MSMO1 Deficiency

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Classifications

Harrison's Chapter

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic MSMO1 variants are required; carriers are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:37195326 SUPPORT Human Clinical

"MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date."

The disease-specific review states the autosomal recessive inheritance pattern for MSMO1 deficiency.

PMID:33161406 SUPPORT Human Clinical

"Segregation analysis in all available family members confirmed recessive inheritance of the mutation."

Family segregation analysis in a consanguineous kindred confirms recessive transmission.

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Mechanistic Hypotheses

1

MSMO1 as a PSORS9 candidate and heterozygote susceptibility factor

msmo1_psors9_common_skin_disease EMERGING

Evidence balance 2 partial

MSMO1 lies within the PSORS9 psoriasis susceptibility interval, and obligate carriers in the index family had raised plasma methylsterols and, in the father, granulocyte activation approaching the proband's. Together these raise the hypothesis that a single hypomorphic MSMO1 allele is a susceptibility factor for common inflammatory skin disease rather than being fully recessive. This is explicitly an unproven hypothesis and is not asserted as a mechanism anywhere in the pathophysiology graph.

Show evidence (2 references)

PMID:24144731 PARTIAL Human Clinical

"SC4MOL is situated within the psoriasis susceptibility locus PSORS9, and may be a genetic risk factor for common skin conditions."

States the PSORS9 candidacy as a possibility, not an established association.

PMID:21285510 PARTIAL Human Clinical

"Methylsterol levels were also increased (though less so) in the plasma of the patient's parents (Table 2), particularly the father, who carries the active site H173Q mutation, suggesting a subclinical effect in the heterozygous state."

Documents a subclinical biochemical effect in heterozygotes, the observation underpinning the hypothesis.

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Discussions and Knowledge Gaps

2

Does any available Msmo1 mouse allele model human MSMO1 deficiency, given that every reported human allele is a hypomorphic missense change while the available mouse alleles are nulls and gene traps, and zebrafish msmo1 nulls are larval lethal?

HUMAN MODEL MISMATCH OPEN msmo1_no_mouse_model

Attached to

pathophysiology#MSMO1 Deficiency

The zebrafish null is lethal, so a mouse null would most plausibly be embryonic or perinatal lethal, and an absence of adult phenotypes in a knockout pipeline would reflect absent homozygotes rather than a benign knockout. No published mouse model reproducing the human microcephaly, cataract and psoriasiform dermatitis phenotype was identified. The informative mammalian in vivo data come from Nsdhl mice, which model CHILD syndrome and are a paralog, not an MSMO1 model.

Proposed experiments

Hypomorphic Msmo1 knock-in mouse

exp_msmo1_hypomorphic_knockin_mouse

Generate and characterise a mouse carrying a recurrent human hypomorphic allele such as p.Tyr244Cys or p.Gly115Arg, and test whether it reproduces the cutaneous, ocular and neurodevelopmental phenotype.

Staging of Msmo1 null lethality in mouse

exp_msmo1_null_lethality_staging

Determine homozygous viability for existing Msmo1 null and gene-trap alleles and stage any embryonic or perinatal lethality, so that an absence of adult phenotypes is not misread as a benign knockout.

Show evidence (1 reference)

PMID:32430393 SUPPORT Model Organism

"Generated msmo1nu81 knockdown mutation resulted in lethality at larval stage."

The lethality of the complete null in zebrafish is what makes a mammalian null a poor model of the hypomorphic human disease.

What is the natural history of MSMO1 deficiency, and does treatment started presymptomatically change neurodevelopmental outcome?

KNOWLEDGE GAP OPEN msmo1_natural_history_gap

No registry, natural history study, survival analysis or quality-of-life measurement exists. All prognostic statements derive from a handful of individually reported patients. The cataract and microcephaly appear fixed before current diagnosis is possible, which is why the disorder is described as only partially treatable, but whether presymptomatic therapy following cascade testing of a sibling would alter the neurodevelopmental trajectory has never been tested.

Proposed experiments

International MSMO1 deficiency registry

exp_msmo1_natural_history_registry

Establish a registry with standardised developmental, ophthalmologic, dermatologic and growth outcome measures to build the first natural history dataset for this disorder.

Presymptomatic treatment of cascade-identified siblings

exp_msmo1_presymptomatic_cascade_treatment

Systematically offer cascade testing at proband diagnosis and start cholesterol plus statin therapy in presymptomatic biallelic siblings, with prospective developmental and cutaneous follow-up.

Show evidence (1 reference)

PMID:37195326 SUPPORT Human Clinical

"MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date."

The tiny reported cohort is the reason no natural history evidence exists.

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Pathophysiology

12

MSMO1 Deficiency

Biallelic missense variants in MSMO1 reduce methylsterol monooxygenase 1 activity, blocking the first oxidative step of sterol C4 demethylation in post-squalene cholesterol biosynthesis.

MSMO1 hgnc:10545 ↓ DECREASED

cholesterol biosynthetic process GO:0006695 ↓ DECREASED

C-4 methylsterol oxidase activity GO:0000254 ↓ DECREASED

Downstream

C4-Methylsterol Accumulation Loss of C4 demethylation blocks consumption of C4-methylsterol substrates.

Impaired Distal Cholesterol Biosynthesis The same enzymatic block reduces flux through the distal pathway to cholesterol.

Impaired Neurodevelopment The enzymatic block is associated with microcephaly, developmental delay and intellectual disability, but the mediating steps between sterol imbalance and cortical development are not established.

Growth Impairment Growth delay and short stature are consistently reported, again without a resolved mechanistic intermediate.

Show evidence (3 references)

PMID:21285510 SUPPORT Human Clinical

"We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."

The index report establishes SC4MOL/MSMO1 loss of function as the causal molecular lesion.

PMID:21285510 SUPPORT Human Clinical

"This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway."

Identifies the specific enzymatic step lost in this disorder.

PMID:37195326 SUPPORT Human Clinical

"The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols."

Confirms the gene, the encoded enzyme and the immediate biochemical consequence.

C4-Methylsterol Accumulation

4-monomethyl and 4,4-dimethylsterols, the meiosis-activating sterols, accumulate in plasma, skin scales and cultured cells because the first C4-demethylation step is blocked.

Downstream

Meiosis-Activating Sterol LXR Signaling Accumulated meiosis-activating sterols act as ligands for liver X receptors.

Disrupted Vesicular Trafficking and EGFR Signaling Methylsterol excess perturbs vesicular trafficking and EGF receptor signaling in patient cells.

Epidermal and Hematopoietic Cell Overproliferation Accumulated meiosis-activating sterols drive overproliferation in skin and blood.

Constitutive Fibroblast IL-6 Production Methylsterol accumulation is associated with constitutive fibroblast IL-6 output that falls when cholesterologenesis is inhibited with simvastatin.

Plasma C4-methylsterols The accumulated sterol pool is measurable as the diagnostic plasma sterol profile.

Elevated circulating monomethyl sterol concentration The accumulated pool is measured clinically as raised plasma monomethylsterols.

Elevated circulating dimethyl sterol concentration The accumulated pool is measured clinically as markedly raised plasma dimethylsterols.

Show evidence (3 references)

PMID:24144731 SUPPORT Human Clinical

"Quantitative sterol analysis of plasma and skin scales from all four patients showed marked elevation of 4α-methyl- and 4, 4'-dimethylsterols, consistent with a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis."

Direct sterol quantification in patients establishes the accumulating species.

PMID:28673550 SUPPORT Human Clinical

"Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."

An independent genotyped patient reproduces the same accumulation pattern.

PMID:21285510 SUPPORT Human Clinical

"C4-Methylsterols are meiosis-activating sterols (MASs)."

Identifies the accumulating C4-methylsterols as the meiosis-activating sterols.

Impaired Distal Cholesterol Biosynthesis

Flux through the post-squalene pathway to cholesterol is reduced because C4-methylsterol intermediates cannot be demethylated, depriving tissues of endogenously synthesised cholesterol.

cholesterol biosynthetic process GO:0006695 ↓ DECREASED

Downstream

Altered Lens Membrane Lipid Composition Reduced cholesterol availability alters the lipid composition of the lens membrane.

Hypocholesterolemia Reduced endogenous synthesis can present as low circulating cholesterol, although this is variable and not obligate across reported patients.

Impaired Chondrocyte Hypertrophy Hypertrophic chondrocytes depend on endogenous cholesterol synthesis and are lost when Msmo1 activity is absent.

Show evidence (2 references)

PMID:41718295 SUPPORT Human Clinical

"The mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane and leading to early cataract formation."

Attributes an MSMO1 clinical feature to impaired cholesterol synthesis.

PMID:32430393 SUPPORT Model Organism

"Our analysis suggests that hypertrophic chondrocytes depend on endogenous cholesterol synthesis, and blocking C4 demethylation exacerbates the cholesterol deficiency phenotype."

The msmo1 zebrafish mutant demonstrates that blocking C4 demethylation produces a cholesterol-deficiency state.

Meiosis-Activating Sterol LXR Signaling

Accumulated meiosis-activating sterols act as ligands for the nuclear receptors LXR alpha and LXR beta, which govern epidermal lipid transport and both innate and adaptive immunity.

LXR alpha hgnc:7966 ↕ DYSREGULATED LXR beta hgnc:7965 ↕ DYSREGULATED

intracellular receptor signaling pathway GO:0030522 ↕ DYSREGULATED

Downstream

Immunocyte Dysregulation LXR-linked signaling changes accompany altered immunocyte phenotype and function.

Show evidence (1 reference)

PMID:21285510 SUPPORT Human Clinical

"MASs serve as ligands for liver X receptors α and β(LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity."

Names the receptors and the two downstream domains they regulate.

Disrupted Vesicular Trafficking and EGFR Signaling

Cells from affected patients show disrupted vesicular trafficking and diminished EGF receptor signaling, a cell-biological consequence of the C4-demethylation block.

vesicle-mediated transport GO:0016192 ↕ DYSREGULATED epidermal growth factor receptor signaling pathway GO:0007173 ↓ DECREASED

Downstream

Epidermal and Hematopoietic Cell Overproliferation Altered intracellular signaling and trafficking contribute to the proliferative epidermal phenotype.

Show evidence (2 references)

PMID:24144731 SUPPORT In Vitro

"Additional studies also demonstrated diminished EGFR signaling and disrupted vesicular trafficking in cells from the affected patients."

