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Classifications

Harrison's Part

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Inheritance

1

X-linked recessive inheritance HP:0001419

MBTPS2 is on Xp22, and affected individuals are male. The locus was mapped to a 5.4 Mb interval between DXS989 and DXS8019 before the gene was identified. Carrier females are not uniformly unaffected. Mosaic cutaneous lesions along Blaschko lines are described, and an ocular sign has been proposed: retinal vascular tortuosity in the carrier mother of two affected boys. That is a single family and is curated as such - it is a lead for examining carriers, not an established carrier test.

X-linked recessive inheritance

Show evidence (3 references)

PMID:19361614 SUPPORT Human Clinical

"Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder."

The X-linked classification and the oculocutaneous framing of the entity.

PMID:19361614 SUPPORT Human Clinical

"Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13"

The mapping interval, which is what established X-linkage before the gene was known.

PMID:15370546 SUPPORT Human Clinical

"Retinal vascular tortuosity may be another clinical sign of carrier status in females."

Graded PARTIAL, and the source's own "may be" is the reason. This is one carrier mother in one family; it supports the proposal, not the sign.

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Subtypes

1

BRESHECK syndrome (severe multisystem end of the spectrum)

The IFAP triad plus intellectual disability and multiple congenital anomalies. The acronym expands to brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia or hypoplasia. Curated as a subtype rather than a separate disease because it is the severe end of one activity continuum, not a different mechanism: the same gene, the same class of hypomorphic allele, and a functional assay showing the same two pathways impaired. The MONDO label itself lumps them - "IFAP syndrome 1, with or without BRESHECK syndrome".

Show evidence (2 references)

PMID:34655156 SUPPORT Human Clinical

"Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies."

Defines BRESHECK as the IFAP triad plus additional features, from the same gene - the basis for curating it as a subtype.

PMID:24313295 SUPPORT Human Clinical

"BRESHECK (brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia) syndrome"

The full expansion of the acronym, curated verbatim so the subtype description does not have to be trusted.

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Discussions and Knowledge Gaps

2

Does loss of ATF6 signalling contribute anything to the IFAP phenotype, or is the disease explained by the SREBP arm alone?

KNOWLEDGE GAP OPEN ifap_atf6_arm_unattached_to_phenotype

Attached to

pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response pathophysiology#Impaired SREBP-Driven Lipid Synthesis

Every account of this disease, including this entry's own description, states that S2P loss impairs both cholesterol homeostasis and the ER stress response. The first half of that is measured and connected to phenotype. The second half is measured and connected to nothing. What exists for the ATF6 arm: a BRESHECK-associated variant fails to activate the ER stress response in vitro, and the gene-identification paper names "ability to cope with ER stress" alongside cholesterol homeostasis as the affected system. What does not exist: any clinical feature of IFAP attributed to ATF6 loss specifically, any tissue in which ER stress has been measured in a patient, and any account of why an ER-stress defect would fall on hair follicle and limbus rather than on the secretory tissues where the UPR matters most. So the two-arm mechanism is stated everywhere and load-bearing nowhere. Every phenotype curated in this entry could be produced by the SREBP arm alone. That is worth flagging rather than smoothing over, because a two-arm story that cannot be broken by any observation is not doing explanatory work. Two things pull in opposite directions, and both belong here. Arguing that the SREBP arm is sufficient: variants in SREBF1 - the gene for SREBP itself, one step downstream of this protease - cause a disease that shares a common clinical spectrum with IFAP. If losing the substrate alone reproduces much of the phenotype, the phenotype does not need the ATF6 arm. That is the strongest available argument for the SREBP arm carrying the disease, and it comes from human genetics rather than from a cell assay. Arguing against dismissing the ATF6 arm: in the one variant where both were tested, the SREBP pathway was *attenuated* while the ER stress response failed outright. If that pattern holds, the ATF6 arm is the more severely affected one, which makes its clinical silence more puzzling rather than less. The SREBF1 comparison also has a limit worth stating. SREBF1 disease is dominant and IFAP is X-linked recessive, and the SREBF1 phenotype includes mucosal involvement that IFAP does not - so the two are not the same phenotype with one mechanism subtracted, and the inference is suggestive rather than clean.

Proposed experiments

ER stress response in patient keratinocytes and limbal epithelial cells

exp_ifap_er_stress_in_patient_keratinocytes

Derive keratinocytes and, where available, limbal epithelial cells from IFAP patients across the severity range, and measure ATF6 processing and downstream UPR target induction under tunicamycin or thapsigargin challenge alongside SREBP target induction in the same cells. This asks whether the two arms are impaired to different degrees in the tissues that actually express the phenotype, rather than in a hamster ovary line.

Would support

pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response

Would refute

pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response

Supporting outcome

Patient keratinocytes show blunted ATF6 processing and UPR target induction, and the magnitude tracks cutaneous severity independently of the SREBP readout.

Refuting outcome

ATF6 processing and UPR target induction are preserved in patient keratinocytes despite a measurable SREBP deficit, placing the whole phenotype on the SREBP arm.

Systematic phenotype comparison of MBTPS2 and SREBF1 disease

ifap_srebf1_phenotype_subtraction

Compare the feature-level phenotype of MBTPS2-related IFAP against SREBF1-related disease in matched cohorts, coded to HPO. Features present in both are candidates for the SREBP arm; features present only in MBTPS2 disease are where the ATF6 arm, or another S2P substrate, would have to act. This is a phenotype subtraction that needs no new laboratory work, only systematic coding of cases already published.

Would support

pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response

Would refute

pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response

Supporting outcome

A reproducible set of MBTPS2-only features remains after subtracting the SREBF1 phenotype, giving the ATF6 arm something specific to explain.

Refuting outcome

The MBTPS2 phenotype is contained within the SREBF1 phenotype, leaving no residual for a second substrate arm to account for.

Show evidence (2 references)

PMID:33742461 SUPPORT Human Clinical

"Recently, variants in SREBF1, a gene coding for a transcription factor related to cholesterol and fatty acid synthesis, have been associated with the disease."

Graded PARTIAL against the ATF6 node. It bears on the question by showing that losing the SREBP substrate alone produces an overlapping phenotype, but it does not measure the ATF6 arm at all, and the two diseases differ in inheritance and in mucosal involvement - so it narrows the ATF6 arm's remaining explanatory role without excluding it.

PMID:34655156 SUPPORT In Vitro

"In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway."

The one experiment measuring both arms, and the source of the asymmetry the rationale points at - attenuated versus failed.

Why do MBTPS2 variants produce a skin-and-eye disease in some families and a bone disease in others?

KNOWLEDGE GAP OPEN ifap_allelic_series_tissue_specificity

Attached to

genetic#MBTPS2

MBTPS2 causes IFAP with or without BRESHECK, keratosis follicularis spinulosa decalvans, an X-linked form of Olmsted syndrome, and osteogenesis imperfecta type XIX. These are not variations in severity of one phenotype - osteogenesis imperfecta is a different organ system from ichthyosis and keratopathy. The review literature is unusually explicit that this is unresolved, which is worth recording because it is easy for a curator to assume the answer is known and merely not looked up. Two features of this entry make the question sharper rather than more diffuse. The activity-severity correlation says residual protease activity sets severity along the IFAP-BRESHECK axis - so if it also set tissue specificity, KFSD and osteogenesis imperfecta would be points on the same line, and they are not. And the same allele can vary in expressivity within IFAP, so allele identity does not fully determine the phenotype even inside one disease. dismech is in an unusual position to notice this, because it already carries entries for two of the other MBTPS2 diseases. A cross-entry comparison of which residues and which functional consequences map to which entity is a concrete piece of work that does not need new data.

Proposed experiments

Residue-level map of MBTPS2 variants across the four allelic diseases

exp_ifap_allelic_series_residue_map

Assemble every reported MBTPS2 variant with its associated clinical entity, map onto the protein's transmembrane and catalytic architecture, and test whether disease assignment separates by domain, by predicted residual activity, or by neither. Assay a matched set in both the SREBP and ATF6 readouts, since only the SREBP arm has been systematically measured.

Would support

pathophysiology#Hypomorphic MBTPS2 Variant pathophysiology#Reduced Regulated Intramembrane Proteolysis

Would refute

pathophysiology#Reduced Regulated Intramembrane Proteolysis

Supporting outcome

Variants segregate by domain or by which substrate arm they preferentially impair, giving a mechanism for the tissue specificity.

Refuting outcome

Variants causing bone and skin disease are interleaved across domains with indistinguishable functional profiles, placing the determinant outside the protein.

Show evidence (1 reference)

PMID:33743732 SUPPORT Other

"While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes"

The review's framing of the gap: function understood, disease mapping not.

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Pathophysiology

6

Hypomorphic MBTPS2 Variant

Missense variants exchanging highly conserved residues, and splice-site variants, in MBTPS2. The allelic spectrum is hypomorphic rather than null: every reported variant leaves some residual protease activity, and the amount left is what the phenotype tracks. That is not merely an observation about severity - it constrains what kind of variant can be pathogenic here. A curator or laboratory assessing a novel MBTPS2 variant should expect partial loss of function, and a variant predicted to abolish the protein entirely would be atypical for this entity rather than a confidently severe allele.

MBTPS2 hgnc:15455

site-2 protease intramembrane cleavage activity GO:0004222 ↓ DECREASED

Downstream

Reduced Regulated Intramembrane Proteolysis

Show evidence (2 references)

PMID:19361614 SUPPORT Human Clinical

"provide evidence that missense mutations exchanging highly conserved amino acids of membrane-bound transcription factor protease, site 2 (MBTPS2) are associated with this phenotype"

The gene-disease assertion and the variant class.

PMID:19361614 SUPPORT In Vitro

"MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling proteins involved in sterol control of transcription and ER stress response."

The enzyme class and the two pathways it serves, which is the whole basis for the two-arm pathograph below.

Reduced Regulated Intramembrane Proteolysis

S2P makes the second cut of a two-cut cascade. SREBP and ATF6 are cleaved first by site-1 protease and then, within the membrane, by S2P, which releases the active transcription-factor domain into the cytosol. Reduce S2P activity and both substrates are released less efficiently. This node is the reason the disease looks pleiotropic. Two entirely unrelated transcriptional programmes share one protease, so a single hypomorphic allele hits lipid synthesis and the stress response together rather than choosing one.

Golgi membrane GO:0000139

Downstream

Impaired SREBP-Driven Lipid Synthesis

Impaired ATF6 Endoplasmic Reticulum Stress Response

Show evidence (2 references)

PMID:33743732 SUPPORT Other

"The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane."

