: - Chronic lifelong: No evidence of self-limitation - Survival documented to adulthood: At least to age 27 years in reported cohort (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33)

Patterns

Remission Patterns: Not applicable; MFLS does not show remission patterns.

Critical Periods: - Prenatal period: Time of IUGR and initial manifestation - Neonatal period: Recognition of lipodystrophy and progeroid features - Early childhood: Period when cardiovascular complications may emerge; important for initiating surveillance - Growth period: Skeletal manifestations become more pronounced with growth

9. INHERITANCE AND POPULATION

Epidemiology

Prevalence: - Extremely rare: Estimated prevalence <1/1,000,000 based on limited case reports (marelli2023marfansyndromeenhanced pages 22-23) - Only approximately 8 patients documented in the literature through 2022 (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33, moriwaki2023acaseof pages 2-4)

Incidence: Not documented due to extreme rarity; insufficient data to calculate incidence rate.

Geographic Distribution: - Cases reported from multiple countries including Japan, Europe, and other regions - No apparent geographic clustering - Appears to be pan-ethnic based on limited available data

For Genetic Etiology

Inheritance Pattern: - Autosomal dominant (AD): All documented cases follow AD inheritance or represent de novo occurrences (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33) - De novo mutations common: At least one case confirmed as de novo (moriwaki2023acaseof pages 1-2)

Penetrance: - Complete penetrance likely: All individuals with documented pathogenic variants manifest disease features - Variable expressivity: Severity and specific features vary among affected individuals, particularly cardiovascular and ocular manifestations (toriello2019prematureageingsyndromes pages 12-13)

Expressivity: - Variable: Marfanoid features, cardiovascular involvement, and ocular findings show variable expression - Consistent core phenotype: Lipodystrophy and progeroid appearance appear consistent across all cases

Genetic Anticipation: Not documented; insufficient multigenerational data available.

Germline Mosaicism: Not documented in available literature.

Founder Effects: No founder effects identified; all reported variants appear to be sporadic or family-specific.

Consanguinity Role: Not applicable; MFLS is autosomal dominant, not requiring consanguinity.

Carrier Frequency: Not applicable for dominant conditions in the traditional sense; extremely rare in general population.

Population Demographics

Affected Populations: - No specific ethnic or demographic groups with higher prevalence identified - Cases reported across different ethnic backgrounds

Sex Ratio: - Available case reports include both males and females - No apparent sex bias documented - Equal susceptibility expected for autosomal dominant inheritance

Age Distribution of Affected Individuals: - Documented age range: 3-27 years in 2022 literature review (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33) - One detailed 2023 case report documented a 9-year-7-month-old patient (moriwaki2023acaseof pages 1-2) - Onset: Prenatal/congenital - Survival to adulthood documented

10. DIAGNOSTICS

Clinical Tests

Laboratory Tests: Standard biochemical testing is not diagnostic but may reveal metabolic abnormalities secondary to lipodystrophy: - Glucose homeostasis assessment - Lipid profile evaluation - Liver function tests (to assess for hepatic steatosis, common in lipodystrophies) - Insulin and C-peptide levels (may be affected)

Biomarkers: - Asprosin levels: Likely reduced in MFLS patients given C-terminal FBN1 truncation, though not routinely measured clinically (muthu2020fibrillin1andfibrillin1derived pages 6-8, muthu2020fibrillin1andfibrillin1derived pages 1-2, summers2024geneticmodelsof pages 6-7)

Imaging Studies: - Echocardiography: Essential for assessing mitral valve function and aortic root diameter; should be performed at diagnosis and periodically thereafter (moriwaki2023acaseof pages 1-2, marelli2023marfansyndromeenhanced pages 22-23) - Skeletal radiography: May document skeletal proportions and marfanoid features - Brain MRI: May be considered if neurological concerns arise - Ophthalmologic examination: Comprehensive eye exam including assessment for myopia, lens position, and corneal abnormalities (moriwaki2023acaseof pages 1-2)

Functional Tests: - Cardiovascular: Echocardiography (LOINC 34552-0) for structural and functional assessment

Pathology Findings: Not routinely obtained; skin or adipose tissue biopsy is not standard for diagnosis.