Establishes the trafficking and EGFR defect in patient-derived cells.

PMID:23125191 PARTIAL In Vitro

"Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3."

Mechanistic corroboration only. This is a cancer-cell siRNA study that co-targets SC4MOL and its C4-demethylation partner NSDHL, the gene of CHILD and CK syndrome, so the result is not MSMO1-patient evidence and the NSDHL arm is not attributable to this disorder.

Epidermal and Hematopoietic Cell Overproliferation

Skin and blood cells overproliferate in the presence of accumulated meiosis-activating sterols; patient fibroblasts show a higher mitotic rate than controls and pharmacological inhibition of the enzyme activates the cell cycle in lymphoblasts.

keratinocyte CL:0000312 fibroblast CL:0000057

cell population proliferation GO:0008283 ↑ INCREASED epidermis development GO:0008544 ↕ DYSREGULATED

Downstream

Psoriasiform dermatitis Epidermal hyperproliferation underlies the psoriasiform cutaneous phenotype.

Ichthyosis The same epidermal disturbance produces the ichthyosiform component of the rash.

Erythroderma Uncontrolled epidermal disease can generalise to erythroderma.

Show evidence (3 references)

PMID:21285510 SUPPORT Human Clinical

"In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood."

Direct patient-level observation of overproliferation in both compartments.

PMID:24144731 SUPPORT In Vitro

"Cellular studies with patient-derived fibroblasts have shown a higher mitotic rate than control cells in cholesterol-depleted medium, with increased de novo cholesterol biosynthesis and accumulation of methylsterols."

Patient fibroblasts demonstrate the increased proliferative rate.

PMID:24144731 SUPPORT In Vitro

"Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts induced activation of the cell cycle."

Pharmacological enzyme inhibition reproduces cell-cycle activation, supporting causality.

Constitutive Fibroblast IL-6 Production

Patient dermal fibroblasts constitutively secrete IL-6 irrespective of passage number, and serum IL-6 and IL-8 are raised. Simvastatin, which lowers sterol-pathway intermediates, significantly reduces that IL-6 output in patient cells, tying the cytokine phenotype to the sterol lesion.

fibroblast CL:0000057

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Psoriasiform dermatitis Fibroblast-derived IL-6 contributes to the inflammatory component of the cutaneous phenotype.

Show evidence (2 references)

PMID:21285510 SUPPORT In Vitro

"Cultures of patient skin fibroblasts showed constitutive production of IL-6 compared with control fibroblasts regardless of passage number (Figure 4D), and IL-6 concentration was further increased with the addition of recombinant TNF-α, a known inducer of IL-6."

Establishes constitutive IL-6 output by patient fibroblasts.

PMID:21285510 SUPPORT Human Clinical

"IL-6 and IL-8 were also elevated in the patient's serum (Supplemental Table 3)."

Serum IL-6 and IL-8 are raised in the index patient, matching the constitutive fibroblast IL-6 output.

Immunocyte Dysregulation

Granulocytes and B cells from patients and obligate carriers show dysregulated immune-related receptors, and patient immunocytes show altered phenotype and in vitro function.

granulocyte CL:0000094 B cell CL:0000236

Downstream

Immune dysfunction Cellular immune dysregulation manifests clinically as immune dysfunction.

Show evidence (4 references)

PMID:24144731 SUPPORT Human Clinical

"Immunologic analyses of granulocytes and B cells from patients and obligate carriers in the patients' families indicated dysregulation of immune-related receptors."

Names the affected immune cell types and the receptor-level abnormality. Classified HUMAN_CLINICAL, matching the analogous CD16+ granulocyte immunophenotyping from PMID:21285510 below: both are direct immunophenotyping of patient blood rather than a cultured-cell experiment.

PMID:21285510 SUPPORT Human Clinical

"SMO deficiency also substantially altered immunocyte phenotype and in vitro function."

Independent support for altered immunocyte phenotype and function.

PMID:21285510 SUPPORT Human Clinical

"We found that activated CD16+ granulocytes (identified by CD25+CD69+ and CD86+HLA-DR+ subsets) were increased 30- and 20-fold in the patient and her father, respectively, compared with healthy controls"

Quantifies the granulocyte activation phenotype in the patient and, notably, in her heterozygous father.

+ 1 more reference

Altered Lens Membrane Lipid Composition

Impaired cholesterol synthesis alters the lipid composition of the lens fiber cell membrane, the proposed route to early lens opacification.

lens fiber cell CL:0011004

Downstream

Congenital cataract Altered lens membrane lipid composition leads to early cataract formation.

Show evidence (1 reference)

PMID:41718295 SUPPORT Human Clinical

"The mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane and leading to early cataract formation."

States the lens-membrane lipid alteration as the proposed intermediate step.

Impaired Chondrocyte Hypertrophy

In the zebrafish msmo1 mutant, loss of enzyme activity causes near-complete loss of the hypertrophic chondrocyte population and severe skeletal patterning defects. No human MSMO1 skeletal finding has yet been tied to this mechanism, so this node is deliberately terminal.

hypertrophic chondrocyte CL:0000743 prehypertrophic chondrocyte CL:0020022

Show evidence (2 references)

PMID:32430393 SUPPORT Model Organism

"In a forward-genetic approach, we have found that a late-onset skeletal mutant, named kolibernu7 , is the result of a cis-acting regulatory mutation leading to loss of methylsterol monooxygenase 1 (msmo1) expression within pre-hypertrophic chondrocytes."

Localises the msmo1 requirement to pre-hypertrophic chondrocytes.

PMID:32430393 SUPPORT Model Organism

"Rescued mutants develop dramatic skeletal abnormalities, with a loss of Msmo1 activity resulting in a more-severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1a expression."

Documents the loss of the hypertrophic chondrocyte population.

Impaired Neurodevelopment

Microcephaly, global developmental delay and intellectual disability are consistent features of the reported cohort; the intervening mechanism between the sterol lesion and cortical development is unresolved.

Downstream

Microcephaly Impaired neurodevelopment presents with reduced head circumference.

Global developmental delay Impaired neurodevelopment presents with global developmental delay.

Intellectual disability Impaired neurodevelopment presents with intellectual disability.

Show evidence (2 references)

PMID:28673550 SUPPORT Human Clinical

"In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."

Summarises the neurodevelopmental features across the published cohort.

PMID:33161406 SUPPORT Human Clinical

"Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology."

Attributes the global developmental impact to methylsterol accumulation.

Growth Impairment

Growth delay in infancy and short stature are recurrent findings in genotyped patients.

Downstream

Growth delay The growth phenotype is recognised in infancy.

Short stature Growth impairment persists into adulthood as short stature in at least one genotyped patient.

Failure to thrive Poor weight gain in early childhood is part of the growth phenotype.

Show evidence (1 reference)

PMID:24144731 SUPPORT Human Clinical

"All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."

Growth delay in infancy is reported across the first described cohort.

✶

Histopathology

1

Psoriasiform epidermal hyperplasia

Skin biopsy shows psoriasiform hyperplasia with dilated dermal papillary capillaries and neutrophils in the epidermis and stratum corneum, plus lipid-laden foamy cells in the dermis. The histology mimics true psoriasis, which is the principal reason for diagnostic delay.

Show evidence (2 references)

PMID:21285510 SUPPORT Human Clinical

"thinning of suprapapillary plate, and neutrophilic epidermal infiltration; these features are characteristic of psoriasis."

Describes the psoriasis-like epidermal histology seen on biopsy of affected skin.

PMID:21285510 SUPPORT Human Clinical

"The arrow shows the intracellular lipid accumulation in the foamy cells in the dermis."

Documents the dermal lipid-laden foamy cells that accompany the psoriasiform epidermal changes.

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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

27

Eye 5

Congenital cataract Developmental cataract HP:0000519

Show evidence (3 references)

PMID:24144731 SUPPORT Human Clinical

"All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."

Congenital cataracts in all patients of the first described cohort.

PMID:28673550 SUPPORT Human Clinical

"In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."

Bilateral congenital cataracts across the reported patients.

PMID:41718295 SUPPORT Human Clinical

"This report describes a patient presenting with global developmental delay and bilateral infantile cataracts found to harbor a homozygous likely pathogenic MSMO1 variant and reviews the literature on MSMO1 deficiency and its association with infantile cataracts."

A further genotyped patient with bilateral infantile cataracts.

Nystagmus Nystagmus HP:0000639

Show evidence (1 reference)

PMID:33161406 SUPPORT Human Clinical

"Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."

Nystagmus explicitly listed among the ocular abnormalities.

Myopia Myopia HP:0000545

Show evidence (1 reference)

PMID:33161406 SUPPORT Human Clinical

"Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."

Myopia explicitly listed among the ocular abnormalities.

Strabismus Strabismus HP:0000486

Show evidence (1 reference)

PMID:33161406 SUPPORT Human Clinical

"Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."

Strabismus explicitly listed among the ocular abnormalities.

Blepharitis Blepharitis HP:0000498

Show evidence (1 reference)

PMID:21285510 SUPPORT Human Clinical

"Note mild microcephaly, lusterless, fine fair hair, and blepharitis."

Blepharitis is documented in the clinical description of the index patient.

Head and Neck 1

Microcephaly Microcephaly HP:0000252

Show evidence (2 references)

PMID:24144731 SUPPORT Human Clinical

"All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."

Microcephaly in all patients of the first described cohort.

PMID:28673550 PARTIAL Human Clinical

"Herein, we describe a new case of SC4MOL deficiency in which a 19-year-old Italian male was affected by bilateral congenital cataracts, growth delay and learning disabilities, behavioral disorders and small stature, but not microcephaly."

Marked PARTIAL because this genotyped patient explicitly lacked microcephaly, showing the feature is not obligate.

Immune 1

Erythroderma Erythroderma HP:0001019

Show evidence (1 reference)

PMID:41413001 SUPPORT Human Clinical

"This progressed to become erythrodermic despite multiple topical treatments as well as systemic treatments including ciclosporin and zinc supplements."

Documents erythroderma in a genotyped MSMO1 patient.

Integument 3

Alopecia Alopecia HP:0001596

Show evidence (1 reference)

PMID:37195326 SUPPORT Human Clinical

"We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity."

Alopecia reported as a novel feature in genotyped MSMO1 siblings.