The intramembrane-cleavage function. Graded OTHER: this is a review's background statement of established biochemistry, not a result the paper reports.

PMID:33743732 SUPPORT Other

"The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses."

States the two-pathway breadth that the fork below represents.

Impaired SREBP-Driven Lipid Synthesis

Less active SREBP reaches the nucleus, so cholesterol and fatty-acid synthesis genes are under-induced. The functional signature of this in the assays used to prove variant pathogenicity is failure to grow in cholesterol-depleted medium - a cell that cannot make its own lipid and is no longer given any. In the epidermis this is the barrier-lipid arm: the cornified envelope depends on locally synthesised lipids, and a follicular hyperkeratosis is what a failing keratinisation programme looks like at the skin surface.

keratinocyte CL:0000312

SREBP signaling pathway GO:0032933 ↓ DECREASED cholesterol biosynthesis GO:0006695 ↓ DECREASED

Experimental models

CHO M19 site-2-protease-deficient complementation assay CELL LINE Quantifies residual S2P activity through its SREBP output, which is what makes the activity-severity correlation measurable. Curated as MEASURES rather than RECAPITULATES on purpose: the cell line does not model IFAP, it assays one function of the mutant protein. Nothing about a hamster ovary cell reproduces a hair follicle or a corneal limbus.

Downstream

Defective Epidermal and Follicular Keratinization

Progressive Vascularising Keratopathy

Show evidence (2 references)

PMID:19361614 SUPPORT In Vitro

"Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids."

The complementation assay that reads out this node, and the two measurements it uses.

PMID:34655156 SUPPORT In Vitro

"In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway."

An independent demonstration in a different variant, and the only single sentence in the literature reviewed here that measures both arms of the fork in the same experiment.

Impaired ATF6 Endoplasmic Reticulum Stress Response

ATF6 is the second S2P substrate, and it is the arm of the unfolded protein response that depends on the same two cuts. A BRESHECK-associated variant was shown to fail to activate the ER stress response entirely, alongside its attenuated SREBP effect. Graded PROVISIONAL rather than ESTABLISHED, and the distinction from the SREBP node is deliberate. The biochemistry is not in doubt - S2P cleaves ATF6, and the assay result is clear. What is not established is that this arm *contributes to the human phenotype*: no clinical feature of IFAP has been tied to loss of ATF6 signalling specifically, and every phenotype the entry curates could in principle be explained by the SREBP arm alone. The node is kept because a mechanism curated only where it is convenient is not a mechanism, and because it predicts things the SREBP arm does not.

ATF6-mediated unfolded protein response GO:0036500 ↓ DECREASED response to endoplasmic reticulum stress GO:0034976 ↓ DECREASED

Show evidence (2 references)

PMID:34655156 SUPPORT In Vitro

"In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway."

The measured failure of ER-stress activation. Note the asymmetry the source itself reports: the SREBP pathway was "attenuated" while the ER stress response failed outright.

PMID:19361614 SUPPORT In Vitro

"Our findings indicate that the phenotypic expression of IFAP syndrome is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol homeostasis and ability to cope with ER stress."

Names both arms together as the affected system, which is the only published statement tying the ER-stress arm to the human phenotype - and it does so by naming the pair rather than by isolating this arm. Graded IN_VITRO despite the sentence being about phenotypic expression in patients, because the quantitative relationship it asserts is measured by the CHO M19 complementation assay; the clinical severity is the variable it is correlated against, not the evidence for the mechanism. Grading it HUMAN_CLINICAL would credit the ER-stress claim with human measurement that was never made - no ER stress has been measured in any IFAP patient tissue, which is the whole point of the discussion this node carries.

Defective Epidermal and Follicular Keratinization

The skin and hair phenotype: spiny follicular hyperkeratosis and near-total absence of scalp hair, eyebrows and eyelashes from birth. Graded PROVISIONAL because the step from an impaired lipid-synthesis programme to this specific histology is inferred, not demonstrated. No study reviewed here measures barrier lipids, cornified envelope composition or follicular differentiation markers in IFAP skin. The disease is defined clinically at this level and mechanistically two levels up, with the connection assumed.

keratinocyte CL:0000312

keratinocyte differentiation GO:0030216 ↓ DECREASED

skin epidermis UBERON:0001003 hair follicle UBERON:0002073

Show evidence (1 reference)

PMID:24313295 SUPPORT Human Clinical

"the typical triad of IFAP syndrome (i.e. ichthyosis, atrichia and photophobia), along with pachyonychia, palmoplantar and periorificial keratoderma"

The cutaneous phenotype including the keratoderma that extends it in some patients.

Progressive Vascularising Keratopathy

The ocular phenotype, and the one that carries the morbidity. Photophobia is the symptom; the disease is a keratopathy that progresses through spontaneous epithelial defects, superficial and deep corneal vascularisation, and scarring to counting-fingers acuity. The most informative observation is developmental rather than static. An infant diagnosed at six days had clear corneas; the epithelial defects appeared at six months, and imaging then showed limbal thickening, peripheral pannus, conjunctivalisation and abnormal hyperreflective epithelium - the picture of limbal stem cell dysfunction. So the cornea is not malformed, it fails to maintain itself, which is a different therapeutic target. Graded PROVISIONAL: the limbal-failure account rests on one prospectively followed infant, and no histology or limbal-marker study has been published.

cornea UBERON:0000964 corneal epithelium UBERON:0001772

Show evidence (3 references)

PMID:32482964 SUPPORT Human Clinical

"The progressive conjunctivalization, spontaneous epithelial defects, and anterior segment optical coherence tomography features are highly suggestive of limbal stem cell dysfunction in IFAP syndrome."

The limbal-failure interpretation, in the authors' own hedged words - "highly suggestive of", which is what the PROVISIONAL grade records.

PMID:32482964 SUPPORT Human Clinical

"Initial examination showed hyperkeratotic eyelids, madarosis, and lagophthalmos, but otherwise clear corneas. He developed bilateral central corneal epithelial defects spontaneously 6 months later"

The developmental sequence - normal cornea at six days, breakdown at six months - which is what distinguishes maintenance failure from malformation.

PMID:15370546 SUPPORT Human Clinical

"Both affected male children had severe photophobia, total superficial and deep corneal vascularization, and reduction of vision to counting fingers."

The endpoint of the progression, in two siblings.

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Pathograph

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

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Phenotypes

7

Eye 1

Photophobia OBLIGATE HP:0000613

Show evidence (1 reference)

PMID:15370546 SUPPORT Human Clinical

"Both affected male children had severe photophobia, total superficial and deep corneal vascularization, and reduction of vision to counting fingers."

Photophobia documented alongside the corneal disease it reflects.

Integument 2

Palmoplantar Keratoderma OCCASIONAL HP:0000982

Show evidence (1 reference)

PMID:24313295 SUPPORT Human Clinical

"this mutation was previously reported in two cases of IFAP without keratoderma, which suggests clinical heterogeneicity of the same mutation in MBTPS2"

The same c.671-9T>G allele with and without keratoderma across three patients - which is why this is banded OCCASIONAL and why the entry does not treat keratoderma as genotype-predicted. The source's spelling "heterogeneicity" is reproduced as published.

Nail Dystrophy OCCASIONAL HP:0008404

Show evidence (1 reference)

PMID:24313295 SUPPORT Human Clinical

"along with pachyonychia, palmoplantar and periorificial keratoderma, which were reminiscent of Olmsted syndrome"

Pachyonychia in the reported patient, curated under the general nail dystrophy term.

Other 4

Ichthyosis Follicularis OBLIGATE HP:0031291

Show evidence (1 reference)

PMID:19361614 SUPPORT Human Clinical

"Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder."

The triad as the definition of the entity, which is what makes each of its three elements obligate.

Atrichia OBLIGATE HP:0500262

Show evidence (2 references)

PMID:19361614 SUPPORT Human Clinical

"Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder."

Atrichia as a defining element of the triad.

PMID:32482964 SUPPORT Human Clinical

"Initial examination showed hyperkeratotic eyelids, madarosis, and lagophthalmos, but otherwise clear corneas."

Madarosis - loss of lashes and brows - documented at six days old, together with the lid changes that make it ocularly consequential.

Corneal Neovascularization FREQUENT HP:0011496

Show evidence (1 reference)

PMID:15370546 SUPPORT Human Clinical

"Males with IFAP have an inexorable progression of corneal vascularization and loss of vision."

The progression and its visual endpoint.

Limbal Stem Cell Deficiency OCCASIONAL HP:0032107

Show evidence (1 reference)

PMID:32482964 SUPPORT Human Clinical

"Anterior segment optical coherence tomography demonstrated a significantly abnormal and hyperreflective epithelial surface overlying a thinned corneal stroma, suggestive of limbal stem cell dysfunction."

Graded PARTIAL and banded OCCASIONAL for the same reason: this is one patient, imaged rather than biopsied, and the source says "suggestive of". The band records how often it has been *looked for*, not how often it is present - it may well be universal.

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Genetic Associations

1

MBTPS2

Gene: MBTPS2 hgnc:15455 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:19361614 SUPPORT In Vitro

"The degree of diminished activity correlated with clinical severity as noted in male patients."

The measured activity-severity correlation, which is the central genotype-phenotype fact of this disease.

PMID:19361614 SUPPORT In Vitro

"These functions were impaired in five mutations as detected in unrelated patients."

The number of patient variants assayed, which bounds how much weight the correlation can carry.

PMID:24313295 SUPPORT Human Clinical

"We report a recurrent intronic mutation in MBTPS2 (c.671-9T>G) in a Chinese patient with the typical triad of IFAP syndrome"

A splice-site variant in the pathogenic spectrum, and the allele behind the variable-expressivity observation.

+ 1 more reference

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Medical Actions

4

Systemic Acitretin

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172

A systemic retinoid, tried for the cutaneous and corneal features. The reported response is partial in a specific and consistent way: skin and corneal erosions improve, alopecia and photophobia do not.

Mechanism Target:

MODULATES Defective Epidermal and Follicular Keratinization — Retinoids act on keratinocyte differentiation, so the plausible target is the keratinisation node rather than the protease defect upstream of it. Curated as MODULATES rather than RESTORES: nothing about the treatment restores S2P activity, and the reported improvement is partial.

Show evidence (1 reference)

PMID:16268889 SUPPORT Human Clinical

"A moderate response to acitretin therapy (1 mg/kg) administered for 6 months was observed, with improvement in cutaneous features and corneal erosions and no change in alopecia or photophobia."

Graded PARTIAL on the source's own terms - a "moderate response" in a single patient, with two of the three triad features explicitly unchanged.