Genetic Testing

Overview: Genetic confirmation requires identification of a pathogenic variant in the FBN1 gene, specifically in the extreme C-terminal region (exons 64-66 or intron 65) (moriwaki2023acaseof pages 1-2, toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 2-4).

Recommended Genetic Testing Approach:

1. Whole Exome Sequencing (WES): - First-tier approach for undiagnosed patients with clinical suspicion - Successfully used in the 2023 case report as part of the IRUD (Initiative on Rare and Undiagnosed Diseases) project (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - Advantages: Comprehensive coverage of coding regions

2. Targeted FBN1 Gene Sequencing: - Appropriate when clinical phenotype strongly suggests MFLS - Should include complete sequencing of all 65 FBN1 exons with particular attention to exons 64-66 - Intronic regions flanking exon 65 should be evaluated for splice-site variants (moriwaki2023acaseof pages 1-2)

3. Gene Panel Testing: - Fibrillinopathy or connective tissue disorder panels including FBN1 - Also captures related conditions (e.g., Marfan syndrome, acromelic dysplasias)

4. Single Gene Testing: - FBN1 gene sequencing when diagnosis is suspected based on clinical criteria

5. Functional Testing (RNA Analysis): - Essential for confirming pathogenicity of intronic variants - Demonstrates exon skipping and NMD escape - Cycloheximide treatment can be used to assess NMD - Successfully employed in 2023 case report using lymphoblastoid cell lines (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - Method: RT-PCR of patient mRNA to detect aberrant transcripts and confirm exon 65 skipping

Specific Testing Considerations: - Deep intronic sequencing: Important since pathogenic intronic variants (e.g., c.8226+5G>A) have been documented (moriwaki2023acaseof pages 1-2) - Confirmation of NMD escape: Functional studies at the mRNA level provide strong evidence for variant pathogenicity (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4) - Trio testing: For de novo variant confirmation

Chromosomal Microarray (CMA): Not diagnostic for MFLS; used to exclude large deletions/duplications. One case report documented normal CMA results (moriwaki2023acaseof pages 1-2).

Karyotyping: Not diagnostic; used to exclude chromosomal abnormalities. Normal karyotype expected.

Clinical Criteria

Diagnostic Criteria: No formal validated diagnostic criteria exist. Clinical diagnosis is based on the combination of:

Major Criteria (all typically present): 1. Generalized or severe partial lipodystrophy present from birth 2. Progeroid facial appearance (secondary to lipodystrophy) 3. Genetic confirmation of FBN1 C-terminal variant (exons 64-66 or intron 65)

Supportive Criteria (variable): 1. Intrauterine growth restriction / low birth weight / preterm birth 2. Marfanoid skeletal features (arachnodactyly, tall stature, joint findings) 3. Severe myopia or other ocular manifestations 4. Cardiovascular findings (mitral regurgitation, aortic root dilatation) 5. Normal neurodevelopment 6. Positive family history (rare, given high frequency of de novo mutations)

Diagnostic Approach: Clinical suspicion based on the triad of lipodystrophy + progeroid appearance + marfanoid features should prompt FBN1 genetic testing, with particular attention to the C-terminal region (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2).

Differential Diagnosis:

Conditions to consider and distinguish:

Classic Marfan Syndrome (MFS, OMIM #154700):
Distinguishing features: MFS typically has normal body fat, no progeroid appearance; FBN1 mutations distributed throughout gene rather than clustered in C-terminal region
Other Lipodystrophy-Associated Progeroid Syndromes:
Mandibuloacral Dysplasia (MAD): Caused by LMNA or ZMPSTE24 mutations; distinct skeletal features
MDPL Syndrome (Mandibular Hypoplasia, Deafness, Progeroid features, Lipodystrophy): Caused by POLD1 mutations; includes deafness and mandibular hypoplasia
Hutchinson-Gilford Progeria Syndrome (HGPS): Caused by LMNA mutations; more severe premature aging, shorter lifespan
Werner Syndrome: Adult-onset; caused by WRN gene mutations
Neonatal Progeroid Syndrome (NPS):
Term sometimes used synonymously with MFLS; also caused by FBN1 C-terminal mutations (muthu2020fibrillin1andfibrillin1derived pages 1-2)
Congenital Generalized Lipodystrophy (CGL):
Caused by mutations in AGPAT2, BSCL2, CAV1, PTRF; lacks marfanoid and progeroid features

Key Distinguishing Feature: The combination of lipodystrophy + progeroid appearance + marfanoid features + FBN1 C-terminal mutation is pathognomonic for MFLS.

Screening

Newborn Screening: MFLS is not included in standard newborn screening programs due to its extreme rarity.

Cascade Screening: - Family members of affected individuals should be offered genetic counseling - Genetic testing for at-risk family members (though most cases are de novo) - Prenatal testing available for families with known pathogenic variants

Carrier Screening: Not applicable for autosomal dominant conditions with de novo mutations.

11. OUTCOME/PROGNOSIS

Survival and Mortality

Survival Rate: - Specific survival statistics not available due to extreme rarity - Documented survival to at least age 27 years in reported cohort (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33)

Life Expectancy: - Appears to be better than other severe progeroid syndromes (e.g., HGPS) - Adult survival documented, suggesting prognosis may be relatively favorable compared to other progeroid conditions - Long-term outcomes beyond third decade not well documented

Mortality Rate: Not documented in available literature due to small number of cases and relatively recent disease delineation.

Disease-Specific Mortality: Potential causes of mortality may include: - Cardiovascular complications (aortic dissection, heart failure) - Metabolic complications of lipodystrophy (though less prominent than in some other lipodystrophies) - Currently unknown; no deaths specifically attributed to MFLS reported in available literature

Morbidity and Function

Morbidity: Disease-related impacts include: - Cosmetic effects of lipodystrophy and progeroid appearance - Visual impairment from severe myopia - Cardiovascular complications requiring monitoring and possible intervention - Potential metabolic complications

Disability Outcomes: - Neurodevelopmental: Preserved cognitive function represents a positive prognostic feature (moriwaki2023acaseof pages 1-2, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - Physical function: Walking achieved at typical age (18 months in documented case); functional mobility appears preserved (moriwaki2023acaseof pages 1-2) - Visual disability: Severe myopia may limit function without correction - Psychosocial impact: Altered appearance may affect quality of life

Quality of Life Measures: Specific quality-of-life data (EQ-5D, SF-36, PROMIS) are not available in the published literature for MFLS patients.

Disease Course

Complications:

Cardiovascular: - Mitral valve regurgitation (documented in at least one case) (moriwaki2023acaseof pages 1-2) - Potential for progressive aortic root dilatation requiring surgical intervention (as in Marfan syndrome) - Risk of aortic dissection (theoretical, based on fibrillinopathy class)

Metabolic: - Insulin resistance potential (common in lipodystrophies) - Hepatic steatosis potential (common in lipodystrophies) - Hypertriglyceridemia risk

Nutritional: - Poor appetite may complicate adequate nutrition (moriwaki2023acaseof pages 1-2) - Very low body weight and BMI

Ocular: - Progressive myopia - Retinal complications of severe myopia - Rare complications like entropion requiring surgical correction (moriwaki2023acaseof pages 1-2)

Recovery Potential: - No recovery or cure documented - Condition is chronic and lifelong - Symptomatic management and supportive care are mainstays

Prediction

Prognostic Factors:

Favorable: - Normal neurodevelopment (moriwaki2023acaseof pages 1-2, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22) - Stable cardiovascular findings on serial echocardiography - Successful management of complications (e.g., surgical correction of entropion)

Potentially Unfavorable: - Progressive aortic root dilatation - Severe cardiovascular involvement - Metabolic complications

Prognostic Biomarkers: - Serial echocardiographic measurements of aortic root diameter - Asprosin levels (investigational; not routinely measured) - No validated prognostic biomarkers currently established

Age-Related Considerations: - Childhood to early adulthood: Period of growth-related skeletal changes and emergence of cardiovascular manifestations - Ongoing monitoring required throughout life

12. TREATMENT

Given the extreme rarity of MFLS and recent disease delineation, no disease-specific therapies have been established through clinical trials. Management is primarily supportive and based on addressing individual manifestations and complications.