Dry skin Dry skin HP:0000958

Show evidence (1 reference)

PMID:24144731 SUPPORT Human Clinical

"The second patient is a 5 year old girl who has just started to develop dry skin and hair changes."

Dry skin as an early cutaneous manifestation in a second patient.

Ichthyosis Ichthyosis HP:0008064

Show evidence (2 references)

PMID:21285510 SUPPORT Human Clinical

"A 13-year-old female presented for evaluation of severe ichthyosiform erythroderma affecting her entire body but sparing the palms"

Documents the ichthyosiform component of the cutaneous phenotype in the index patient.

PMID:21695019 SUPPORT Human Clinical

"Finally, a prominent skin phenotype has been described in two patients with SC4MOL deficiency, who present with a severe ichthyosiform dermatosis and psoriasiform features."

The one SC4MOL-specific sentence in this family-wide cutaneous review confirms the ichthyosiform component.

Limbs 1

Polydactyly Polydactyly HP:0010442

Show evidence (1 reference)

PMID:37195326 SUPPORT Human Clinical

"We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity."

Polydactyly reported as a novel feature in genotyped MSMO1 siblings.

Musculoskeletal 2

Spasticity Spasticity HP:0001257

Show evidence (1 reference)

PMID:37195326 SUPPORT Human Clinical

"We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity."

Spasticity reported as a novel feature in genotyped MSMO1 siblings.

Delayed skeletal maturation Delayed skeletal maturation HP:0002750

Show evidence (1 reference)

PMID:21285510 SUPPORT Human Clinical

"A skeletal survey showed delayed skeletal maturation, but bone morphology was normal."

Skeletal survey in the index patient documents delayed maturation with preserved morphology.

Nervous System 3

Global developmental delay Global developmental delay HP:0001263

Show evidence (2 references)

PMID:41718295 SUPPORT Human Clinical

"This report describes a patient presenting with global developmental delay and bilateral infantile cataracts found to harbor a homozygous likely pathogenic MSMO1 variant and reviews the literature on MSMO1 deficiency and its association with infantile cataracts."

Global developmental delay in a genotyped MSMO1 patient.

PMID:41413001 SUPPORT Human Clinical

"Other syndromic features were apparent from presentation and developed over follow-up with global developmental delay, microcephaly, congenital cataracts corrected age 3, and skeletal abnormalities (inward curving little finger)."

A second genotyped patient with global developmental delay.

Intellectual disability Intellectual disability HP:0001249

Show evidence (2 references)

PMID:28673550 SUPPORT Human Clinical

"In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."

Intellectual disability listed among the core features.

PMID:33161406 SUPPORT Human Clinical

"Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."

Severe intellectual disability in two genotyped siblings.

Motor delay Motor delay HP:0001270

Show evidence (1 reference)

PMID:33161406 SUPPORT Human Clinical

"Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."

Motor delay reported in two genotyped siblings.

Constitutional 1

Arthralgia Arthralgia HP:0002829

Show evidence (1 reference)

PMID:21285510 SUPPORT Human Clinical

"We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."

Arthralgias reported in the index MSMO1 patient.

Growth 3

Growth delay Growth delay HP:0001510

Show evidence (2 references)

PMID:24144731 SUPPORT Human Clinical

"All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."

Growth delay in all patients of the first described cohort.

PMID:37195326 SUPPORT Human Clinical

"Clinically, MSMO1 deficiency is characterized by growth and developmental delay, often in association with congenital cataracts, microcephaly, psoriasiform dermatitis and immune dysfunction."

The disease-specific review lists growth delay as a defining feature.

Short stature Short stature HP:0004322

Show evidence (1 reference)

PMID:28673550 SUPPORT Human Clinical

"Herein, we describe a new case of SC4MOL deficiency in which a 19-year-old Italian male was affected by bilateral congenital cataracts, growth delay and learning disabilities, behavioral disorders and small stature, but not microcephaly."

Small stature in a genotyped 19-year-old patient.

Failure to thrive Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:21285510 SUPPORT Human Clinical

"Also notable in the patient's medical history are congenital cataracts, mild developmental delay, microcephaly (head circumference 53.5 cm at the age of 13 years, <3rd percentile; 50th percentile for a 7.5-year-old), and failure to thrive."

The index case description records failure to thrive alongside the cataract, developmental delay and microcephaly triad.

Other 7

Psoriasiform dermatitis Psoriasiform dermatitis HP:0003765

Show evidence (3 references)

PMID:21285510 SUPPORT Human Clinical

"We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."

The index MSMO1 patient had psoriasiform dermatitis.

PMID:24144731 SUPPORT Human Clinical

"The first patient has suffered since the age of six years from severe, diffuse, psoriasiform dermatitis, sparing only her palms."

Describes the severity and distribution of the dermatitis.

PMID:33161406 SUPPORT Human Clinical

"Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."

Independent genotyped siblings with the same cutaneous phenotype.

Immune dysfunction Abnormality of immune system physiology HP:0010978

Show evidence (2 references)

PMID:28673550 SUPPORT Human Clinical

"In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."

Immune dysfunction reported as a core clinical feature.

PMID:21285510 SUPPORT Human Clinical

"SMO deficiency also substantially altered immunocyte phenotype and in vitro function."

Laboratory characterisation of the immune abnormality in the index patient.

Optic nerve hypoplasia Optic nerve hypoplasia HP:0000609

Show evidence (1 reference)

PMID:33161406 SUPPORT Human Clinical

"Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."

Optic hypoplasia explicitly listed among the ocular abnormalities.

Clinodactyly of the 5th finger Clinodactyly of the 5th finger HP:0004209

Show evidence (1 reference)

PMID:41413001 SUPPORT Human Clinical

"Other syndromic features were apparent from presentation and developed over follow-up with global developmental delay, microcephaly, congenital cataracts corrected age 3, and skeletal abnormalities (inward curving little finger)."

The reported inward curving little finger is curated as clinodactyly of the 5th finger, the closest HPO concept; the source uses descriptive rather than ontology language.

Hypocholesterolemia Hypocholesterolemia HP:0003146

Show evidence (1 reference)

PMID:21285510 PARTIAL Human Clinical

"Her serum lipid profile showed a persistently low total cholesterol level (85 mg/dl; normal, 140-176), low HDL (28 mg/dl; normal, 35-75), and low LDL (49 mg/dl; normal, 70-160) but normal triglycerides (84 mg/dl; normal, 50-200)"

Marked PARTIAL because this documents hypocholesterolemia in the index patient only; later reported MSMO1 patients have had normal cholesterol, so the finding is supportive rather than defining.

Elevated circulating monomethyl sterol concentration Elevated circulating monomethyl sterol concentration HP:6000753

Show evidence (1 reference)

PMID:21285510 SUPPORT Human Clinical

"The profile showed 20- and 500-fold elevation of 4 α-monomethyl sterols and 4, 4 ′-dimethyl sterols, respectively"

GC-MS sterol profiling quantifies the monomethylsterol elevation.

Elevated circulating dimethyl sterol concentration Elevated circulating dimethyl sterol concentration HP:6000754

Show evidence (2 references)

PMID:21285510 SUPPORT Human Clinical

"The profile showed 20- and 500-fold elevation of 4 α-monomethyl sterols and 4, 4 ′-dimethyl sterols, respectively"

The same GC-MS profile quantifies the far larger dimethylsterol elevation.

PMID:21285510 SUPPORT Human Clinical

"Dimethylsterol (peak 6) is most elevated in skin, suggesting the preferential accumulation of 4,4′-dimethylsterols in the patient's skin."

Documents preferential cutaneous deposition, the rationale for topical therapy.

🧬

Genetic Associations

1

MSMO1 (Causative)

Gene: MSMO1 hgnc:10545

Autosomal recessive

Show evidence (5 references)

PMID:21285510 SUPPORT Human Clinical

"We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."

Landmark study identifying SC4MOL/MSMO1 as the causative gene.

PMID:28673550 SUPPORT Human Clinical

"confirmed mutations in each allele (c.731A>G, p.Y244C, which is already known, and c.605G>A, p.G202E, which is a novel variant)"

Documents compound heterozygous MSMO1 alleles with parental segregation.

PMID:33161406 SUPPORT Human Clinical

"We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81A>C; p.Asn27Thr in MSMO1."

Adds a homozygous missense allele identified by exome sequencing.

+ 2 more references

💊

Medical Actions

5

Systemic cholesterol supplementation with statin therapy

Action: Pharmacotherapy NCIT:C15986

Agent: cholesterol CHEBI:16113 simvastatin CHEBI:9150

Oral cholesterol supplementation replaces the deficient end product while an oral statin reduces flux into the blocked pathway and thereby the toxic methylsterol load. Reported regimens have combined systemic cholesterol, statin and bile acid. This combination is documented specifically in MSMO1-genotyped patients, not extrapolated from the other post-squalene disorders.

Mechanism Target:

INHIBITS C4-Methylsterol Accumulation — Statin therapy reduces flux into the pathway and lowers the toxic methylsterol pool.

Show evidence (1 reference)

PMID:41413001 SUPPORT Human Clinical

"Topical (2% simvastatin/2% cholesterol cream) and oral statin was commenced to reduce the toxic accumulation of methylsterols, along with cholesterol replacement to replace the downstream deficiency."

States the mechanistic rationale of the statin arm in a genotyped MSMO1 patient.

BYPASSES Impaired Distal Cholesterol Biosynthesis — Exogenous cholesterol supplies the end product that the blocked pathway cannot make.

Show evidence (1 reference)

PMID:41413001 SUPPORT Human Clinical

"Topical (2% simvastatin/2% cholesterol cream) and oral statin was commenced to reduce the toxic accumulation of methylsterols, along with cholesterol replacement to replace the downstream deficiency."

States the mechanistic rationale of the cholesterol-replacement arm.

Show evidence (4 references)

PMID:37195326 SUPPORT Human Clinical

"Treatment with oral and topical cholesterol supplements and statins was reported to improve the biochemical, immunological, and cutaneous findings, supporting a potential treatment following the precision diagnosis of MSMO1 deficiency."

The disease-specific review summarises improvement of biochemical, immunological and cutaneous findings in MSMO1 patients.