Show evidence (1 reference)

PMID:16268889 SUPPORT Human Clinical

"We describe a 3-year-old male patient with the ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome, who developed cutaneous and ocular involvement in infancy."

Establishes the evidence base as a single three-year-old patient, which is the fact that most constrains how this treatment should be read.

Ocular Surface Protection

Action: Supportive Care NCIT:C15747

The mainstay of ocular care, and on the limbal-failure reading of the disease it is a holding measure rather than a treatment of the lesion. Aggressive lubrication, prophylactic antibiotics and lateral tarsorrhaphy maintained a stable corneal surface in the one infant followed prospectively from diagnosis.

Mechanism Target:

MODULATES Progressive Vascularising Keratopathy — Protects the ocular surface without addressing the limbal stem-cell failure that is failing to maintain it.

Show evidence (1 reference)

PMID:32482964 SUPPORT Human Clinical

"The corneal surface was maintained with lubrication and tarsorrhaphy and has remained stable since."

The reported outcome of surface protection in that patient.

Show evidence (1 reference)

PMID:32482964 SUPPORT Human Clinical

"which were managed with aggressive lubrication, prophylactic antibiotics, and bilateral permanent lateral tarsorrhaphies at 7 months of age"

The specific measures used, with the age at which they were needed.

Emollients and Urea Keratolytics

Action: Pharmacotherapy NCIT:C15986

Agent: urea CHEBI:16199

The cutaneous mainstay, and the treatment most IFAP patients are actually on. Topical urea for the plantar keratoderma and constant moisturisers for the generalized xerosis. Curated because its absence left the entry offering nothing for the skin except a systemic retinoid evidenced by one three-year-old - which misrepresents ordinary care for this disease.

Mechanism Target:

MODULATES Defective Epidermal and Follicular Keratinization — Urea is keratolytic and humectant, acting on the abnormal stratum corneum itself rather than on the protease defect that produced it. Symptomatic by construction, which is why the effect is MODULATES.

Show evidence (1 reference)

PMID:38089015 SUPPORT Human Clinical

"The patient was given symptomatic treatment with urea cream for plantar keratoderma and was advised to apply constant moisturizers to avoid generalized xerosis."

The topical regimen as given, with the indication for each component.

Show evidence (1 reference)

PMID:38089015 SUPPORT Human Clinical

"Dermatological and ophthalmological follow-ups were recommended."

Graded PARTIAL: the source reports what was prescribed and that follow-up was arranged, not an assessed response. No outcome is claimed here.

Amniotic Membrane Transplantation

Action: Surgical Procedure NCIT:C15329

The standard intervention for limbal stem cell deficiency, and on this entry's reading of the ocular disease it is the treatment aimed at the actual lesion rather than at the surface consequence. The one published IFAP case combined it with systemic acitretin, so the two cannot be separated in that report - which is stated rather than glossed, because the improvement reported includes neuropsychomotor development, which no ocular surface procedure explains.

Mechanism Target:

MODULATES Progressive Vascularising Keratopathy — Provides a substrate for epithelial healing over a limbus that is failing to maintain the corneal surface. It supports the failing compartment rather than restoring it, so MODULATES rather than RESTORES.

Show evidence (1 reference)

PMID:21670910 SUPPORT Human Clinical

"After three months using systemic retinoid (Acitretina) and posterior amniotic membrane transplantation in the left eye, there was a significant improvement of photophobia, corneal erosions and neuropsychomotor development."

Graded PARTIAL because the transplant and the retinoid were given together and the reported improvement cannot be attributed to either alone. The inclusion of neuropsychomotor development among the improvements is a further reason for caution - it is not an outcome an ocular procedure would produce, and its presence suggests the assessment was global rather than eye-specific.

Show evidence (1 reference)

PMID:21670910 SUPPORT Human Clinical

"He was treated with artificial tears and punctal occlusion with small improvement of photophobia."

The prior, purely surface-directed treatment and its limited effect - which is the comparison that makes the subsequent intervention interesting, and is consistent with the surface not being where the lesion is.

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Diagnosis

3

Recognition of the clinical triad (PRESENT)

The diagnosis starts as a pattern recognition: ichthyosis follicularis, atrichia and photophobia together, in a male, from birth or the first year. Each element alone is unremarkable; the combination is not.

Markers: Generalized spiny follicular keratotic papules, near-total absence of scalp hair, eyebrows and eyelashes, and photophobia. Non-scarring alopecia is the discriminating quality - scarring alopecia points at KFSD instead.

Show evidence (1 reference)

PMID:38089015 SUPPORT Human Clinical

"The alopecia was non-scarring and was accompanied by mild generalized xerosis, photophobia, and recurrent angular cheilitis."

A worked presentation, including the non-scarring quality of the alopecia that separates IFAP from KFSD at the bedside.

MBTPS2 sequencing or exome sequencing (PRESENT)

Confirmatory. Both missense and splice-site variants are pathogenic, and the intronic ones (c.671-9T>G, c.970+5G>A) will be missed by an exon-only analysis that does not extend into flanking intronic sequence - which matters because one of them is recurrent.

Results: A hemizygous hypomorphic MBTPS2 variant in an affected male. Expect partial rather than complete loss of function; a variant predicted to abolish the protein entirely would be atypical for this entity.

Show evidence (1 reference)

PMID:38089015 SUPPORT Human Clinical

"The genetic testing confirmed an X-linked recessive inheritance of IFAP syndrome without BRESHECK syndrome due to the mutation in the MBTPS2 (300294) gene located on chromosome Xp22.12."

Molecular confirmation in practice, and an example of the genotype being used to place a patient at the IFAP rather than the BRESHECK end.

Anterior segment optical coherence tomography (PRESENT)

Curated as a diagnostic because of what it changes rather than what it confirms. Slit-lamp examination shows the corneal surface breaking down; AS-OCT showed the abnormal hyperreflective epithelium over thinned stroma that reframed the ocular disease as limbal stem cell dysfunction rather than exposure keratopathy - which is a different therapeutic target. This entry's `pathophysiology` leans on that reframing, so leaving the modality that produced it out of `diagnosis:` was an inconsistency.

Markers: Limbal thickening, peripheral corneal pannus, conjunctivalisation, and an abnormal hyperreflective epithelial surface over thinned corneal stroma.

Show evidence (1 reference)

PMID:32482964 SUPPORT Human Clinical

"Anterior segment optical coherence tomography demonstrated a significantly abnormal and hyperreflective epithelial surface overlying a thinned corneal stroma, suggestive of limbal stem cell dysfunction."

The imaging finding and the interpretation it supports.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No prevalence or incidence figure exists. The commonly repeated count is "40 cases reported", and that number deserves a caveat rather than repetition: it comes from the introduction of a case report about Hodgkin lymphoma in an IFAP patient, not from a systematic review or a registry. It is a background sentence in a paper about something else, and no method for arriving at it is given. It is curated because it is the only quantitative anchor available and because a reader will otherwise meet it uncited elsewhere, but it is graded PARTIAL and rate_per_100000 is left empty.

Show evidence (1 reference)

PMID:28654459 SUPPORT Human Clinical

"A total of 40 cases has been reported, but no correlation with Hodgkin lymphoma has been reported yet."

Graded PARTIAL because of what the sentence is: a background count in the introduction of a report about a different question, with no stated method. It bounds the literature loosely and is not a prevalence measurement.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from IFAP Syndrome 1:

SREBF1-related hereditary mucoepithelial dysplasia (IFAP syndrome 2)

Overlapping Features The differential that genetic testing actually resolves, and the one with the largest consequence for counselling: it is autosomal dominant, so the recurrence risk is entirely different from the X-linked recessive risk this entry carries. It is also the mechanistically interesting one. SREBF1 encodes SREBP - the substrate of the protease curated here, one step downstream. A dominant SREBF1 disease that shares this much of the clinical spectrum is evidence about which of the two S2P substrate arms carries the phenotype, and it is used as such in the ATF6 discussion below rather than left as a diagnostic footnote. Note the naming. MONDO carries this as MONDO:0100221 "IFAP syndrome 2", and the clinical literature calls it hereditary mucoepithelial dysplasia. They are the same concept approached from two directions; a search on one name alone will miss the other.

Distinguishing Features

Autosomal dominant, so an affected parent or a dominant pedigree argues for SREBF1 and against MBTPS2.
Mucosal involvement and perineal erythema are HMD features not typical of IFAP.
Alopecia is non-scarring in both, so it does not separate them; the mucosal findings and the inheritance pattern do.

Show evidence (3 references)

PMID:33742461 SUPPORT Human Clinical

"Hereditary mucoepithelial dysplasia (HMD) is a dominantly inherited disease characterized by keratitis, non-scarring alopecia, skin lesions including follicular keratosis, perineal erythema, and mucosal involvement."

The HMD phenotype and its dominant inheritance, which is what makes this differential consequential rather than academic.

PMID:33742461 SUPPORT Human Clinical

"Recently, variants in SREBF1, a gene coding for a transcription factor related to cholesterol and fatty acid synthesis, have been associated with the disease."

Identifies the gene as SREBF1 and, in the same sentence, its role in the lipid-synthesis programme that MBTPS2 activates - the basis for the mechanistic argument in the ATF6 discussion.

PMID:33742461 SUPPORT Human Clinical

"These two syndromes share a common clinical spectrum."

The overlap that makes this a differential rather than an unrelated condition.

Keratosis follicularis spinulosa decalvans

Overlapping Features The nearest allelic differential, and the one most likely to be confused. Also MBTPS2, also X-linked, also follicular hyperkeratosis with hair loss and photophobia - but the hair loss is progressive and cicatricial rather than congenital atrichia, and the corneal disease is milder.

Distinguishing Features

Atrichia in IFAP is congenital and near-total; hair loss in KFSD is progressive and scarring.
Both are MBTPS2 disorders, so the gene result does not separate them - the phenotype does.

Show evidence (1 reference)

PMID:33743732 SUPPORT Other

"how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis..."

Establishes KFSD as an allelic disorder of the same gene, which is what makes it a differential that genetic testing alone cannot resolve.

X-linked Olmsted syndrome

Overlapping Features Also allelic. The distinction is genuinely contested rather than merely difficult: a patient with the IFAP triad plus Olmsted-like periorificial and palmoplantar keratoderma has been reported, and the authors argued the overlap may challenge whether the X-linked form of Olmsted syndrome exists as an independent condition at all.

Distinguishing Features

Periorificial and palmoplantar keratoderma is the Olmsted-like element; it occurs in IFAP patients too, including with a variant that produced IFAP without keratoderma in others.