Pharmacotherapy

Current Pharmacological Approaches: No specific pharmacological treatments have been established for MFLS. Management of complications may include:

For Cardiovascular Manifestations: - Beta-blockers or angiotensin receptor blockers (ARBs): May be considered for aortic root dilatation, based on Marfan syndrome management principles - Examples: Atenolol, losartan - NCIT: C47393 (Beta Adrenergic Receptor Antagonist), C47425 (Angiotensin Receptor Antagonist) - Evidence from Marfan syndrome literature, not specifically MFLS

For Metabolic Complications (if present): - Insulin sensitizers may be considered if insulin resistance develops - Lipid-lowering agents if dyslipidemia occurs - NCIT: C61613 (Insulin Sensitizing Agent), C29348 (Antilipemic Agent)

Pharmacogenomics: No specific pharmacogenomic considerations documented for MFLS.

Advanced Therapeutics

Gene Therapy: Not currently available; no gene therapy trials for MFLS.

Cell Therapy: Not applicable for current management.

RNA-Based Therapies: - Theoretical potential: Antisense oligonucleotides (ASOs) or other RNA-based approaches could theoretically target mutant FBN1 transcripts - Not currently available: No clinical trials or established protocols

Targeted Therapies: - Recombinant asprosin: Animal model data suggest asprosin replacement therapy could rescue hypophagia phenotype (summers2024geneticmodelsof pages 6-7) - Experimental status: Not yet available for human use; represents potential future therapeutic avenue - NCIT: C1909 (Protein Therapy) - investigational

Immunotherapies: Not applicable to MFLS pathophysiology.

Surgical and Interventional

Cardiovascular Surgery: - Aortic root replacement: May be required if progressive aortic root dilatation occurs, following principles from Marfan syndrome management - Valve repair/replacement: May be needed for severe mitral regurgitation - NCIT: C157786 (Aortic Valve Replacement), C157774 (Mitral Valve Repair)

Ophthalmologic Surgery: - Entropion correction: Successfully performed in one documented case for bilateral upper and lower lid entropion with corneal damage (moriwaki2023acaseof pages 1-2) - Lens surgery: May be required if ectopia lentis causes significant visual impairment - NCIT: C15278 (Ophthalmic Surgical Procedure)

Other Surgical Interventions: - Skeletal surgery for severe joint contractures (if present) - Cosmetic procedures (optional, patient preference)

Supportive and Rehabilitative

Supportive Care: - Nutritional support: Important given poor appetite and very low BMI (moriwaki2023acaseof pages 1-2) - Dietary counseling - Caloric supplementation if needed - NCIT: C15327 (Nutritional Support)

Cardiovascular monitoring: Serial echocardiography per institutional protocols or Marfan syndrome guidelines
NCIT: C16250 (Monitoring)
Ophthalmologic care: Regular eye examinations, corrective lenses for myopia
NCIT: C15234 (Ophthalmologic Assessment)
Genetic counseling: Essential for families to understand inheritance, recurrence risk, and reproductive options
NCIT: C17005 (Genetic Counseling)

Rehabilitation: - Physical therapy: May be beneficial for joint issues - Occupational therapy: To address any functional limitations - Psychological support: To address psychosocial impacts of altered appearance - NCIT: C15331 (Physical Therapy), C15329 (Occupational Therapy), C15325 (Psychotherapy)

Experimental

Clinical Trials: No clinical trials specifically for MFLS are documented in available databases. Given the extreme rarity, participation in natural history studies or case registries would be valuable.