PMID:37195326 SUPPORT Human Clinical

"Based on previously published treatment algorithms, we initiated a modified dosage regime with systemic cholesterol supplementation, statins and bile acid along with topical application of a cholesterol/statin formulation."

Describes the systemic component of the regimen used in genotyped siblings.

PMID:33161406 SUPPORT Human Clinical

"The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement."

Independent genotyped siblings improved on the oral plus topical combination.

+ 1 more reference

Topical cholesterol and statin formulation

Action: Pharmacotherapy NCIT:C15986

Agent: simvastatin CHEBI:9150 cholesterol CHEBI:16113

A compounded cream containing cholesterol and a statin, applied to affected skin. In a genotyped MSMO1 infant a 2% simvastatin plus 2% cholesterol cream combined with oral statin produced almost complete clearance of a previously treatment-refractory psoriasiform eruption, and in two other genotyped sibships it improved dermatitis and permitted some hair regrowth.

Mechanism Target:

MODULATES Epidermal and Hematopoietic Cell Overproliferation — Topical cholesterol plus statin targets the cutaneous arm of the disease, with near-complete clearance of the psoriasiform eruption reported.

Show evidence (1 reference)

PMID:41413001 SUPPORT Human Clinical

"Improvement in her skin, with almost complete clearance after only after a few months of treatment has been life changing."

Documents near-complete cutaneous clearance on the topical plus oral regimen.

Target Phenotypes: Psoriasiform dermatitis HP:0003765

Show evidence (3 references)

PMID:41413001 SUPPORT Human Clinical

"Topical (2% simvastatin/2% cholesterol cream) and oral statin was commenced to reduce the toxic accumulation of methylsterols, along with cholesterol replacement to replace the downstream deficiency."

Specifies the topical formulation used in a genotyped MSMO1 patient.

PMID:37195326 SUPPORT Human Clinical

"This resulted in a marked improvement of psoriasiform dermatitis and some hair growth."

Reports the cutaneous and hair response to the combined topical and systemic regimen.

PMID:33161406 SUPPORT Human Clinical

"The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement."

Independent genotyped siblings improved with the topical component of the regimen.

Oral acitretin

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172

A systemic retinoid used before the metabolic diagnosis was made. It reduced skin severity significantly in one genotyped MSMO1 patient but left residual inflammatory skin, so it is recorded as partially effective symptomatic therapy rather than disease-directed treatment.

Target Phenotypes: Psoriasiform dermatitis HP:0003765

Show evidence (1 reference)

PMID:41413001 PARTIAL Human Clinical

"Oral acitretin reduced skin severity significantly."

Marked PARTIAL because the same report notes continued impact from inflammatory skin afterwards, so acitretin gave incomplete symptomatic benefit and did not address the sterol lesion.

Conventional psoriasis-directed therapy

Action: Pharmacotherapy NCIT:C15986

Standard antipsoriatic treatment does not work in MSMO1 deficiency. In the index patient topical corticosteroids, calcipotriene, cyclosporine A, etanercept, phototherapy and oral isotretinoin were all tried without durable response. Anti-TNF therapy is mechanistically inappropriate because serum TNF-alpha is normal in this disorder. Recorded here as negative evidence so that the entry documents what NOT to do.

Target Phenotypes: Psoriasiform dermatitis HP:0003765

Show evidence (2 references)

PMID:21285510 REFUTE Human Clinical

"However, while her skin briefly improved with cyclosporine A, she did not exhibit a long-term response to any of the therapies."

The preceding sentence in the same report lists the therapies tried in the index patient (topical corticosteroids, calcipotriene, cyclosporine A, etanercept, phototherapy and oral isotretinoin); this sentence records that none produced a durable response.

PMID:41413001 REFUTE Human Clinical

"This progressed to become erythrodermic despite multiple topical treatments as well as systemic treatments including ciclosporin and zinc supplements."

A second genotyped patient likewise progressed on conventional topical and systemic therapy.

Cataract surgery

Action: Surgical Procedure NCIT:C15329

Surgical removal of the congenital cataract, performed in reported patients in infancy or early childhood. Necessary because the lens opacity is structural and is not reversed by metabolic therapy.

Target Phenotypes: Congenital cataract HP:0000519

Show evidence (1 reference)

PMID:41413001 SUPPORT Human Clinical

"Other syndromic features were apparent from presentation and developed over follow-up with global developmental delay, microcephaly, congenital cataracts corrected age 3, and skeletal abnormalities (inward curving little finger)."

Documents surgical correction of the congenital cataracts in a genotyped MSMO1 patient.

🔬

Biochemical Markers

1

Plasma C4-methylsterols (INCREASED)

Context: Diagnostic sterol profile. Marked elevation of 4-monomethyl and 4,4-dimethylsterols in plasma and skin scales is the biochemical signature that distinguishes this disorder from the other post-squalene defects.

Pathograph Readouts

Readout Of C4-Methylsterol Accumulation Positive Diagnostic

Elevated plasma C4-monomethyl and C4-dimethyl sterols report the substrate pool accumulating immediately upstream of the MSMO1 block.

Show evidence (1 reference)

PMID:28673550 SUPPORT Human Clinical

"Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."

Blood sterol profiling reads out the accumulated substrate pool.

Show evidence (2 references)

PMID:24144731 SUPPORT Human Clinical

"Quantitative sterol analysis of plasma and skin scales from all four patients showed marked elevation of 4α-methyl- and 4, 4'-dimethylsterols, consistent with a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis."

Quantitative sterol analysis in patients establishes the diagnostic elevation.

PMID:28673550 SUPPORT Human Clinical

"Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."

Independent confirmation of the same plasma sterol pattern.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from MSMO1 Deficiency:

Smith-Lemli-Opitz syndrome MONDO:0010035

Overlapping Features The best-known post-squalene cholesterol biosynthesis disorder, caused by DHCR7 deficiency at the terminal step. It shares microcephaly, growth restriction and intellectual disability with MSMO1 deficiency but is distinguished biochemically by elevated 7-dehydrocholesterol with low cholesterol rather than accumulated C4-methylsterols, and clinically by 2-3 toe syndactyly and male genital underdevelopment rather than psoriasiform dermatitis with congenital cataract.

Distinguishing Features

Caused by DHCR7 rather than MSMO1
Elevated 7-dehydrocholesterol with low cholesterol, not elevated C4-methylsterols
2-3 toe syndactyly and male genital underdevelopment are characteristic
Psoriasiform dermatitis and congenital cataract are not core features

Show evidence (1 reference)

PMID:23042573 SUPPORT Human Clinical

"This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome."

Positions SC4MOL deficiency as a distinct entity within the group of post-squalene sterol synthesis disorders that also contains Smith-Lemli-Opitz syndrome.

CHILD syndrome Not Yet Curated MONDO:0010621

Overlapping Features Congenital hemidysplasia with ichthyosiform erythroderma and limb defects, caused by NSDHL variants. NSDHL is the immediate partner of MSMO1 in the same C4-demethylation complex and CHILD syndrome is the disorder for which topical cholesterol plus statin therapy is best known, so treatment and mechanism literature is easily misattributed between the two. CHILD syndrome is X-linked dominant with characteristically lateralised skin and limb involvement, whereas MSMO1 deficiency is autosomal recessive with generalised psoriasiform dermatitis.

Distinguishing Features

Caused by NSDHL, the immediate C4-demethylation partner of MSMO1, rather than MSMO1 itself
X-linked dominant with male lethality, not autosomal recessive
Strikingly lateralised (hemidysplastic) skin and ipsilateral limb defects
Congenital cataract, microcephaly and immune dysfunction are not its defining triad
Allelic with CK syndrome - both are NSDHL disorders that accumulate methyl sterols, so the discriminator against CK syndrome is clinical (lateralised cutaneous/limb disease in females) and not biochemical

Show evidence (2 references)

PMID:21695019 SUPPORT Human Clinical

"Finally, a prominent skin phenotype has been described in two patients with SC4MOL deficiency, who present with a severe ichthyosiform dermatosis and psoriasiform features."

This family-wide cutaneous review separates SC4MOL deficiency from CHILD syndrome and the other distal cholesterol disorders it covers.

PMID:21129721 SUPPORT Human Clinical

"As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels."

Establishes that CHILD syndrome and CK syndrome are allelic NSDHL disorders sharing methyl sterol accumulation, so the two cannot be separated from each other on the accumulating sterol alone.

CK syndrome Not Yet Curated MONDO:0010441

Overlapping Features The second, brain-predominant NSDHL disorder. Like CHILD syndrome it is caused by variants in NSDHL, the partner of MSMO1 in the same C4-demethylation complex, and like MSMO1 deficiency it accumulates methyl sterols and presents with intellectual disability - so both the mechanism sentences and the sterol-profile sentences of this literature are easy to misattribute to MSMO1. It is separated from MSMO1 deficiency by X-linked recessive inheritance in males, by cortical brain malformation with an asthenic build rather than psoriasiform dermatitis with congenital cataract, and by the deficient enzyme being NSDHL (the C4 decarboxylase step) rather than MSMO1 (the C4 methyl oxidase step).

Distinguishing Features

Deficient enzyme is NSDHL, not the MSMO1 sterol-C4-methyl oxidase
Accumulating sterols are methyl sterols shared with CHILD syndrome, whereas MSMO1 deficiency accumulates both 4-monomethyl and 4,4-dimethylsterols upstream of the NSDHL step
X-linked recessive, affecting males, rather than autosomal recessive
Cortical brain malformation, dysmorphism and asthenic build dominate; the psoriasiform/ichthyosiform skin phenotype of MSMO1 deficiency is not its presenting feature
Separated from its allelic disorder CHILD syndrome by the absence of lateralised ichthyosiform skin and ipsilateral limb defects

Show evidence (3 references)

PMID:21129721 SUPPORT Human Clinical

"CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build."

Gives the inheritance pattern and the brain-predominant clinical core that separate CK syndrome from MSMO1 deficiency.

PMID:21129721 SUPPORT Human Clinical

"As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels."

Names the accumulating sterol class in CK syndrome and its allelism with CHILD syndrome, the molecular discriminator against both CHILD syndrome and MSMO1 deficiency.

PMID:23042573 SUPPORT Human Clinical

"This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome."

A family-wide review treats SC4MOL deficiency and CK syndrome as the two newly described members of the same post-squalene group, which is the shared-language setting in which their evidence gets mixed up.