Show evidence (1 reference)

PMID:24313295 SUPPORT Human Clinical

"The concomitance of Olmsted syndrome-like features in this patient with IFAP may challenge the existence of the X-linked form of Olmsted syndrome as an independent condition."

The authors' own nosological doubt, which is the substance of this differential rather than a list of separating features.

🧫

Experimental Models

1

CHO M19 site-2-protease-deficient complementation assay CELL_LINE

Chinese hamster ovary M19 cells lack endogenous S2P and therefore cannot grow without exogenous cholesterol and lipid. Transfecting human MBTPS2 rescues them, and patient variants rescue them only partially - read out both by an SRE-regulated reporter and by growth in lipid-free medium. This is the assay the entire pathogenicity classification of MBTPS2 variants rests on, and it is the reason the severity relationship in this disease is quantitative rather than categorical.

Pathograph links

Impaired SREBP-Driven Lipid Synthesis measures fidelity: moderate Quantifies residual S2P activity through its SREBP output, which is what makes the activity-severity correlation measurable. Curated as MEASURES rather than RECAPITULATES on purpose: the cell line does not model IFAP, it assays one function of the mutant protein. Nothing about a hamster ovary cell reproduces a hair follicle or a corneal limbus.

Limitations: Two limits worth stating. The readout is the SREBP arm; the assay in its original form says nothing about ATF6, which is why the ER-stress node is graded lower. And a rodent ovary-derived line carries none of the tissue-specific context that determines why the phenotype falls on skin, hair and cornea rather than on the many other tissues that need SREBP.

Readouts

SRE-regulated reporter induction and growth in lipid-free medium

Direction: DECREASED

Interpretation: Patient variants complement the M19 deficiency less well than wild-type MBTPS2, and the shortfall is graded rather than all-or-none.

Show evidence (1 reference)

PMID:19361614 SUPPORT In Vitro

"Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids."

The two readouts of the assay, in the paper that established it for this gene.

Show evidence (1 reference)

PMID:19361614 SUPPORT In Vitro

"The degree of diminished activity correlated with clinical severity as noted in male patients."

Supports treating this assay as informative for the disease: its output tracks the clinical phenotype.

{ }

Source YAML

click to show

name: IFAP Syndrome 1
creation_date: "2026-08-29T12:40:00Z"
category: Mendelian
disease_term:
  preferred_term: IFAP syndrome
  term:
    id: MONDO:0100213
    label: IFAP syndrome 1, with or without BRESHECK syndrome
description: >-
  IFAP syndrome is an X-linked genodermatosis defined by a congenital triad -
  ichthyosis follicularis, atrichia, and photophobia - caused by hypomorphic
  variants in MBTPS2, which encodes site-2 protease (S2P).

  The reason one protease produces skin, hair and eye disease at once is that S2P
  is not a pathway enzyme but a shared switch. It performs the second,
  membrane-embedded cut of regulated intramembrane proteolysis, and it does so for
  two unrelated regulators: SREBP, which drives cholesterol and fatty-acid
  synthesis, and ATF6, which carries the endoplasmic-reticulum stress response.
  Losing S2P activity therefore degrades barrier lipid synthesis and the ER stress
  response together, in every tissue that depends on either - the cornified
  epidermis, the hair follicle, and the corneal and limbal epithelium.

  The disease has an unusual property that makes it worth curating carefully:
  severity is a dose of enzyme activity rather than a category. Every reported
  allele is hypomorphic - complete loss of S2P is presumably not viable - and the
  original gene-identification study measured residual protease activity for five
  patient variants in a complementation assay and found the degree of diminished
  activity correlated with clinical severity. The same continuum runs from
  isolated IFAP up to BRESHECK syndrome, the IFAP triad plus intellectual
  disability and multiple congenital anomalies, which is curated here as a subtype
  rather than as a separate disease.

  The eye is the organ that carries most of the morbidity and the part most often
  under-described. Photophobia is not a symptom of dry eye but the surface
  expression of a progressive vascularising keratopathy, and anterior-segment
  imaging in an infant followed from six days old points at limbal stem cell
  dysfunction as the lesion - which reframes the ocular problem from one of
  lubrication to one of stem-cell failure.
parents:
- hereditary disease
- Genodermatosis
synonyms:
- IFAP
- ichthyosis follicularis, atrichia and photophobia syndrome
- ichthyosis follicularis-alopecia-photophobia syndrome
- IFAP/BRESHECK syndrome
- MBTPS2-related IFAP syndrome
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
    notes: >-
      The presenting features are cutaneous and the diagnosis is usually made by a
      dermatologist on the triad.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      An X-linked Mendelian disorder mapped by linkage and identified by
      candidate-gene sequencing.
references:
- reference: PMID:19361614
  title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
- reference: PMID:33743732
  title: "MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders."
- reference: PMID:34655156
  title: "A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response."
- reference: PMID:32482964
  title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
- reference: PMID:15370546
  title: "Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome."
- reference: PMID:24313295
  title: "Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient."
- reference: PMID:16268889
  title: "Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin."
- reference: PMID:28654459
  title: "Hodgkin Lymphoma in a Patient With IFAP Syndrome: A Case Report and Review of Literature."
- reference: PMID:33742461
  title: "Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum."
- reference: PMID:38089015
  title: "Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome in a Saudi Child: A Case Report."
- reference: PMID:21670910
  title: "Ichthyosis follicularis, alopecia and photophobia syndrome (IFAP): report of the first case with ocular and cutaneous manifestations in Brazil with a favorable response to treatment."
- reference: PMID:30431684
  title: "A novel autosomal recessive GJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss, and punctate palmoplantar keratoderma."
has_subtypes:
- name: BRESHECK
  display_name: BRESHECK syndrome (severe multisystem end of the spectrum)
  description: >-
    The IFAP triad plus intellectual disability and multiple congenital anomalies.
    The acronym expands to brain anomalies, retardation of mentality and growth,
    ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear
    deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and
    kidney dysplasia or hypoplasia.

    Curated as a subtype rather than a separate disease because it is the severe
    end of one activity continuum, not a different mechanism: the same gene, the
    same class of hypomorphic allele, and a functional assay showing the same two
    pathways impaired. The MONDO label itself lumps them - "IFAP syndrome 1, with
    or without BRESHECK syndrome".
  evidence:
  - reference: PMID:34655156
    reference_title: "A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by
      the IFAP triad plus intellectual disability and multiple congenital
      anomalies.
    explanation: >-
      Defines BRESHECK as the IFAP triad plus additional features, from the same
      gene - the basis for curating it as a subtype.
  - reference: PMID:24313295
    reference_title: "Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BRESHECK (brain anomalies, retardation of mentality and growth, ectodermal
      dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and
      deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney
      dysplasia/hypoplasia) syndrome
    explanation: >-
      The full expansion of the acronym, curated verbatim so the subtype
      description does not have to be trusted.
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    MBTPS2 is on Xp22, and affected individuals are male. The locus was mapped to
    a 5.4 Mb interval between DXS989 and DXS8019 before the gene was identified.

    Carrier females are not uniformly unaffected. Mosaic cutaneous lesions along
    Blaschko lines are described, and an ocular sign has been proposed: retinal
    vascular tortuosity in the carrier mother of two affected boys. That is a
    single family and is curated as such - it is a lead for examining carriers,
    not an established carrier test.
  evidence:
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a
      rare X-linked, oculocutaneous human disorder.
    explanation: >-
      The X-linked classification and the oculocutaneous framing of the entity.
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and
      DXS8019 on Xp22.11-p22.13
    explanation: >-
      The mapping interval, which is what established X-linkage before the gene
      was known.
  - reference: PMID:15370546
    reference_title: "Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Retinal vascular tortuosity may be another clinical sign of carrier status
      in females.
    explanation: >-
      Graded PARTIAL, and the source's own "may be" is the reason. This is one
      carrier mother in one family; it supports the proposal, not the sign.
pathophysiology:
- name: Hypomorphic MBTPS2 Variant
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Missense variants exchanging highly conserved residues, and splice-site
    variants, in MBTPS2. The allelic spectrum is hypomorphic rather than null:
    every reported variant leaves some residual protease activity, and the amount
    left is what the phenotype tracks.

    That is not merely an observation about severity - it constrains what kind of
    variant can be pathogenic here. A curator or laboratory assessing a novel
    MBTPS2 variant should expect partial loss of function, and a variant predicted
    to abolish the protein entirely would be atypical for this entity rather than
    a confidently severe allele.
  genes:
  - preferred_term: MBTPS2
    term:
      id: hgnc:15455
      label: MBTPS2
  molecular_functions:
  - preferred_term: site-2 protease intramembrane cleavage activity
    modifier: DECREASED
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
  evidence:
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      provide evidence that missense mutations exchanging highly conserved amino
      acids of membrane-bound transcription factor protease, site 2 (MBTPS2) are
      associated with this phenotype
    explanation: >-
      The gene-disease assertion and the variant class.
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling
      proteins involved in sterol control of transcription and ER stress
      response.
    explanation: >-
      The enzyme class and the two pathways it serves, which is the whole basis
      for the two-arm pathograph below.
  downstream:
  - target: Reduced Regulated Intramembrane Proteolysis
    causal_link_type: DIRECT
- name: Reduced Regulated Intramembrane Proteolysis
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    S2P makes the second cut of a two-cut cascade. SREBP and ATF6 are cleaved
    first by site-1 protease and then, within the membrane, by S2P, which releases
    the active transcription-factor domain into the cytosol. Reduce S2P activity
    and both substrates are released less efficiently.

    This node is the reason the disease looks pleiotropic. Two entirely unrelated
    transcriptional programmes share one protease, so a single hypomorphic allele
    hits lipid synthesis and the stress response together rather than choosing one.
  cellular_components:
  - preferred_term: Golgi membrane
    term:
      id: GO:0000139
      label: Golgi membrane
  evidence:
  - reference: PMID:33743732
    reference_title: "MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription
      factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and
      activates several signaling and regulatory proteins from the membrane.
    explanation: >-
      The intramembrane-cleavage function. Graded OTHER: this is a review's
      background statement of established biochemistry, not a result the paper
      reports.
  - reference: PMID:33743732
    reference_title: "MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The MBTPS2 is critical for a myriad of cellular processes, ranging from the
      regulation of cholesterol homeostasis to unfolded protein responses.
    explanation: >-
      States the two-pathway breadth that the fork below represents.
  downstream:
  - target: Impaired SREBP-Driven Lipid Synthesis
    causal_link_type: DIRECT
  - target: Impaired ATF6 Endoplasmic Reticulum Stress Response
    causal_link_type: DIRECT
- name: Impaired SREBP-Driven Lipid Synthesis
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Less active SREBP reaches the nucleus, so cholesterol and fatty-acid synthesis
    genes are under-induced. The functional signature of this in the assays used to
    prove variant pathogenicity is failure to grow in cholesterol-depleted medium -
    a cell that cannot make its own lipid and is no longer given any.