Emerging Approaches: - Asprosin replacement therapy (preclinical stage based on animal models) (summers2024geneticmodelsof pages 6-7) - TGF-β pathway modulators (investigational in related conditions)

Treatment Outcomes

Response Rates: Not documented due to lack of disease-specific therapies.

Side Effects and Adverse Events: Standard monitoring for adverse effects of any medications used (e.g., beta-blockers, ARBs) according to standard protocols.

Treatment Strategy

Multidisciplinary Management: Given the multisystem nature of MFLS, a multidisciplinary team approach is essential: - Geneticist/clinical geneticist - Cardiologist - Ophthalmologist - Endocrinologist/metabolism specialist - Nutritionist - Genetic counselor - Psychologist/mental health professional - Primary care physician for coordination

Surveillance Protocol (Proposed based on organ system involvement): - Cardiovascular: Echocardiography at diagnosis, then annually or more frequently if abnormalities detected - Ophthalmologic: Annual comprehensive eye examinations - Growth and nutrition: Regular monitoring of growth parameters, BMI, nutritional status - Metabolic: Periodic assessment of glucose homeostasis, lipid profile, liver function - Skeletal: Monitoring for progressive skeletal changes; orthopedic consultation as needed

Treatment Algorithms: No established treatment algorithms exist for MFLS. Management should be individualized based on each patient's specific manifestations, following principles from: - Marfan syndrome guidelines for cardiovascular management - Lipodystrophy management principles for metabolic complications - Standard supportive care for growth and nutrition

Personalized Medicine Approaches: - Genotype-specific considerations: All MFLS patients have C-terminal FBN1 mutations, but severity of individual manifestations varies - Phenotype-guided management: Surveillance and interventions tailored to each patient's specific organ system involvement

13. PREVENTION

Prevention Levels

Primary Prevention: Not applicable for preventing disease occurrence, as MFLS results from genetic mutations, predominantly de novo.

Secondary Prevention (Early Detection): - Prenatal diagnosis: Available for families with known pathogenic variants - Early recognition: Awareness of the clinical triad (lipodystrophy + progeroid appearance + marfanoid features) allows earlier diagnosis - Early cardiovascular screening: Echocardiography at diagnosis enables detection of cardiovascular abnormalities before complications

Tertiary Prevention (Preventing Complications): - Regular cardiovascular surveillance to detect progressive aortic root dilatation or valve dysfunction early - Ophthalmologic monitoring to optimize vision correction - Nutritional support to prevent malnutrition - Psychological support to address psychosocial impacts

Screening and Early Detection

Genetic Screening: - Prenatal testing: Available for pregnancies in families with known FBN1 pathogenic variants - Preimplantation genetic diagnosis (PGD): Option for families with known variants planning assisted reproduction - Carrier screening: Not applicable for autosomal dominant conditions with predominantly de novo occurrence

Risk Stratification: - Offspring of affected individuals have 50% recurrence risk (though most cases are de novo) - Advanced paternal age may be associated with increased de novo mutation risk (general principle)

Behavioral Interventions

Lifestyle Modifications: Not applicable for disease prevention, as MFLS is genetic.

For Management: - Adequate nutrition important given poor appetite and low body weight - Regular medical follow-up essential

Counseling

Genetic Counseling: Essential component of care, including: - Explanation of diagnosis and inheritance pattern (autosomal dominant) - Recurrence risk assessment (50% for affected individuals; very low for unaffected parents of de novo case, with small risk of germline mosaicism) - Reproductive options discussion (prenatal diagnosis, PGD) - Psychosocial support - NCIT: C17005 (Genetic Counseling)

Prophylaxis

Cardiovascular Prophylaxis: - Beta-blockers or ARBs may be considered prophylactically for aortic protection, following Marfan syndrome principles - NCIT: C15205 (Prophylaxis)