Lathosterolosis Not Yet Curated MONDO:0011816

Overlapping Features A post-squalene disorder caused by deficiency of sterol-C5-desaturase (SC5D), two steps downstream of the MSMO1 block. Like MSMO1 deficiency it is autosomal recessive, is diagnosed on a plasma sterol profile and has been treated with a statin, so its therapeutic and biochemical language closely parallels this entry. The discriminator is which sterol accumulates: lathosterol in lathosterolosis versus 4-monomethyl and 4,4-dimethylsterols in MSMO1 deficiency.

Distinguishing Features

Deficient enzyme is SC5D (3-beta-hydroxysteroid-delta-5-desaturase / sterol-C5-desaturase), not MSMO1
Lathosterol accumulates in plasma and fibroblasts, whereas MSMO1 deficiency accumulates 4-monomethyl and 4,4-dimethylsterols
Presents as a Smith-Lemli-Opitz-like malformation syndrome with dysmorphism and multiple congenital anomalies rather than the microcephaly-cataract-psoriasiform-dermatitis triad

Show evidence (3 references)

PMID:24142275 SUPPORT Human Clinical

"Lathosterolosis is an inborn error of cholesterol biosynthesis due to deficiency of the enzyme 3-beta-hydroxysteroid-delta-5-desaturase (or sterol-C5-desaturase or SC5D)."

Names the deficient enzyme and gene that separate lathosterolosis from MSMO1 deficiency.

PMID:24142275 SUPPORT Human Clinical

"We report a patient with dysmorphism, multiple congenital anomalies, and developmental delay, initially suspected to have Smith-Lemli-Opitz syndrome, who was later found to have elevated levels of lathosterol in both plasma and fibroblasts."

Documents the accumulating sterol in a genotyped patient - the biochemical discriminator on the same sterol profile used to diagnose MSMO1 deficiency.

PMID:21695019 SUPPORT Human Clinical

"Although the PI is unaware of lathosterolosis cases in the US, several patients have been described in Europe, and all have prominent ichthyosis."

Lathosterolosis shares prominent ichthyosis with MSMO1 deficiency, so the cutaneous phenotype does not separate them and the sterol profile must.

Desmosterolosis Not Yet Curated MONDO:0011217

Overlapping Features A post-squalene disorder caused by deficiency of 3beta-hydroxysterol-Delta24-reductase (DHCR24). It sits in the same autosomal recessive, sterol-profile-diagnosed group as MSMO1 deficiency and is routinely tabulated alongside it, but desmosterol rather than C4-methylsterol is the accumulating species, and it presents with prominent congenital anomalies and minimal skin disease - close to the inverse of the MSMO1 cutaneous-predominant phenotype.

Distinguishing Features

Deficient enzyme is DHCR24 (3beta-hydroxysterol Delta24-reductase), not MSMO1
Desmosterol accumulates in plasma, tissue and cultured cells, whereas MSMO1 deficiency accumulates 4-monomethyl and 4,4-dimethylsterols
Prominent congenital anomalies with minimal skin abnormality, the opposite emphasis to the severe ichthyosiform/psoriasiform dermatitis of MSMO1 deficiency

Show evidence (2 references)

PMID:11519011 SUPPORT Human Clinical

"Patients with desmosterolosis have elevated levels of the cholesterol precursor desmosterol, in plasma, tissue, and cultured cells; this abnormality suggests a deficiency of the enzyme 3beta-hydroxysterol Delta24-reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of..."

Gives both halves of the molecular discriminator - the deficient enzyme and the accumulating sterol.

PMID:21695019 SUPPORT Human Clinical

"Furthermore, a US kindred38 and several additional patients in Europe14 have been described with desmosterolosis, a disorder that displays prominent congenital anomalies, but minimal evidence of skin abnormalities."

The cutaneous contrast against the severe ichthyosiform dermatosis described for SC4MOL deficiency in the same review.

{ }

Source YAML

click to show

name: MSMO1 Deficiency
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
synonyms:
- MCCPD
- microcephaly, congenital cataract, and psoriasiform dermatitis
- SC4MOL deficiency
- sterol-C4-methyl oxidase deficiency
- SMO deficiency
description: >-
  MSMO1 deficiency is an ultrarare autosomal recessive post-squalene disorder of
  cholesterol biosynthesis caused by biallelic missense variants in MSMO1 (older
  literature: SC4MOL), which encodes methylsterol monooxygenase 1. The enzyme
  performs the first oxidative step of C4 demethylation, converting
  C4-methylsterols to cholesterol precursors. Loss of activity produces a dual
  biochemical lesion: accumulation of 4-monomethyl and 4,4-dimethylsterols
  (the meiosis-activating sterols) upstream of the block, and impaired distal
  cholesterol synthesis downstream of it. The clinical picture reported across
  the small published cohort combines microcephaly, congenital cataracts,
  growth and developmental delay, intellectual disability, immune dysfunction
  and a treatment-refractory psoriasiform dermatitis. Combined cholesterol
  supplementation plus statin therapy, given orally and topically, has improved
  the biochemical, immunological and cutaneous findings in reported patients.
disease_term:
  preferred_term: MSMO1 deficiency
  term:
    id: MONDO:0014793
    label: microcephaly-congenital cataract-psoriasiform dermatitis syndrome
parents:
- Cholesterol biosynthesis disorder
- Inborn Error of Metabolism
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:37195326
      reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date."
      explanation: A monogenic autosomal recessive disorder diagnosed by sequencing belongs to the genetics chapter.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:33161406
      reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sterol-C4-methyl oxidase (SC4MOL) deficiency was recently described as an autosomal recessive cholesterol biosynthesis disorder caused by mutations in the MSMO1 (sometimes also referred to as SC4MOL) gene."
      explanation: The disorder is an inborn error of cholesterol biosynthesis, a metabolic condition.
  - classification_value: DERMATOLOGY
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."
      explanation: Psoriasiform dermatitis is a defining and often presenting manifestation, placing the disorder in the dermatology chapter.
  icimd_category:
  - classification_value: sterol_metabolism
    evidence:
    - reference: PMID:23042573
      reference_title: "Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome."
      explanation: SC4MOL deficiency is classified among the disorders of sterol synthesis.
notes: >-
  Scope and provenance notes for this entry.


  (1) No GeneReviews chapter exists for MSMO1 deficiency. PubMed searches for
  "MSMO1 GeneReviews[All Fields]", "microcephaly congenital cataract
  psoriasiform dermatitis AND GeneReviews[All Fields]" and a sterol-wide
  GeneReviews title search all returned zero records on 2026-08-01, so the
  mandatory GeneReviews phenotype baseline does not apply here. The phenotype
  baseline used instead is the union of the published case reports and the two
  disease-specific reviews (PMID:24144731, PMID:37195326).


  (2) Named-entity-confusion discipline. MSMO1 deficiency sits inside the
  post-squalene cholesterol-biosynthesis family (DHCR7/Smith-Lemli-Opitz,
  NSDHL/CHILD and CK syndrome, DHCR24/desmosterolosis, SC5D/lathosterolosis),
  whose papers share near-identical sterol-pathway and statin-plus-cholesterol
  language. Every citation in this entry was checked for the enzyme the reported
  cohort actually has variants in. Family-wide reviews are cited only for
  sentences that name SC4MOL/MSMO1 explicitly (PMID:23042573, PMID:21695019),
  and the one cited SC4MOL mechanism paper that co-implicates NSDHL
  (PMID:23125191, cancer-cell siRNA study) is recorded as PARTIAL because it is
  neither MSMO1-patient material nor SC4MOL-specific in its NSDHL arm. The three
  treatment citations (PMID:33161406, PMID:37195326, PMID:41413001) are all
  MSMO1-genotyped patients, so the cholesterol-plus-statin evidence here is
  attributed to MSMO1 disease and not borrowed from CHILD syndrome, where the
  same topical formulation is better known.


  (3) Phenotype frequency bands are deliberately omitted throughout. Fewer than
  ten patients have been reported in total (PMID:37195326 counts five cases as
  of 2023) and the reviews disagree on denominators, so no published
  denominator supports an HPO frequency band. Recording the observation without
  a band is preferred to guessing one.


  (4) Hypocholesterolemia is curated as a variable, non-obligate finding, not
  as the diagnostic signature. Unlike Smith-Lemli-Opitz syndrome, low
  cholesterol is inconsistent across MSMO1 patients: the index patient had a
  persistently low total cholesterol (PMID:21285510), but the deep-research
  review of the full published series records normal total cholesterol in
  several later patients. Methylsterol elevation, not hypocholesterolemia, is
  the obligate biochemical signature, so normal cholesterol must not be treated
  as excluding the diagnosis. The evidence item for hypocholesterolemia is
  marked PARTIAL for that reason.


  (5) Published case tallies conflict and none is repeated here as fact.
  PMID:24144731 (2014) reported four patients from three families;
  PMID:33161406 (2020) said five patients from four unrelated families;
  PMID:37195326 (2023) said five cases and then added two siblings. Summing the
  primary reports cited here gives a larger total. The prevalence record
  therefore uses the qualitative ULTRA_RARE tier with the individual
  denominators recorded in its notes rather than asserting a single count.


  (6) No Orphanet (ORPHA:488168) or ClinGen (CGGV/CGDS) structured-source
  record could be cited. Neither identifier is present in references_cache and
  generating one would require a data MANIFEST bump, which is blocked by the
  stale, un-refreshable pins tracked in #7622. The structured-source citation
  is skipped rather than fabricated.


  (7) The Impaired Chondrocyte Hypertrophy node is deliberately terminal. Its
  only support is the zebrafish msmo1 mutant (PMID:32430393); the human
  skeletal findings reported so far (delayed skeletal maturation in
  PMID:21285510, polydactyly in PMID:37195326, an inward curving little
  finger in PMID:41413001) have not been mechanistically tied to
  that chondrocyte defect, so no causal edge is drawn between them.