    In the epidermis this is the barrier-lipid arm: the cornified envelope depends
    on locally synthesised lipids, and a follicular hyperkeratosis is what a
    failing keratinisation programme looks like at the skin surface.
  biological_processes:
  - preferred_term: SREBP signaling pathway
    modifier: DECREASED
    term:
      id: GO:0032933
      label: SREBP signaling pathway
  - preferred_term: cholesterol biosynthesis
    modifier: DECREASED
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Wild-type MBTPS2 was able to complement the protease deficiency in Chinese
      hamster M19 cells as shown by induction of an SRE-regulated reporter gene in
      transient transfection experiments and by growth of stably transfected cells
      in media devoid of cholesterol and lipids.
    explanation: >-
      The complementation assay that reads out this node, and the two measurements
      it uses.
  - reference: PMID:34655156
    reference_title: "A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro modeling supports variant pathogenicity, with impaired cell growth
      in cholesterol-depleted media, attenuated activation of the sterol
      regulatory element-binding protein pathway, and failure to activate the
      endoplasmic reticulum stress response pathway.
    explanation: >-
      An independent demonstration in a different variant, and the only single
      sentence in the literature reviewed here that measures both arms of the
      fork in the same experiment.
  downstream:
  - target: Defective Epidermal and Follicular Keratinization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Progressive Vascularising Keratopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired ATF6 Endoplasmic Reticulum Stress Response
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    ATF6 is the second S2P substrate, and it is the arm of the unfolded protein
    response that depends on the same two cuts. A BRESHECK-associated variant was
    shown to fail to activate the ER stress response entirely, alongside its
    attenuated SREBP effect.

    Graded PROVISIONAL rather than ESTABLISHED, and the distinction from the SREBP
    node is deliberate. The biochemistry is not in doubt - S2P cleaves ATF6, and
    the assay result is clear. What is not established is that this arm
    *contributes to the human phenotype*: no clinical feature of IFAP has been
    tied to loss of ATF6 signalling specifically, and every phenotype the entry
    curates could in principle be explained by the SREBP arm alone. The node is
    kept because a mechanism curated only where it is convenient is not a
    mechanism, and because it predicts things the SREBP arm does not.
  biological_processes:
  - preferred_term: ATF6-mediated unfolded protein response
    modifier: DECREASED
    term:
      id: GO:0036500
      label: ATF6-mediated unfolded protein response
  - preferred_term: response to endoplasmic reticulum stress
    modifier: DECREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  evidence:
  - reference: PMID:34655156
    reference_title: "A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro modeling supports variant pathogenicity, with impaired cell growth
      in cholesterol-depleted media, attenuated activation of the sterol
      regulatory element-binding protein pathway, and failure to activate the
      endoplasmic reticulum stress response pathway.
    explanation: >-
      The measured failure of ER-stress activation. Note the asymmetry the source
      itself reports: the SREBP pathway was "attenuated" while the ER stress
      response failed outright.
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our findings indicate that the phenotypic expression of IFAP syndrome is
      quantitatively related to a reduced function of a key cellular regulatory
      system affecting cholesterol homeostasis and ability to cope with ER stress.
    explanation: >-
      Names both arms together as the affected system, which is the only
      published statement tying the ER-stress arm to the human phenotype - and it
      does so by naming the pair rather than by isolating this arm.

      Graded IN_VITRO despite the sentence being about phenotypic expression in
      patients, because the quantitative relationship it asserts is measured by
      the CHO M19 complementation assay; the clinical severity is the variable it
      is correlated against, not the evidence for the mechanism. Grading it
      HUMAN_CLINICAL would credit the ER-stress claim with human measurement that
      was never made - no ER stress has been measured in any IFAP patient tissue,
      which is the whole point of the discussion this node carries.
- name: Defective Epidermal and Follicular Keratinization
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: PROVISIONAL
  description: >-
    The skin and hair phenotype: spiny follicular hyperkeratosis and near-total
    absence of scalp hair, eyebrows and eyelashes from birth.

    Graded PROVISIONAL because the step from an impaired lipid-synthesis programme
    to this specific histology is inferred, not demonstrated. No study reviewed here
    measures barrier lipids, cornified envelope composition or follicular
    differentiation markers in IFAP skin. The disease is defined clinically at this
    level and mechanistically two levels up, with the connection assumed.
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  - preferred_term: hair follicle
    term:
      id: UBERON:0002073
      label: hair follicle
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  evidence:
  - reference: PMID:24313295
    reference_title: "Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the typical triad of IFAP syndrome (i.e. ichthyosis, atrichia and
      photophobia), along with pachyonychia, palmoplantar and periorificial
      keratoderma
    explanation: >-
      The cutaneous phenotype including the keratoderma that extends it in some
      patients.
- name: Progressive Vascularising Keratopathy
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: PROVISIONAL
  description: >-
    The ocular phenotype, and the one that carries the morbidity. Photophobia is
    the symptom; the disease is a keratopathy that progresses through spontaneous
    epithelial defects, superficial and deep corneal vascularisation, and scarring
    to counting-fingers acuity.

    The most informative observation is developmental rather than static. An
    infant diagnosed at six days had clear corneas; the epithelial defects appeared
    at six months, and imaging then showed limbal thickening, peripheral pannus,
    conjunctivalisation and abnormal hyperreflective epithelium - the picture of
    limbal stem cell dysfunction. So the cornea is not malformed, it fails to
    maintain itself, which is a different therapeutic target.

    Graded PROVISIONAL: the limbal-failure account rests on one prospectively
    followed infant, and no histology or limbal-marker study has been published.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  - preferred_term: corneal epithelium
    term:
      id: UBERON:0001772
      label: corneal epithelium
  evidence:
  - reference: PMID:32482964
    reference_title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The progressive conjunctivalization, spontaneous epithelial defects, and
      anterior segment optical coherence tomography features are highly suggestive
      of limbal stem cell dysfunction in IFAP syndrome.
    explanation: >-
      The limbal-failure interpretation, in the authors' own hedged words -
      "highly suggestive of", which is what the PROVISIONAL grade records.
  - reference: PMID:32482964
    reference_title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial examination showed hyperkeratotic eyelids, madarosis, and
      lagophthalmos, but otherwise clear corneas. He developed bilateral central
      corneal epithelial defects spontaneously 6 months later
    explanation: >-
      The developmental sequence - normal cornea at six days, breakdown at six
      months - which is what distinguishes maintenance failure from malformation.
  - reference: PMID:15370546
    reference_title: "Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both affected male children had severe photophobia, total superficial and
      deep corneal vascularization, and reduction of vision to counting fingers.
    explanation: >-
      The endpoint of the progression, in two siblings.
phenotypes:
- category: Dermatological
  name: Ichthyosis Follicularis
  frequency: OBLIGATE
  description: >-
    Generalized spiny keratotic follicular papules, present from birth. The first
    element of the defining triad.
  phenotype_term:
    preferred_term: Ichthyosis follicularis
    term:
      id: HP:0031291
      label: Ichthyosis follicularis
  evidence:
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a
      rare X-linked, oculocutaneous human disorder.
    explanation: >-
      The triad as the definition of the entity, which is what makes each of its
      three elements obligate.
- category: Dermatological
  name: Atrichia
  frequency: OBLIGATE
  description: >-
    Near-total absence of scalp hair, eyebrows and eyelashes. The absent eyelashes
    and hyperkeratotic lids also contribute to the ocular surface problem, so this
    is not a purely cosmetic feature.
  phenotype_term:
    preferred_term: Atrichia
    term:
      id: HP:0500262
      label: Atrichia
  evidence:
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a
      rare X-linked, oculocutaneous human disorder.
    explanation: >-
      Atrichia as a defining element of the triad.
  - reference: PMID:32482964
    reference_title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial examination showed hyperkeratotic eyelids, madarosis, and
      lagophthalmos, but otherwise clear corneas.
    explanation: >-
      Madarosis - loss of lashes and brows - documented at six days old, together
      with the lid changes that make it ocularly consequential.
- category: Ophthalmological
  name: Photophobia
  frequency: OBLIGATE
  description: >-
    The third element of the triad, and a surface symptom of the keratopathy rather
    than an independent finding.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:15370546
    reference_title: "Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both affected male children had severe photophobia, total superficial and
      deep corneal vascularization, and reduction of vision to counting fingers.
    explanation: >-
      Photophobia documented alongside the corneal disease it reflects.
- category: Ophthalmological
  name: Corneal Neovascularization
  frequency: FREQUENT
  description: >-
    Superficial and deep corneal vascularisation, progressing to scarring and
    severe visual loss. Described as inexorable in the two siblings followed for
    it.
  phenotype_term:
    preferred_term: Corneal neovascularization
    term:
      id: HP:0011496
      label: Corneal neovascularization
  evidence:
  - reference: PMID:15370546
    reference_title: "Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males with IFAP have an inexorable progression of corneal vascularization
      and loss of vision.
    explanation: >-
      The progression and its visual endpoint.
- category: Ophthalmological
  name: Limbal Stem Cell Deficiency
  frequency: OCCASIONAL
  description: >-
    Limbal thickening, peripheral pannus, conjunctivalisation and abnormal
    hyperreflective epithelium over thinned stroma. Curated as a distinct phenotype
    rather than folded into the keratopathy, because it names a different lesion
    with different implications for treatment.
  phenotype_term:
    preferred_term: Limbal stem cell deficiency
    term:
      id: HP:0032107
      label: Limbal stem cell deficiency
  evidence:
  - reference: PMID:32482964
    reference_title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anterior segment optical coherence tomography demonstrated a significantly
      abnormal and hyperreflective epithelial surface overlying a thinned corneal
      stroma, suggestive of limbal stem cell dysfunction.
    explanation: >-
      Graded PARTIAL and banded OCCASIONAL for the same reason: this is one
      patient, imaged rather than biopsied, and the source says "suggestive of".
      The band records how often it has been *looked for*, not how often it is
      present - it may well be universal.
- category: Dermatological
  name: Palmoplantar Keratoderma
  frequency: OCCASIONAL
  description: >-
    Present in some patients and absent in others carrying the identical variant,
    which is the clearest published example of variable expressivity in this
    disease.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:24313295
    reference_title: "Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this mutation was previously reported in two cases of IFAP without
      keratoderma, which suggests clinical heterogeneicity of the same mutation in
      MBTPS2
    explanation: >-
      The same c.671-9T>G allele with and without keratoderma across three
      patients - which is why this is banded OCCASIONAL and why the entry does not
      treat keratoderma as genotype-predicted. The source's spelling
      "heterogeneicity" is reproduced as published.
- category: Dermatological
  name: Nail Dystrophy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:24313295
    reference_title: "Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with pachyonychia, palmoplantar and periorificial keratoderma, which
      were reminiscent of Olmsted syndrome
    explanation: >-
      Pachyonychia in the reported patient, curated under the general nail
      dystrophy term.
genetic:
- name: MBTPS2
  gene_term:
    preferred_term: MBTPS2
    term:
      id: hgnc:15455
      label: MBTPS2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  features: >-
    MBTPS2 encodes site-2 protease, a membrane-embedded zinc metalloprotease that
    performs the intramembrane cleavage step of regulated intramembrane
    proteolysis for SREBP and ATF6. Both missense and splice-site variants are
    pathogenic.
  notes: >-
    Three things about this gene that a variant-interpretation reader needs.