14. OTHER SPECIES / NATURAL DISEASE

Model Organisms

Mouse Models: A mouse model with a small deletion encompassing the exon 65-intron 65 junction has been generated to study asprosin deficiency and MFLS-related phenotypes (summers2024geneticmodelsof pages 6-7, summers2024geneticmodelsof pages 15-16):

Model Characteristics: - Genotype: Deletion at FBN1 exon 65-intron 65 junction - Inheritance: Heterozygous mice studied to model autosomal dominant human condition - Phenotype recapitulation: - Hypophagia (reduced food intake) - Reduced adiposity - Resistance to diet-induced obesity - Protection from diet-induced diabetes - Molecular confirmation: Asprosin deficiency confirmed in these mice - Therapeutic validation: Recombinant asprosin treatment rescued hypophagia phenotype (summers2024geneticmodelsof pages 6-7)

Research Applications: - Understanding asprosin's role in appetite regulation and metabolism - Testing potential therapeutic interventions (e.g., asprosin replacement) - Studying mechanisms of lipodystrophy

Model Limitations: - Mice may not fully recapitulate all human features, particularly marfanoid skeletal manifestations and cardiovascular findings - Lifespan and developmental trajectory differences between mice and humans

Cattle Model: A cattle model with FBN1 variant causing asprosin deficiency has been described as potentially useful for studying lipodystrophy aspects of MFLS (summers2024geneticmodelsof pages 6-7): - Larger animal model may better recapitulate some aspects of human physiology - Natural occurrence suggests evolutionary conservation of asprosin function

Rabbit Model: Mentioned in literature but details not extensively documented in available sources (summers2024geneticmodelsof pages 6-7, summers2024geneticmodelsof pages 15-16).

Zebrafish: A zebrafish model using CRISPR/Cas9 has been generated for FBN1 genetic defects, though specific application to MFLS not detailed in available evidence.

Natural Disease in Other Species

Veterinary Relevance: - Cattle with natural FBN1 variants have been identified (summers2024geneticmodelsof pages 6-7) - No documented naturally occurring MFLS-equivalent syndromes in companion animals (dogs, cats)

Comparative Biology

Evolutionary Conservation: - Fibrillin-1 is highly conserved across species - FBN1 gene present in mammals, birds, and other vertebrates - Asprosin appears to be a mammalian-specific hormone

Comparative Pathology: - Fibrillin-1 deficiency causes connective tissue abnormalities across species - Lipodystrophy phenotype appears consistent in mammals with asprosin deficiency

Transmission

Zoonotic Potential: Not applicable; MFLS is not an infectious disease.

Cross-Species Susceptibility: Not applicable.

15. SUMMARY AND FUTURE DIRECTIONS

Marfanoid-Progeroid-Lipodystrophy Syndrome (MFLS, OMIM #616914) is an ultra-rare autosomal dominant fibrillinopathy caused by specific heterozygous variants in the extreme C-terminal region of the FBN1 gene (exons 64-66, intron 65) (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33, moriwaki2023acaseof pages 1-2). With approximately 8 patients documented in the literature through 2022, MFLS represents one of the rarest human genetic disorders (araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33).

The syndrome is characterized by a distinctive triad of generalized lipodystrophy, progeroid appearance, and variable marfanoid features, with onset evident from birth (toriello2019prematureageingsyndromes pages 12-13, moriwaki2023acaseof pages 1-2). The pathophysiology involves truncated fibrillin-1 protein production (with escape from nonsense-mediated decay), asprosin hormone deficiency, dysregulated TGF-β signaling, and impaired adipogenesis (moriwaki2023acaseof pages 1-2, muthu2020fibrillin1andfibrillin1derived pages 6-8, araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22, muthu2020fibrillin1andfibrillin1derived pages 2-4, moriwaki2023acaseof pages 2-4).

Key advances in 2023 include the first experimental confirmation of exon 65 skipping and NMD escape in a clinical sample, providing crucial functional validation of the molecular mechanism (moriwaki2023acaseof pages 1-2, moriwaki2023acaseof pages 2-4). Animal models, particularly mice with exon 65 junction deletions, have demonstrated the causal role of asprosin deficiency in hypophagia and reduced adiposity, suggesting potential therapeutic avenues (summers2024geneticmodelsof pages 6-7).