  (8) Scope of the differential_diagnoses block. All five autosomal or
  X-linked post-squalene disorders whose evidence is most at risk of being
  attributed to MSMO1 are modelled here, each with the deficient enzyme and
  the accumulating sterol as the discriminator: DHCR7/7-dehydrocholesterol
  (Smith-Lemli-Opitz), NSDHL/methyl sterols (CHILD syndrome and its allelic
  disorder CK syndrome), SC5D/lathosterol (lathosterolosis) and
  DHCR24/desmosterol (desmosterolosis). Because CHILD syndrome and CK syndrome
  are allelic NSDHL disorders that share methyl sterol accumulation
  (PMID:21129721), they are discriminated from each other clinically rather
  than biochemically. Three further members of the family tabulated in the
  deep-research artifact are deliberately not modelled: CDPX2/EBP,
  HEM-Greenberg dysplasia/LBR and Antley-Bixler/POR. Each is defined by a
  skeletal or craniofacial feature that has not been reported in any MSMO1
  patient cited here (chondrodysplasia punctata, moth-eaten lethal skeletal
  dysplasia, craniosynostosis with disordered steroidogenesis). Grepping
  references_cache across the fourteen references cited by this entry for
  EBP, LBR, POR, CDPX2, Conradi, Greenberg and Antley-Bixler returns hits only
  in PMID:21285510, PMID:21695019 and PMID:23125191, and in each case the
  neighbouring disorder is discussed as a contrast rather than as a source of
  MSMO1 findings; PMID:21285510 in particular reports that SC4MOL- and
  NSDHL-deficient patients accumulate 4,4'-dimethylsterols in skin while
  EBP-deficient patients do not, which is the molecular discriminator against
  CDPX2. The chondrodysplasia punctata contrast is additionally recorded on
  the Delayed skeletal maturation phenotype, where normal bone morphology is
  the discriminating observation.
inheritance:
- name: Autosomal recessive
  description: Biallelic MSMO1 variants are required; carriers are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date."
    explanation: The disease-specific review states the autosomal recessive inheritance pattern for MSMO1 deficiency.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Segregation analysis in all available family members confirmed recessive inheritance of the mutation."
    explanation: Family segregation analysis in a consanguineous kindred confirms recessive transmission.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Derivation: only case-level denominators exist. PMID:24144731 (2014)
    described four patients from three families; PMID:33161406 (2020) counted
    five patients from four unrelated families; PMID:37195326 (2023) counted
    five cases and added two more siblings. No population-based rate has ever
    been published, so no numeric rate_per_100000 is recorded and the
    qualitative ULTRA_RARE tier is used.
  evidence:
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date."
    explanation: The most recent disease-specific review characterises the disorder as ultrarare with five reported cases.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 5 patients from 4 unrelated families with SC4MOL deficiency have been reported."
    explanation: Provides the published case denominator underpinning the ultra-rare classification.
pathophysiology:
- name: MSMO1 Deficiency
  biological_scale: MOLECULAR
  description: >-
    Biallelic missense variants in MSMO1 reduce methylsterol monooxygenase 1
    activity, blocking the first oxidative step of sterol C4 demethylation in
    post-squalene cholesterol biosynthesis.
  genes:
  - preferred_term: MSMO1
    term:
      id: hgnc:10545
      label: MSMO1
    modifier: DECREASED
  molecular_functions:
  - preferred_term: C-4 methylsterol oxidase activity
    term:
      id: GO:0000254
      label: C-4 methylsterol oxidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: cholesterol biosynthetic process
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."
    explanation: The index report establishes SC4MOL/MSMO1 loss of function as the causal molecular lesion.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway."
    explanation: Identifies the specific enzymatic step lost in this disorder.
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols."
    explanation: Confirms the gene, the encoded enzyme and the immediate biochemical consequence.
  downstream:
  - target: C4-Methylsterol Accumulation
    description: Loss of C4 demethylation blocks consumption of C4-methylsterol substrates.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37195326
      reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols."
      explanation: Directly links MSMO1 variants to methylsterol accumulation.
    - reference: PMID:41413001
      reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It also causes an upstream accumulation of toxic methylsterols."
      explanation: A genotyped MSMO1 patient report describes upstream methylsterol accumulation as a consequence of the enzyme deficiency.
  - target: Impaired Distal Cholesterol Biosynthesis
    description: The same enzymatic block reduces flux through the distal pathway to cholesterol.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41718295
      reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MSMO1, encoding a key enzyme in the cholesterol synthesis pathway, is associated with an autosomal recessive condition characterized by microcephaly, ocular abnormalities, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
      explanation: Places MSMO1 as a key cholesterol-synthesis enzyme whose loss impairs the pathway.
    - reference: PMID:32430393
      reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We demonstrated that this is a result of both cholesterol deprivation and sterol intermediate accumulation by creating a mutation eliminating activity of Lanosterol synthase (Lss)."
      explanation: The zebrafish msmo1 mutant dissects the phenotype into a cholesterol-deprivation arm and a sterol-intermediate-accumulation arm.
  - target: Impaired Neurodevelopment
    description: >-
      The enzymatic block is associated with microcephaly, developmental delay
      and intellectual disability, but the mediating steps between sterol
      imbalance and cortical development are not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41718295
      reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MSMO1, encoding a key enzyme in the cholesterol synthesis pathway, is associated with an autosomal recessive condition characterized by microcephaly, ocular abnormalities, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
      explanation: Associates the MSMO1 enzymatic defect with the neurodevelopmental phenotype without specifying intermediates.
  - target: Growth Impairment
    description: >-
      Growth delay and short stature are consistently reported, again without a
      resolved mechanistic intermediate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37195326
      reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinically, MSMO1 deficiency is characterized by growth and developmental delay, often in association with congenital cataracts, microcephaly, psoriasiform dermatitis and immune dysfunction."
      explanation: Places growth delay among the defining features of the enzymatic deficiency.
- name: C4-Methylsterol Accumulation
  biological_scale: MOLECULAR
  description: >-
    4-monomethyl and 4,4-dimethylsterols, the meiosis-activating sterols,
    accumulate in plasma, skin scales and cultured cells because the first
    C4-demethylation step is blocked.
  chemical_entities:
  - preferred_term: 4,4-dimethylsterol
    term:
      id: CHEBI:143563
      label: 3beta-hydroxy-4,4-dimethylsteroid
    modifier: INCREASED
  - preferred_term: 4alpha-methylzymosterol
    term:
      id: CHEBI:1949
      label: 4alpha-methylzymosterol
    modifier: INCREASED
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantitative sterol analysis of plasma and skin scales from all four patients showed marked elevation of 4α-methyl- and 4, 4'-dimethylsterols, consistent with a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis."
    explanation: Direct sterol quantification in patients establishes the accumulating species.
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."
    explanation: An independent genotyped patient reproduces the same accumulation pattern.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C4-Methylsterols are meiosis-activating sterols (MASs)."
    explanation: Identifies the accumulating C4-methylsterols as the meiosis-activating sterols.
  downstream:
  - target: Meiosis-Activating Sterol LXR Signaling
    description: Accumulated meiosis-activating sterols act as ligands for liver X receptors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MASs serve as ligands for liver X receptors α and β(LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity."
      explanation: Establishes the receptor through which accumulated methylsterols signal.
  - target: Disrupted Vesicular Trafficking and EGFR Signaling
    description: Methylsterol excess perturbs vesicular trafficking and EGF receptor signaling in patient cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24144731
      reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Additional studies also demonstrated diminished EGFR signaling and disrupted vesicular trafficking in cells from the affected patients."
      explanation: Patient-derived cells show the trafficking and EGFR abnormality downstream of the sterol block.
  - target: Epidermal and Hematopoietic Cell Overproliferation
    description: Accumulated meiosis-activating sterols drive overproliferation in skin and blood.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood."
      explanation: The index study directly attributes cell overproliferation to methylsterol accumulation.
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This ratio peaked after 2-3 days growth in the cholesterol-restricted medium and corresponded with peaks of cellular methylsterols and total protein."
      explanation: The proliferative index tracked with cellular methylsterol content, tying proliferation to substrate accumulation rather than to cholesterol level alone.
  - target: Constitutive Fibroblast IL-6 Production
    description: >-
      Methylsterol accumulation is associated with constitutive fibroblast IL-6
      output that falls when cholesterologenesis is inhibited with simvastatin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we treated control and patient fibroblasts with simvastatin, which reduces cholesterol biosynthesis intermediates including methylsterols (23, 24). After 24 hours, IL-6 production by patient fibroblasts was significantly decreased"
      explanation: Pharmacological reduction of sterol-pathway intermediates lowers IL-6, linking the cytokine phenotype to the sterol lesion.
  - target: Plasma C4-methylsterols
    description: The accumulated sterol pool is measurable as the diagnostic plasma sterol profile.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28673550
      reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."
      explanation: Blood sterol profiling is the readout of the accumulated pool.
  - target: Elevated circulating monomethyl sterol concentration
    description: The accumulated pool is measured clinically as raised plasma monomethylsterols.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The profile showed 20- and 500-fold elevation of 4 α-monomethyl sterols and 4, 4 ′-dimethyl sterols, respectively"
      explanation: Quantifies the monomethylsterol elevation produced by the block.
  - target: Elevated circulating dimethyl sterol concentration
    description: The accumulated pool is measured clinically as markedly raised plasma dimethylsterols.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The profile showed 20- and 500-fold elevation of 4 α-monomethyl sterols and 4, 4 ′-dimethyl sterols, respectively"
      explanation: Quantifies the far larger dimethylsterol elevation produced by the block.
- name: Impaired Distal Cholesterol Biosynthesis
  biological_scale: MOLECULAR
  description: >-
    Flux through the post-squalene pathway to cholesterol is reduced because
    C4-methylsterol intermediates cannot be demethylated, depriving tissues of
    endogenously synthesised cholesterol.
  chemical_entities:
  - preferred_term: cholesterol
    term:
      id: CHEBI:16113
      label: cholesterol
    modifier: DECREASED
  biological_processes:
  - preferred_term: cholesterol biosynthetic process
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:41718295
    reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane and leading to early cataract formation."
    explanation: Attributes an MSMO1 clinical feature to impaired cholesterol synthesis.
  - reference: PMID:32430393
    reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our analysis suggests that hypertrophic chondrocytes depend on endogenous cholesterol synthesis, and blocking C4 demethylation exacerbates the cholesterol deficiency phenotype."
    explanation: The msmo1 zebrafish mutant demonstrates that blocking C4 demethylation produces a cholesterol-deficiency state.
  downstream:
  - target: Altered Lens Membrane Lipid Composition
    description: Reduced cholesterol availability alters the lipid composition of the lens membrane.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41718295
      reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane and leading to early cataract formation."
      explanation: States the proposed mechanistic step from cholesterol deficiency to altered lens membrane lipids.