    First, the genotype-phenotype relationship here is quantitative and was
    measured, not inferred. The gene-identification study assayed five patient
    variants for residual activity and found the degree of diminished activity
    correlated with clinical severity in male patients. That is unusually direct
    for a rare disease, and it is why the disease-BRESHECK continuum is curated as
    one entity.

    Second, that correlation coexists with real variable expressivity within a
    single allele. The intronic variant c.671-9T>G produced IFAP with Olmsted-like
    keratoderma in one patient and IFAP without keratoderma in two others. So
    residual activity predicts severity along the main axis while leaving
    individual features unpredictable - both statements are true and neither
    should be dropped.

    Third, MBTPS2 is an allelic series across several distinct diseases: IFAP with
    or without BRESHECK, keratosis follicularis spinulosa decalvans, an X-linked
    form of Olmsted syndrome, and osteogenesis imperfecta type XIX. Two of those
    already have dismech entries. Why the same gene produces a bone disease in one
    family and a skin-and-eye disease in another is explicitly unresolved in the
    review literature - it is not a matter of a curator not having looked it up.
  evidence:
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The degree of diminished activity correlated with clinical severity as noted
      in male patients.
    explanation: >-
      The measured activity-severity correlation, which is the central
      genotype-phenotype fact of this disease.
  - reference: PMID:19361614
    reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These functions were impaired in five mutations as detected in unrelated
      patients.
    explanation: >-
      The number of patient variants assayed, which bounds how much weight the
      correlation can carry.
  - reference: PMID:24313295
    reference_title: "Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a recurrent intronic mutation in MBTPS2 (c.671-9T>G) in a Chinese
      patient with the typical triad of IFAP syndrome
    explanation: >-
      A splice-site variant in the pathogenic spectrum, and the allele behind the
      variable-expressivity observation.
  - reference: PMID:33743732
    reference_title: "MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      how mutations in the MBTPS2 gene lead to several human disorders with
      different phenotypes including Ichthyosis Follicularis, Atrichia and
      Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis
      Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis
      Imperfecta type XIX remains obscure
    explanation: >-
      The allelic series and, in the same sentence, the explicit statement that
      how one gene produces them is unresolved.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No prevalence or incidence figure exists. The commonly repeated count is
    "40 cases reported", and that number deserves a caveat rather than
    repetition: it comes from the introduction of a case report about Hodgkin
    lymphoma in an IFAP patient, not from a systematic review or a registry. It is
    a background sentence in a paper about something else, and no method for
    arriving at it is given.

    It is curated because it is the only quantitative anchor available and because
    a reader will otherwise meet it uncited elsewhere, but it is graded PARTIAL and
    rate_per_100000 is left empty.
  evidence:
  - reference: PMID:28654459
    reference_title: "Hodgkin Lymphoma in a Patient With IFAP Syndrome: A Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 40 cases has been reported, but no correlation with Hodgkin
      lymphoma has been reported yet.
    explanation: >-
      Graded PARTIAL because of what the sentence is: a background count in the
      introduction of a report about a different question, with no stated method.
      It bounds the literature loosely and is not a prevalence measurement.
treatments:
- name: Systemic Acitretin
  description: >-
    A systemic retinoid, tried for the cutaneous and corneal features. The reported
    response is partial in a specific and consistent way: skin and corneal erosions
    improve, alopecia and photophobia do not.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_mechanisms:
  - target: Defective Epidermal and Follicular Keratinization
    treatment_effect: MODULATES
    description: >-
      Retinoids act on keratinocyte differentiation, so the plausible target is the
      keratinisation node rather than the protease defect upstream of it. Curated
      as MODULATES rather than RESTORES: nothing about the treatment restores S2P
      activity, and the reported improvement is partial.
    evidence:
    - reference: PMID:16268889
      reference_title: "Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A moderate response to acitretin therapy (1 mg/kg) administered for 6
        months was observed, with improvement in cutaneous features and corneal
        erosions and no change in alopecia or photophobia.
      explanation: >-
        Graded PARTIAL on the source's own terms - a "moderate response" in a
        single patient, with two of the three triad features explicitly unchanged.
  evidence:
  - reference: PMID:16268889
    reference_title: "Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a 3-year-old male patient with the ichthyosis follicularis,
      alopecia and photophobia (IFAP) syndrome, who developed cutaneous and ocular
      involvement in infancy.
    explanation: >-
      Establishes the evidence base as a single three-year-old patient, which is
      the fact that most constrains how this treatment should be read.
  notes: >-
    The deep-research report that accompanied this curation proposed NCIT:C29496
    as the term for "Acitretin ~1 mg/kg". That identifier does not exist in NCIT -
    its own term-validation section flagged it as most likely invented. The
    treatment is instead curated with the generic Pharmacotherapy action term plus
    a CHEBI therapeutic_agent, which is the pattern CLAUDE.md prescribes and which
    validates.

    A dose does not belong in an ontology binding in any case. The 1 mg/kg figure
    lives in the evidence snippet, where it is attributable.
- name: Ocular Surface Protection
  description: >-
    The mainstay of ocular care, and on the limbal-failure reading of the disease
    it is a holding measure rather than a treatment of the lesion. Aggressive
    lubrication, prophylactic antibiotics and lateral tarsorrhaphy maintained a
    stable corneal surface in the one infant followed prospectively from diagnosis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Progressive Vascularising Keratopathy
    treatment_effect: MODULATES
    description: >-
      Protects the ocular surface without addressing the limbal stem-cell failure
      that is failing to maintain it.
    evidence:
    - reference: PMID:32482964
      reference_title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The corneal surface was maintained with lubrication and tarsorrhaphy and
        has remained stable since.
      explanation: >-
        The reported outcome of surface protection in that patient.
  evidence:
  - reference: PMID:32482964
    reference_title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which were managed with aggressive lubrication, prophylactic antibiotics,
      and bilateral permanent lateral tarsorrhaphies at 7 months of age
    explanation: >-
      The specific measures used, with the age at which they were needed.
  notes: >-
    Curated with an explicit target link even though it is supportive care, because
    on this entry's reading the ocular problem is stem-cell failure and surface
    protection is the only thing currently offered against it. Saying that plainly
    is more useful than leaving the ocular arm with no treatment attached.
- name: Emollients and Urea Keratolytics
  description: >-
    The cutaneous mainstay, and the treatment most IFAP patients are actually on.
    Topical urea for the plantar keratoderma and constant moisturisers for the
    generalized xerosis.

    Curated because its absence left the entry offering nothing for the skin
    except a systemic retinoid evidenced by one three-year-old - which
    misrepresents ordinary care for this disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: urea
      term:
        id: CHEBI:16199
        label: urea
  target_mechanisms:
  - target: Defective Epidermal and Follicular Keratinization
    treatment_effect: MODULATES
    description: >-
      Urea is keratolytic and humectant, acting on the abnormal stratum corneum
      itself rather than on the protease defect that produced it. Symptomatic by
      construction, which is why the effect is MODULATES.
    evidence:
    - reference: PMID:38089015
      reference_title: "Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome in a Saudi Child: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was given symptomatic treatment with urea cream for plantar
        keratoderma and was advised to apply constant moisturizers to avoid
        generalized xerosis.
      explanation: >-
        The topical regimen as given, with the indication for each component.
  evidence:
  - reference: PMID:38089015
    reference_title: "Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome in a Saudi Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dermatological and ophthalmological follow-ups were recommended.
    explanation: >-
      Graded PARTIAL: the source reports what was prescribed and that follow-up
      was arranged, not an assessed response. No outcome is claimed here.
- name: Amniotic Membrane Transplantation
  description: >-
    The standard intervention for limbal stem cell deficiency, and on this entry's
    reading of the ocular disease it is the treatment aimed at the actual lesion
    rather than at the surface consequence.

    The one published IFAP case combined it with systemic acitretin, so the two
    cannot be separated in that report - which is stated rather than glossed,
    because the improvement reported includes neuropsychomotor development, which
    no ocular surface procedure explains.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Progressive Vascularising Keratopathy
    treatment_effect: MODULATES
    description: >-
      Provides a substrate for epithelial healing over a limbus that is failing to
      maintain the corneal surface. It supports the failing compartment rather
      than restoring it, so MODULATES rather than RESTORES.
    evidence:
    - reference: PMID:21670910
      reference_title: "Ichthyosis follicularis, alopecia and photophobia syndrome (IFAP): report of the first case with ocular and cutaneous manifestations in Brazil with a favorable response to treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After three months using systemic retinoid (Acitretina) and posterior
        amniotic membrane transplantation in the left eye, there was a significant
        improvement of photophobia, corneal erosions and neuropsychomotor
        development.
      explanation: >-
        Graded PARTIAL because the transplant and the retinoid were given together
        and the reported improvement cannot be attributed to either alone. The
        inclusion of neuropsychomotor development among the improvements is a
        further reason for caution - it is not an outcome an ocular procedure
        would produce, and its presence suggests the assessment was global rather
        than eye-specific.
  evidence:
  - reference: PMID:21670910
    reference_title: "Ichthyosis follicularis, alopecia and photophobia syndrome (IFAP): report of the first case with ocular and cutaneous manifestations in Brazil with a favorable response to treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was treated with artificial tears and punctal occlusion with small
      improvement of photophobia.
    explanation: >-
      The prior, purely surface-directed treatment and its limited effect - which
      is the comparison that makes the subsequent intervention interesting, and
      is consistent with the surface not being where the lesion is.
experimental_models:
- name: CHO M19 site-2-protease-deficient complementation assay
  experimental_model_type: CELL_LINE
  description: >-
    Chinese hamster ovary M19 cells lack endogenous S2P and therefore cannot grow
    without exogenous cholesterol and lipid. Transfecting human MBTPS2 rescues
    them, and patient variants rescue them only partially - read out both by an
    SRE-regulated reporter and by growth in lipid-free medium.