Future Research Directions: 1. Expanded natural history studies to better define long-term prognosis 2. Development of asprosin replacement therapy based on animal model success 3. Investigation of TGF-β pathway modulators as potential treatments 4. Establishment of patient registries to facilitate research 5. Further characterization of genotype-phenotype correlations 6. Development of evidence-based management guidelines

Clinical Implications: - Multidisciplinary care is essential for optimal management - Cardiovascular surveillance should follow principles from Marfan syndrome management - Genetic counseling is crucial for families - Preserved neurodevelopment represents an important positive prognostic feature - Recognition of the diagnostic triad enables earlier diagnosis and appropriate management

This comprehensive knowledge base entry provides a foundation for improved recognition, diagnosis, and management of this ultra-rare disorder, while highlighting key areas requiring further research.

References

(araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 19-22): David Araújo-Vilar, Antía Fernández-Pombo, Silvia Cobelo-Gómez, Ana I. Castro, and Sofía Sánchez-Iglesias. Lipodystrophy-associated progeroid syndromes. Hormones, 21:555-571, Jul 2022. URL: https://doi.org/10.1007/s42000-022-00386-7, doi:10.1007/s42000-022-00386-7. This article has 17 citations and is from a peer-reviewed journal.
(toriello2019prematureageingsyndromes pages 12-13): Helga V. Toriello and Caleb P. Bupp. Premature ageing syndromes. Harper's Textbook of Pediatric Dermatology, pages 1725-1742, Nov 2019. URL: https://doi.org/10.1002/9781119142812.ch137, doi:10.1002/9781119142812.ch137. This article has 7 citations.
(moriwaki2023acaseof pages 1-2): Takahito Moriwaki, Mitsuo Masuno, Miho Nagata, Yasuki Ishihara, Yohei Miyashita, Yoshihiro Asano, Kayo Takao, Kazumi Tawa, Yasuko Yamanouchi, Atsushi Miki, and Takanobu Otomo. A case of marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay. Human Genome Variation, Oct 2023. URL: https://doi.org/10.1038/s41439-023-00255-8, doi:10.1038/s41439-023-00255-8. This article has 1 citations.
(araujovilar2022lipodystrophyassociatedprogeroidsyndromes pages 30-33): David Araújo-Vilar, Antía Fernández-Pombo, Silvia Cobelo-Gómez, Ana I. Castro, and Sofía Sánchez-Iglesias. Lipodystrophy-associated progeroid syndromes. Hormones, 21:555-571, Jul 2022. URL: https://doi.org/10.1007/s42000-022-00386-7, doi:10.1007/s42000-022-00386-7. This article has 17 citations and is from a peer-reviewed journal.
(muthu2020fibrillin1andfibrillin1derived pages 1-2): Muthu L. Muthu and Dieter P. Reinhardt. Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders. Journal of Cell Communication and Signaling, 14:159-173, Apr 2020. URL: https://doi.org/10.1007/s12079-020-00566-3, doi:10.1007/s12079-020-00566-3. This article has 80 citations and is from a peer-reviewed journal.
(moriwaki2023acaseof pages 2-4): Takahito Moriwaki, Mitsuo Masuno, Miho Nagata, Yasuki Ishihara, Yohei Miyashita, Yoshihiro Asano, Kayo Takao, Kazumi Tawa, Yasuko Yamanouchi, Atsushi Miki, and Takanobu Otomo. A case of marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay. Human Genome Variation, Oct 2023. URL: https://doi.org/10.1038/s41439-023-00255-8, doi:10.1038/s41439-023-00255-8. This article has 1 citations.
(muthu2020fibrillin1andfibrillin1derived pages 6-8): Muthu L. Muthu and Dieter P. Reinhardt. Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders. Journal of Cell Communication and Signaling, 14:159-173, Apr 2020. URL: https://doi.org/10.1007/s12079-020-00566-3, doi:10.1007/s12079-020-00566-3. This article has 80 citations and is from a peer-reviewed journal.
(muthu2020fibrillin1andfibrillin1derived pages 12-13): Muthu L. Muthu and Dieter P. Reinhardt. Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders. Journal of Cell Communication and Signaling, 14:159-173, Apr 2020. URL: https://doi.org/10.1007/s12079-020-00566-3, doi:10.1007/s12079-020-00566-3. This article has 80 citations and is from a peer-reviewed journal.
(muthu2020fibrillin1andfibrillin1derived pages 2-4): Muthu L. Muthu and Dieter P. Reinhardt. Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders. Journal of Cell Communication and Signaling, 14:159-173, Apr 2020. URL: https://doi.org/10.1007/s12079-020-00566-3, doi:10.1007/s12079-020-00566-3. This article has 80 citations and is from a peer-reviewed journal.
(muthu2020fibrillin1andfibrillin1derived pages 4-6): Muthu L. Muthu and Dieter P. Reinhardt. Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders. Journal of Cell Communication and Signaling, 14:159-173, Apr 2020. URL: https://doi.org/10.1007/s12079-020-00566-3, doi:10.1007/s12079-020-00566-3. This article has 80 citations and is from a peer-reviewed journal.
(summers2024geneticmodelsof pages 6-7): Kim M. Summers. Genetic models of fibrillinopathies. Genetics, Nov 2024. URL: https://doi.org/10.1093/genetics/iyad189, doi:10.1093/genetics/iyad189. This article has 21 citations and is from a domain leading peer-reviewed journal.
(marelli2023marfansyndromeenhanced pages 22-23): Susan Marelli, Emanuele Micaglio, Jacopo Taurino, Paolo Salvi, Erica Rurali, Gianluca L. Perrucci, Claudia Dolci, Nathasha Samali Udugampolage, Rosario Caruso, Davide Gentilini, Giuliana Trifiro’, Edward Callus, Alessandro Frigiola, Carlo De Vincentiis, Carlo Pappone, Gianfranco Parati, and Alessandro Pini. Marfan syndrome: enhanced diagnostic tools and follow-up management strategies. Diagnostics, 13:2284, Jul 2023. URL: https://doi.org/10.3390/diagnostics13132284, doi:10.3390/diagnostics13132284. This article has 55 citations.
(summers2024geneticmodelsof pages 15-16): Kim M. Summers. Genetic models of fibrillinopathies. Genetics, Nov 2024. URL: https://doi.org/10.1093/genetics/iyad189, doi:10.1093/genetics/iyad189. This article has 21 citations and is from a domain leading peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	6
Resolved	6
Unresolved (possible confabulation)	0
Unverifiable	0

All extracted references resolved successfully.

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

COMPREHENSIVE RESEARCH REPORT: MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

1. DISEASE INFORMATION

Overview

Key Identifiers

Synonyms and Alternative Names

Data Source

2. ETIOLOGY

Disease Causal Factors

Risk Factors

Protective Factors

Gene-Environment Interactions

3. PHENOTYPES

Core Phenotypic Features

Phenotype Onset, Severity, and Progression

Quality of Life Impact

4. GENETIC/MOLECULAR INFORMATION

Causal Gene

Pathogenic Variants

Modifier Genes

Epigenetic Information

Chromosomal Abnormalities

5. ENVIRONMENTAL INFORMATION

Environmental Factors

Lifestyle Factors

Infectious Agents

6. MECHANISM / PATHOPHYSIOLOGY

Molecular Pathways

Cellular Processes

Protein Dysfunction

Metabolic Changes

Tissue Damage Mechanisms

Causal Chain Summary

7. ANATOMICAL STRUCTURES AFFECTED

Organ Level

Tissue and Cell Level

Subcellular Level

Localization

8. TEMPORAL DEVELOPMENT

Onset

Progression

Patterns