    This is the assay the entire pathogenicity classification of MBTPS2 variants
    rests on, and it is the reason the severity relationship in this disease is
    quantitative rather than categorical.
  modeled_mechanisms:
  - target: Impaired SREBP-Driven Lipid Synthesis
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Quantifies residual S2P activity through its SREBP output, which is what
      makes the activity-severity correlation measurable.

      Curated as MEASURES rather than RECAPITULATES on purpose: the cell line does
      not model IFAP, it assays one function of the mutant protein. Nothing about
      a hamster ovary cell reproduces a hair follicle or a corneal limbus.
    limitations: >-
      Two limits worth stating. The readout is the SREBP arm; the assay in its
      original form says nothing about ATF6, which is why the ER-stress node is
      graded lower. And a rodent ovary-derived line carries none of the
      tissue-specific context that determines why the phenotype falls on skin,
      hair and cornea rather than on the many other tissues that need SREBP.
    readouts:
    - name: SRE-regulated reporter induction and growth in lipid-free medium
      target: Impaired SREBP-Driven Lipid Synthesis
      direction: DECREASED
      interpretation: >-
        Patient variants complement the M19 deficiency less well than wild-type
        MBTPS2, and the shortfall is graded rather than all-or-none.
      evidence:
      - reference: PMID:19361614
        reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Wild-type MBTPS2 was able to complement the protease deficiency in
          Chinese hamster M19 cells as shown by induction of an SRE-regulated
          reporter gene in transient transfection experiments and by growth of
          stably transfected cells in media devoid of cholesterol and lipids.
        explanation: >-
          The two readouts of the assay, in the paper that established it for this
          gene.
    evidence:
    - reference: PMID:19361614
      reference_title: "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The degree of diminished activity correlated with clinical severity as
        noted in male patients.
      explanation: >-
        Supports treating this assay as informative for the disease: its output
        tracks the clinical phenotype.
differential_diagnoses:
- name: SREBF1-related hereditary mucoepithelial dysplasia (IFAP syndrome 2)
  description: >-
    The differential that genetic testing actually resolves, and the one with the
    largest consequence for counselling: it is autosomal dominant, so the
    recurrence risk is entirely different from the X-linked recessive risk this
    entry carries.

    It is also the mechanistically interesting one. SREBF1 encodes SREBP - the
    substrate of the protease curated here, one step downstream. A dominant
    SREBF1 disease that shares this much of the clinical spectrum is evidence
    about which of the two S2P substrate arms carries the phenotype, and it is
    used as such in the ATF6 discussion below rather than left as a diagnostic
    footnote.

    Note the naming. MONDO carries this as MONDO:0100221 "IFAP syndrome 2", and
    the clinical literature calls it hereditary mucoepithelial dysplasia. They
    are the same concept approached from two directions; a search on one name
    alone will miss the other.
  distinguishing_features:
  - Autosomal dominant, so an affected parent or a dominant pedigree argues for SREBF1 and against MBTPS2.
  - Mucosal involvement and perineal erythema are HMD features not typical of IFAP.
  - Alopecia is non-scarring in both, so it does not separate them; the mucosal findings and the inheritance pattern do.
  evidence:
  - reference: PMID:33742461
    reference_title: "Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary mucoepithelial dysplasia (HMD) is a dominantly inherited disease
      characterized by keratitis, non-scarring alopecia, skin lesions including
      follicular keratosis, perineal erythema, and mucosal involvement.
    explanation: >-
      The HMD phenotype and its dominant inheritance, which is what makes this
      differential consequential rather than academic.
  - reference: PMID:33742461
    reference_title: "Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, variants in SREBF1, a gene coding for a transcription factor
      related to cholesterol and fatty acid synthesis, have been associated with
      the disease.
    explanation: >-
      Identifies the gene as SREBF1 and, in the same sentence, its role in the
      lipid-synthesis programme that MBTPS2 activates - the basis for the
      mechanistic argument in the ATF6 discussion.
  - reference: PMID:33742461
    reference_title: "Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These two syndromes share a common clinical spectrum.
    explanation: >-
      The overlap that makes this a differential rather than an unrelated
      condition.
- name: GJB2-related ichthyosis follicularis with hearing loss and keratoderma
  description: >-
    A separate autosomal recessive syndrome in which ichthyosis follicularis
    occurs with severe bilateral sensorineural hearing loss and punctate
    palmoplantar keratoderma, from compound heterozygous GJB2 variants. Included
    because it shows the cutaneous element is not specific to the SREBP pathway at
    all.
  distinguishing_features:
  - Severe bilateral sensorineural hearing loss, which is not a feature of MBTPS2-related IFAP.
  - Autosomal recessive with GJB2 variants including the common c.35delG frameshift.
  evidence:
  - reference: PMID:30431684
    reference_title: "A novel autosomal recessive GJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss, and punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ichthyosis follicularis, a distinct cutaneous entity reported in combination
      with atrichia, and photophobia has been associated with mutations in
      MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis
      follicularis, bilateral severe sensorineural hearing loss and punctate
      palmoplantar keratoderma in two families.
    explanation: >-
      States both the MBTPS2 association and the distinct GJB2 syndrome that
      shares the cutaneous finding.
- name: Keratosis follicularis spinulosa decalvans
  description: >-
    The nearest allelic differential, and the one most likely to be confused. Also
    MBTPS2, also X-linked, also follicular hyperkeratosis with hair loss and
    photophobia - but the hair loss is progressive and cicatricial rather than
    congenital atrichia, and the corneal disease is milder.
  distinguishing_features:
  - Atrichia in IFAP is congenital and near-total; hair loss in KFSD is progressive and scarring.
  - Both are MBTPS2 disorders, so the gene result does not separate them - the phenotype does.
  evidence:
  - reference: PMID:33743732
    reference_title: "MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      how mutations in the MBTPS2 gene lead to several human disorders with
      different phenotypes including Ichthyosis Follicularis, Atrichia and
      Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis
      Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis
      Imperfecta type XIX remains obscure
    explanation: >-
      Establishes KFSD as an allelic disorder of the same gene, which is what makes
      it a differential that genetic testing alone cannot resolve.
- name: X-linked Olmsted syndrome
  description: >-
    Also allelic. The distinction is genuinely contested rather than merely
    difficult: a patient with the IFAP triad plus Olmsted-like periorificial and
    palmoplantar keratoderma has been reported, and the authors argued the overlap
    may challenge whether the X-linked form of Olmsted syndrome exists as an
    independent condition at all.
  distinguishing_features:
  - Periorificial and palmoplantar keratoderma is the Olmsted-like element; it occurs in IFAP patients too, including with a variant that produced IFAP without keratoderma in others.
  evidence:
  - reference: PMID:24313295
    reference_title: "Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The concomitance of Olmsted syndrome-like features in this patient with IFAP
      may challenge the existence of the X-linked form of Olmsted syndrome as an
      independent condition.
    explanation: >-
      The authors' own nosological doubt, which is the substance of this
      differential rather than a list of separating features.
diagnosis:
- name: Recognition of the clinical triad
  presence: PRESENT
  description: >-
    The diagnosis starts as a pattern recognition: ichthyosis follicularis,
    atrichia and photophobia together, in a male, from birth or the first year.
    Each element alone is unremarkable; the combination is not.
  markers: >-
    Generalized spiny follicular keratotic papules, near-total absence of scalp
    hair, eyebrows and eyelashes, and photophobia. Non-scarring alopecia is the
    discriminating quality - scarring alopecia points at KFSD instead.
  evidence:
  - reference: PMID:38089015
    reference_title: "Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome in a Saudi Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The alopecia was non-scarring and was accompanied by mild generalized
      xerosis, photophobia, and recurrent angular cheilitis.
    explanation: >-
      A worked presentation, including the non-scarring quality of the alopecia
      that separates IFAP from KFSD at the bedside.
- name: MBTPS2 sequencing or exome sequencing
  presence: PRESENT
  description: >-
    Confirmatory. Both missense and splice-site variants are pathogenic, and the
    intronic ones (c.671-9T>G, c.970+5G>A) will be missed by an exon-only
    analysis that does not extend into flanking intronic sequence - which matters
    because one of them is recurrent.
  results: >-
    A hemizygous hypomorphic MBTPS2 variant in an affected male. Expect partial
    rather than complete loss of function; a variant predicted to abolish the
    protein entirely would be atypical for this entity.
  evidence:
  - reference: PMID:38089015
    reference_title: "Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome in a Saudi Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genetic testing confirmed an X-linked recessive inheritance of IFAP
      syndrome without BRESHECK syndrome due to the mutation in the MBTPS2
      (300294) gene located on chromosome Xp22.12.
    explanation: >-
      Molecular confirmation in practice, and an example of the genotype being
      used to place a patient at the IFAP rather than the BRESHECK end.
- name: Anterior segment optical coherence tomography
  presence: PRESENT
  description: >-
    Curated as a diagnostic because of what it changes rather than what it
    confirms. Slit-lamp examination shows the corneal surface breaking down; AS-OCT
    showed the abnormal hyperreflective epithelium over thinned stroma that
    reframed the ocular disease as limbal stem cell dysfunction rather than
    exposure keratopathy - which is a different therapeutic target.

    This entry's `pathophysiology` leans on that reframing, so leaving the
    modality that produced it out of `diagnosis:` was an inconsistency.
  markers: >-
    Limbal thickening, peripheral corneal pannus, conjunctivalisation, and an
    abnormal hyperreflective epithelial surface over thinned corneal stroma.
  evidence:
  - reference: PMID:32482964
    reference_title: "Limbal Stem Cell Dysfunction in Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anterior segment optical coherence tomography demonstrated a significantly
      abnormal and hyperreflective epithelial surface overlying a thinned corneal
      stroma, suggestive of limbal stem cell dysfunction.
    explanation: >-
      The imaging finding and the interpretation it supports.
discussions:
- discussion_id: ifap_atf6_arm_unattached_to_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does loss of ATF6 signalling contribute anything to the IFAP phenotype, or is
    the disease explained by the SREBP arm alone?
  attaches_to:
  - "pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response"
  - "pathophysiology#Impaired SREBP-Driven Lipid Synthesis"
  rationale: >-
    Every account of this disease, including this entry's own description, states
    that S2P loss impairs both cholesterol homeostasis and the ER stress response.
    The first half of that is measured and connected to phenotype. The second half
    is measured and connected to nothing.

    What exists for the ATF6 arm: a BRESHECK-associated variant fails to activate
    the ER stress response in vitro, and the gene-identification paper names
    "ability to cope with ER stress" alongside cholesterol homeostasis as the
    affected system. What does not exist: any clinical feature of IFAP attributed
    to ATF6 loss specifically, any tissue in which ER stress has been measured in a
    patient, and any account of why an ER-stress defect would fall on hair follicle
    and limbus rather than on the secretory tissues where the UPR matters most.

    So the two-arm mechanism is stated everywhere and load-bearing nowhere. Every
    phenotype curated in this entry could be produced by the SREBP arm alone. That
    is worth flagging rather than smoothing over, because a two-arm story that
    cannot be broken by any observation is not doing explanatory work.

    Two things pull in opposite directions, and both belong here.

    Arguing that the SREBP arm is sufficient: variants in SREBF1 - the gene for
    SREBP itself, one step downstream of this protease - cause a disease that
    shares a common clinical spectrum with IFAP. If losing the substrate alone
    reproduces much of the phenotype, the phenotype does not need the ATF6 arm.
    That is the strongest available argument for the SREBP arm carrying the
    disease, and it comes from human genetics rather than from a cell assay.

    Arguing against dismissing the ATF6 arm: in the one variant where both were
    tested, the SREBP pathway was *attenuated* while the ER stress response failed
    outright. If that pattern holds, the ATF6 arm is the more severely affected
    one, which makes its clinical silence more puzzling rather than less.

    The SREBF1 comparison also has a limit worth stating. SREBF1 disease is
    dominant and IFAP is X-linked recessive, and the SREBF1 phenotype includes
    mucosal involvement that IFAP does not - so the two are not the same
    phenotype with one mechanism subtracted, and the inference is suggestive
    rather than clean.
  proposed_experiments:
  - experiment_id: exp_ifap_er_stress_in_patient_keratinocytes
    name: ER stress response in patient keratinocytes and limbal epithelial cells
    description: >-
      Derive keratinocytes and, where available, limbal epithelial cells from IFAP
      patients across the severity range, and measure ATF6 processing and
      downstream UPR target induction under tunicamycin or thapsigargin challenge
      alongside SREBP target induction in the same cells. This asks whether the two
      arms are impaired to different degrees in the tissues that actually express
      the phenotype, rather than in a hamster ovary line.
    would_support:
    - "pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response"
    supporting_outcome:
    - Patient keratinocytes show blunted ATF6 processing and UPR target induction, and the magnitude tracks cutaneous severity independently of the SREBP readout.
    would_refute:
    - "pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response"
    refuting_outcome:
    - ATF6 processing and UPR target induction are preserved in patient keratinocytes despite a measurable SREBP deficit, placing the whole phenotype on the SREBP arm.
  - experiment_id: ifap_srebf1_phenotype_subtraction
    name: Systematic phenotype comparison of MBTPS2 and SREBF1 disease
    description: >-
      Compare the feature-level phenotype of MBTPS2-related IFAP against
      SREBF1-related disease in matched cohorts, coded to HPO. Features present in
      both are candidates for the SREBP arm; features present only in MBTPS2
      disease are where the ATF6 arm, or another S2P substrate, would have to act.
      This is a phenotype subtraction that needs no new laboratory work, only
      systematic coding of cases already published.
    would_support:
    - "pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response"
    supporting_outcome:
    - A reproducible set of MBTPS2-only features remains after subtracting the SREBF1 phenotype, giving the ATF6 arm something specific to explain.
    would_refute:
    - "pathophysiology#Impaired ATF6 Endoplasmic Reticulum Stress Response"
    refuting_outcome:
    - The MBTPS2 phenotype is contained within the SREBF1 phenotype, leaving no residual for a second substrate arm to account for.
  evidence:
  - reference: PMID:33742461
    reference_title: "Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, variants in SREBF1, a gene coding for a transcription factor
      related to cholesterol and fatty acid synthesis, have been associated with
      the disease.
    explanation: >-
      Graded PARTIAL against the ATF6 node. It bears on the question by showing
      that losing the SREBP substrate alone produces an overlapping phenotype, but
      it does not measure the ATF6 arm at all, and the two diseases differ in
      inheritance and in mucosal involvement - so it narrows the ATF6 arm's
      remaining explanatory role without excluding it.
  - reference: PMID:34655156
    reference_title: "A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro modeling supports variant pathogenicity, with impaired cell growth
      in cholesterol-depleted media, attenuated activation of the sterol
      regulatory element-binding protein pathway, and failure to activate the
      endoplasmic reticulum stress response pathway.
    explanation: >-
      The one experiment measuring both arms, and the source of the asymmetry the
      rationale points at - attenuated versus failed.
- discussion_id: ifap_allelic_series_tissue_specificity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do MBTPS2 variants produce a skin-and-eye disease in some families and a
    bone disease in others?
  attaches_to:
  - "genetic#MBTPS2"
  rationale: >-
    MBTPS2 causes IFAP with or without BRESHECK, keratosis follicularis spinulosa
    decalvans, an X-linked form of Olmsted syndrome, and osteogenesis imperfecta
    type XIX. These are not variations in severity of one phenotype - osteogenesis
    imperfecta is a different organ system from ichthyosis and keratopathy.

    The review literature is unusually explicit that this is unresolved, which is
    worth recording because it is easy for a curator to assume the answer is known
    and merely not looked up.

    Two features of this entry make the question sharper rather than more diffuse.
    The activity-severity correlation says residual protease activity sets severity
    along the IFAP-BRESHECK axis - so if it also set tissue specificity, KFSD and
    osteogenesis imperfecta would be points on the same line, and they are not.
    And the same allele can vary in expressivity within IFAP, so allele identity
    does not fully determine the phenotype even inside one disease.

    dismech is in an unusual position to notice this, because it already carries
    entries for two of the other MBTPS2 diseases. A cross-entry comparison of which
    residues and which functional consequences map to which entity is a concrete
    piece of work that does not need new data.
  proposed_experiments:
  - experiment_id: exp_ifap_allelic_series_residue_map
    name: Residue-level map of MBTPS2 variants across the four allelic diseases
    description: >-
      Assemble every reported MBTPS2 variant with its associated clinical entity,
      map onto the protein's transmembrane and catalytic architecture, and test
      whether disease assignment separates by domain, by predicted residual
      activity, or by neither. Assay a matched set in both the SREBP and ATF6
      readouts, since only the SREBP arm has been systematically measured.
    would_support:
    - "pathophysiology#Hypomorphic MBTPS2 Variant"
    - "pathophysiology#Reduced Regulated Intramembrane Proteolysis"
    supporting_outcome:
    - Variants segregate by domain or by which substrate arm they preferentially impair, giving a mechanism for the tissue specificity.
    would_refute:
    - "pathophysiology#Reduced Regulated Intramembrane Proteolysis"
    refuting_outcome:
    - Variants causing bone and skin disease are interleaved across domains with indistinguishable functional profiles, placing the determinant outside the protein.
  evidence:
  - reference: PMID:33743732
    reference_title: "MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While its functional role has become much clearer in the recent years, how
      mutations in the MBTPS2 gene lead to several human disorders with different
      phenotypes
    explanation: >-
      The review's framing of the gap: function understood, disease mapping not.
notes: >-
  Lump/split calls. BRESHECK is a has_subtypes entry, not a separate disease - the
  MONDO label itself lumps them, the gene and allele class are the same, and the
  functional assay shows the same two pathways impaired. The other MBTPS2
  diseases are kept separate, and that asymmetry is deliberate: BRESHECK is the
  severe end of the same phenotype, while KFSD, Olmsted syndrome and osteogenesis
  imperfecta type XIX are different phenotypes that happen to share a gene. Two of
  those already have dismech entries.

  Nomenclature. The disease name uses "atrichia" in some sources and "alopecia" in
  others, and both spellings are in the published titles cited here. The synonym
  list carries both because a search on one alone will miss papers.

  What is deliberately not curated. The disease is described in the literature as
  X-linked recessive, and the entry uses HP:0001419 accordingly - but the carrier
  findings, mosaic Blaschko-linear skin lesions and retinal vascular tortuosity,
  sit awkwardly with a strictly recessive label, and no source reviewed here
  resolves that.

  Recurrent infections, and why the phenotype is left out rather than just the
  mechanism. The proposed SREBP-NF-kB explanation is excluded because it rests on
  LPS-stimulation experiments in an unrelated system with no IFAP patient data
  attached. The phenotype itself is excluded for a separate reason: no source
  fetched here reports it with a denominator or in a named patient. It appears in
  review prose as a listed feature, which is a citation chain rather than an
  observation, and recurrent angular cheilitis - which is reported in one patient
  - is a different thing. If a series reports infection frequency this should be
  curated; the omission is a gap, not a judgement that the feature is absent.

  Also not curated: the Hodgkin lymphoma association, which is a single case and
  the source itself presents as a first report rather than an established risk;
  and Drosophila S2P mutants, which are informative about the enzyme but are not
  a disease model.

  On GeneReviews. There is no GeneReviews chapter for MBTPS2 or IFAP - a PubMed
  search of GeneReviews[Book] against MBTPS2, "IFAP syndrome", "ichthyosis
  follicularis" and "keratosis follicularis spinulosa" returns nothing. Only the
  general Ichthyosis Overview exists, which is not disease-specific. Recorded so
  the next curator does not have to re-derive it.

  Provenance. Built from primary literature with an OpenScientist deep-research
  report run alongside and committed under research/. The report supplied most of
  the reference set, each verified on PubMed and fetched through
  'just fetch-reference' before use. Two of its ontology suggestions were rejected
  on its own validation evidence: NCIT:C29496 for "Acitretin ~1 mg/kg", which does
  not exist in NCIT, and HP:0033052 offered as "Angular cheilitis / periorificial
  keratotic plaques" when that identifier is "Non-epileptic seizure" - a
  mislabelling that would have put a seizure phenotype into a genodermatosis. It
  also gave MBTPS2 as HGNC:7375; the correct identifier is hgnc:15455, as the
  curation stub recorded. The "40 cases reported" figure it surfaced is curated
  but graded PARTIAL, because its source is a background sentence in a case report
  about Hodgkin lymphoma rather than a systematic count.

📚

References & Deep Research

References

12

PMID:19361614

IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.