  - target: Hypocholesterolemia
    description: >-
      Reduced endogenous synthesis can present as low circulating cholesterol,
      although this is variable and not obligate across reported patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Her serum lipid profile showed a persistently low total cholesterol level (85 mg/dl; normal, 140-176), low HDL (28 mg/dl; normal, 35-75), and low LDL (49 mg/dl; normal, 70-160) but normal triglycerides (84 mg/dl; normal, 50-200)"
      explanation: >-
        Marked PARTIAL because hypocholesterolemia is documented here in the
        index patient only; later reported MSMO1 patients had normal
        cholesterol, so the edge is real but not obligate.
  - target: Impaired Chondrocyte Hypertrophy
    description: Hypertrophic chondrocytes depend on endogenous cholesterol synthesis and are lost when Msmo1 activity is absent.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32430393
      reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Rescued mutants develop dramatic skeletal abnormalities, with a loss of Msmo1 activity resulting in a more-severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1a expression."
      explanation: Loss of Msmo1 activity in zebrafish removes the hypertrophic chondrocyte population.
- name: Meiosis-Activating Sterol LXR Signaling
  biological_scale: MOLECULAR
  description: >-
    Accumulated meiosis-activating sterols act as ligands for the nuclear
    receptors LXR alpha and LXR beta, which govern epidermal lipid transport and
    both innate and adaptive immunity.
  genes:
  - preferred_term: LXR alpha
    term:
      id: hgnc:7966
      label: NR1H3
    modifier: DYSREGULATED
  - preferred_term: LXR beta
    term:
      id: hgnc:7965
      label: NR1H2
    modifier: DYSREGULATED
  biological_processes:
  - preferred_term: intracellular receptor signaling pathway
    term:
      id: GO:0030522
      label: intracellular receptor signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MASs serve as ligands for liver X receptors α and β(LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity."
    explanation: Names the receptors and the two downstream domains they regulate.
  downstream:
  - target: Immunocyte Dysregulation
    description: LXR-linked signaling changes accompany altered immunocyte phenotype and function.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "SMO deficiency also substantially altered immunocyte phenotype and in vitro function."
      explanation: Documents the immunocyte abnormality in the index patient.
- name: Disrupted Vesicular Trafficking and EGFR Signaling
  biological_scale: CELLULAR
  description: >-
    Cells from affected patients show disrupted vesicular trafficking and
    diminished EGF receptor signaling, a cell-biological consequence of the
    C4-demethylation block.
  biological_processes:
  - preferred_term: vesicle-mediated transport
    term:
      id: GO:0016192
      label: vesicle-mediated transport
    modifier: DYSREGULATED
  - preferred_term: epidermal growth factor receptor signaling pathway
    term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additional studies also demonstrated diminished EGFR signaling and disrupted vesicular trafficking in cells from the affected patients."
    explanation: Establishes the trafficking and EGFR defect in patient-derived cells.
  - reference: PMID:23125191
    reference_title: Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation.
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3."
    explanation: >-
      Mechanistic corroboration only. This is a cancer-cell siRNA study that
      co-targets SC4MOL and its C4-demethylation partner NSDHL, the gene of
      CHILD and CK syndrome, so the result is not MSMO1-patient evidence and
      the NSDHL arm is not attributable to this disorder.
  downstream:
  - target: Epidermal and Hematopoietic Cell Overproliferation
    description: Altered intracellular signaling and trafficking contribute to the proliferative epidermal phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24144731
      reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings suggest that methylsterols play an important role in epidermal biology by their influence on cell proliferation, intracellular signaling, vesicular trafficking and immune response."
      explanation: Groups proliferation, signaling and trafficking as the linked epidermal consequences of methylsterol excess.
- name: Epidermal and Hematopoietic Cell Overproliferation
  biological_scale: CELLULAR
  description: >-
    Skin and blood cells overproliferate in the presence of accumulated
    meiosis-activating sterols; patient fibroblasts show a higher mitotic rate
    than controls and pharmacological inhibition of the enzyme activates the
    cell cycle in lymphoblasts.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  - preferred_term: epidermis development
    term:
      id: GO:0008544
      label: epidermis development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood."
    explanation: Direct patient-level observation of overproliferation in both compartments.
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cellular studies with patient-derived fibroblasts have shown a higher mitotic rate than control cells in cholesterol-depleted medium, with increased de novo cholesterol biosynthesis and accumulation of methylsterols."
    explanation: Patient fibroblasts demonstrate the increased proliferative rate.
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts induced activation of the cell cycle."
    explanation: Pharmacological enzyme inhibition reproduces cell-cycle activation, supporting causality.
  downstream:
  - target: Psoriasiform dermatitis
    description: Epidermal hyperproliferation underlies the psoriasiform cutaneous phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24144731
      reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings suggest that methylsterols play an important role in epidermal biology by their influence on cell proliferation, intracellular signaling, vesicular trafficking and immune response."
      explanation: Links methylsterol-driven proliferation to epidermal biology in this disorder.
    - reference: PMID:21695019
      reference_title: "Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Finally, a prominent skin phenotype has been described in two patients with SC4MOL deficiency, who present with a severe ichthyosiform dermatosis and psoriasiform features."
      explanation: >-
        Marked PARTIAL because this review covers the whole post-squalene
        family and is dominated by CHILD syndrome and Conradi-Hunermann-Happle;
        only this sentence is SC4MOL-specific, and it establishes the cutaneous
        phenotype rather than the proliferative mechanism.
  - target: Ichthyosis
    description: The same epidermal disturbance produces the ichthyosiform component of the rash.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21695019
      reference_title: "Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Finally, a prominent skin phenotype has been described in two patients with SC4MOL deficiency, who present with a severe ichthyosiform dermatosis and psoriasiform features."
      explanation: >-
        Marked PARTIAL: this is the only SC4MOL-specific sentence in a
        family-wide cutaneous review, and it establishes the ichthyosiform
        phenotype rather than the proliferative mechanism behind it.
  - target: Erythroderma
    description: Uncontrolled epidermal disease can generalise to erythroderma.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41413001
      reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This progressed to become erythrodermic despite multiple topical treatments as well as systemic treatments including ciclosporin and zinc supplements."
      explanation: A genotyped MSMO1 patient progressed from psoriasiform rash to erythroderma.
- name: Constitutive Fibroblast IL-6 Production
  biological_scale: CELLULAR
  description: >-
    Patient dermal fibroblasts constitutively secrete IL-6 irrespective of
    passage number, and serum IL-6 and IL-8 are raised. Simvastatin, which
    lowers sterol-pathway intermediates, significantly reduces that IL-6 output
    in patient cells, tying the cytokine phenotype to the sterol lesion.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cultures of patient skin fibroblasts showed constitutive production of IL-6 compared with control fibroblasts regardless of passage number (Figure 4D), and IL-6 concentration was further increased with the addition of recombinant TNF-α, a known inducer of IL-6."
    explanation: Establishes constitutive IL-6 output by patient fibroblasts.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-6 and IL-8 were also elevated in the patient's serum (Supplemental Table 3)."
    explanation: Serum IL-6 and IL-8 are raised in the index patient, matching the constitutive fibroblast IL-6 output.
  downstream:
  - target: Psoriasiform dermatitis
    description: Fibroblast-derived IL-6 contributes to the inflammatory component of the cutaneous phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Elevation of IL-6 and IL-8 has been demonstrated in psoriatic skin and fibroblasts and is considered an amplifier of skin inflammation (21)."
      explanation: Places the elevated IL-6 in the causal context of psoriasiform skin inflammation.
- name: Immunocyte Dysregulation
  biological_scale: CELLULAR
  description: >-
    Granulocytes and B cells from patients and obligate carriers show
    dysregulated immune-related receptors, and patient immunocytes show altered
    phenotype and in vitro function.
  cell_types:
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunologic analyses of granulocytes and B cells from patients and obligate carriers in the patients' families indicated dysregulation of immune-related receptors."
    explanation: >-
      Names the affected immune cell types and the receptor-level abnormality.
      Classified HUMAN_CLINICAL, matching the analogous CD16+ granulocyte
      immunophenotyping from PMID:21285510 below: both are direct
      immunophenotyping of patient blood rather than a cultured-cell
      experiment.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMO deficiency also substantially altered immunocyte phenotype and in vitro function."
    explanation: Independent support for altered immunocyte phenotype and function.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that activated CD16+ granulocytes (identified by CD25+CD69+ and CD86+HLA-DR+ subsets) were increased 30- and 20-fold in the patient and her father, respectively, compared with healthy controls"
    explanation: Quantifies the granulocyte activation phenotype in the patient and, notably, in her heterozygous father.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Upregulation of TLR-2, but not TLR-4, is considered typical for patients with psoriasis (17) or psoriatic arthritis (18), but not those with rheumatoid arthritis."
    explanation: Contextualises the granulocyte TLR-2 high, TLR-4 low pattern seen in the patient as a psoriasis-like innate-immune signature.
  downstream:
  - target: Immune dysfunction
    description: Cellular immune dysregulation manifests clinically as immune dysfunction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28673550
      reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
      explanation: Immune dysfunction is listed among the core clinical features of the reported cohort.
- name: Altered Lens Membrane Lipid Composition
  biological_scale: TISSUE
  description: >-
    Impaired cholesterol synthesis alters the lipid composition of the lens
    fiber cell membrane, the proposed route to early lens opacification.
  cell_types:
  - preferred_term: lens fiber cell
    term:
      id: CL:0011004
      label: lens fiber cell
  evidence:
  - reference: PMID:41718295
    reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane and leading to early cataract formation."
    explanation: States the lens-membrane lipid alteration as the proposed intermediate step.
  downstream:
  - target: Congenital cataract
    description: Altered lens membrane lipid composition leads to early cataract formation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41718295
      reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane and leading to early cataract formation."
      explanation: Completes the proposed chain from membrane lipid change to cataract.
- name: Impaired Chondrocyte Hypertrophy
  biological_scale: TISSUE
  description: >-
    In the zebrafish msmo1 mutant, loss of enzyme activity causes near-complete
    loss of the hypertrophic chondrocyte population and severe skeletal
    patterning defects. No human MSMO1 skeletal finding has yet been tied to
    this mechanism, so this node is deliberately terminal.
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  - preferred_term: prehypertrophic chondrocyte
    term:
      id: CL:0020022
      label: prehypertrophic chondrocyte
  evidence:
  - reference: PMID:32430393
    reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In a forward-genetic approach, we have found that a late-onset skeletal mutant, named kolibernu7 , is the result of a cis-acting regulatory mutation leading to loss of methylsterol monooxygenase 1 (msmo1) expression within pre-hypertrophic chondrocytes."
    explanation: Localises the msmo1 requirement to pre-hypertrophic chondrocytes.
  - reference: PMID:32430393
    reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rescued mutants develop dramatic skeletal abnormalities, with a loss of Msmo1 activity resulting in a more-severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1a expression."
    explanation: Documents the loss of the hypertrophic chondrocyte population.
- name: Impaired Neurodevelopment
  biological_scale: ORGANISM
  description: >-
    Microcephaly, global developmental delay and intellectual disability are
    consistent features of the reported cohort; the intervening mechanism
    between the sterol lesion and cortical development is unresolved.
  evidence:
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
    explanation: Summarises the neurodevelopmental features across the published cohort.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology."
    explanation: Attributes the global developmental impact to methylsterol accumulation.
  downstream:
  - target: Microcephaly
    description: Impaired neurodevelopment presents with reduced head circumference.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28673550
      reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
      explanation: Microcephaly is listed among the infancy-onset features.
  - target: Global developmental delay
    description: Impaired neurodevelopment presents with global developmental delay.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41718295
      reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This report describes a patient presenting with global developmental delay and bilateral infantile cataracts found to harbor a homozygous likely pathogenic MSMO1 variant and reviews the literature on MSMO1 deficiency and its association with infantile cataracts."
      explanation: A genotyped MSMO1 patient presented with global developmental delay.
  - target: Intellectual disability
    description: Impaired neurodevelopment presents with intellectual disability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28673550
      reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
      explanation: Intellectual disability is listed among the core features.
- name: Growth Impairment
  biological_scale: ORGANISM
  description: >-
    Growth delay in infancy and short stature are recurrent findings in
    genotyped patients.
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."
    explanation: Growth delay in infancy is reported across the first described cohort.
  downstream:
  - target: Growth delay
    description: The growth phenotype is recognised in infancy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24144731
      reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."
      explanation: Directly supports growth delay as a manifestation.
  - target: Short stature
    description: Growth impairment persists into adulthood as short stature in at least one genotyped patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28673550
      reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Herein, we describe a new case of SC4MOL deficiency in which a 19-year-old Italian male was affected by bilateral congenital cataracts, growth delay and learning disabilities, behavioral disorders and small stature, but not microcephaly."
      explanation: A 19-year-old genotyped patient had small stature.
  - target: Failure to thrive
    description: Poor weight gain in early childhood is part of the growth phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21285510
      reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Also notable in the patient's medical history are congenital cataracts, mild developmental delay, microcephaly (head circumference 53.5 cm at the age of 13 years, <3rd percentile; 50th percentile for a 7.5-year-old), and failure to thrive."
      explanation: >-
        The index case description lists failure to thrive alongside cataract,
        developmental delay and microcephaly.
phenotypes:
- name: Psoriasiform dermatitis
  category: Dermatologic
  description: >-
    Severe, often treatment-refractory psoriasiform dermatitis, in the index
    patient diffuse and sparing only the palms.
  phenotype_term:
    preferred_term: Psoriasiform dermatitis
    term:
      id: HP:0003765
      label: Psoriasiform dermatitis
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."
    explanation: The index MSMO1 patient had psoriasiform dermatitis.
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first patient has suffered since the age of six years from severe, diffuse, psoriasiform dermatitis, sparing only her palms."
    explanation: Describes the severity and distribution of the dermatitis.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."
    explanation: Independent genotyped siblings with the same cutaneous phenotype.
- name: Congenital cataract
  category: Ophthalmologic
  description: Bilateral cataracts present congenitally or in infancy.
  phenotype_term:
    preferred_term: Congenital cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."
    explanation: Congenital cataracts in all patients of the first described cohort.
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
    explanation: Bilateral congenital cataracts across the reported patients.
  - reference: PMID:41718295
    reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report describes a patient presenting with global developmental delay and bilateral infantile cataracts found to harbor a homozygous likely pathogenic MSMO1 variant and reviews the literature on MSMO1 deficiency and its association with infantile cataracts."
    explanation: A further genotyped patient with bilateral infantile cataracts.
- name: Microcephaly
  category: Growth
  description: >-
    Reduced head circumference reported in infancy in most patients, although
    at least one genotyped adult patient did not have microcephaly.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."
    explanation: Microcephaly in all patients of the first described cohort.
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe a new case of SC4MOL deficiency in which a 19-year-old Italian male was affected by bilateral congenital cataracts, growth delay and learning disabilities, behavioral disorders and small stature, but not microcephaly."
    explanation: >-
      Marked PARTIAL because this genotyped patient explicitly lacked
      microcephaly, showing the feature is not obligate.
- name: Growth delay
  category: Growth
  description: Growth delay recognised in infancy.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy."
    explanation: Growth delay in all patients of the first described cohort.
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, MSMO1 deficiency is characterized by growth and developmental delay, often in association with congenital cataracts, microcephaly, psoriasiform dermatitis and immune dysfunction."
    explanation: The disease-specific review lists growth delay as a defining feature.
- name: Global developmental delay
  category: Neurologic
  description: Delayed acquisition of developmental milestones across domains.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41718295
    reference_title: Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report describes a patient presenting with global developmental delay and bilateral infantile cataracts found to harbor a homozygous likely pathogenic MSMO1 variant and reviews the literature on MSMO1 deficiency and its association with infantile cataracts."
    explanation: Global developmental delay in a genotyped MSMO1 patient.
  - reference: PMID:41413001
    reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other syndromic features were apparent from presentation and developed over follow-up with global developmental delay, microcephaly, congenital cataracts corrected age 3, and skeletal abnormalities (inward curving little finger)."
    explanation: A second genotyped patient with global developmental delay.
- name: Intellectual disability
  category: Neurologic
  description: Intellectual disability, described as severe in some patients.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
    explanation: Intellectual disability listed among the core features.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."
    explanation: Severe intellectual disability in two genotyped siblings.
- name: Immune dysfunction
  category: Immunologic
  description: >-
    Clinically reported immune dysfunction, corresponding to dysregulated
    immune-related receptors on granulocytes and B cells.
  phenotype_term:
    preferred_term: Immune dysfunction
    term:
      id: HP:0010978
      label: Abnormality of immune system physiology
  evidence:
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability."
    explanation: Immune dysfunction reported as a core clinical feature.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMO deficiency also substantially altered immunocyte phenotype and in vitro function."
    explanation: Laboratory characterisation of the immune abnormality in the index patient.
- name: Motor delay
  category: Neurologic
  description: Delayed motor milestones.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."
    explanation: Motor delay reported in two genotyped siblings.
- name: Nystagmus
  category: Ophthalmologic
  description: Part of the ocular abnormality spectrum beyond cataract.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."
    explanation: Nystagmus explicitly listed among the ocular abnormalities.
- name: Optic nerve hypoplasia
  category: Ophthalmologic
  description: Optic hypoplasia reported alongside other ocular findings.
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  evidence:
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."
    explanation: Optic hypoplasia explicitly listed among the ocular abnormalities.
- name: Myopia
  category: Ophthalmologic
  description: Refractive error reported in the ocular spectrum.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."
    explanation: Myopia explicitly listed among the ocular abnormalities.
- name: Strabismus
  category: Ophthalmologic
  description: Ocular misalignment reported in the ocular spectrum.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay."
    explanation: Strabismus explicitly listed among the ocular abnormalities.
- name: Alopecia
  category: Dermatologic
  description: Hair loss, reported as a newly recognised feature in a consanguineous sibship.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity."
    explanation: Alopecia reported as a novel feature in genotyped MSMO1 siblings.
- name: Polydactyly
  category: Skeletal
  description: Supernumerary digits, reported as a newly recognised feature.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity."
    explanation: Polydactyly reported as a novel feature in genotyped MSMO1 siblings.
- name: Spasticity
  category: Neurologic
  description: Increased muscle tone, reported as a newly recognised feature.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity."
    explanation: Spasticity reported as a novel feature in genotyped MSMO1 siblings.
- name: Arthralgia
  category: Musculoskeletal
  description: Joint pain reported in the index patient.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."
    explanation: Arthralgias reported in the index MSMO1 patient.
- name: Erythroderma
  category: Dermatologic
  description: >-
    Progression of the psoriasiform rash to erythroderma despite topical and
    systemic therapy in an infant later found to carry compound heterozygous
    MSMO1 variants.
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:41413001
    reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This progressed to become erythrodermic despite multiple topical treatments as well as systemic treatments including ciclosporin and zinc supplements."
    explanation: Documents erythroderma in a genotyped MSMO1 patient.
- name: Short stature
  category: Growth
  description: Small stature persisting into adulthood.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we describe a new case of SC4MOL deficiency in which a 19-year-old Italian male was affected by bilateral congenital cataracts, growth delay and learning disabilities, behavioral disorders and small stature, but not microcephaly."
    explanation: Small stature in a genotyped 19-year-old patient.
- name: Dry skin
  category: Dermatologic
  description: >-
    Early or milder cutaneous presentation, seen with hair changes in a young
    patient before severe dermatitis developed.
  phenotype_term:
    preferred_term: Dry skin
    term:
      id: HP:0000958
      label: Dry skin
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second patient is a 5 year old girl who has just started to develop dry skin and hair changes."
    explanation: Dry skin as an early cutaneous manifestation in a second patient.
- name: Clinodactyly of the 5th finger
  category: Skeletal
  description: >-
    Inward curving little finger, the skeletal abnormality described in a
    genotyped infant.
  phenotype_term:
    preferred_term: Inward curving little finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:41413001
    reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other syndromic features were apparent from presentation and developed over follow-up with global developmental delay, microcephaly, congenital cataracts corrected age 3, and skeletal abnormalities (inward curving little finger)."
    explanation: >-
      The reported inward curving little finger is curated as clinodactyly of
      the 5th finger, the closest HPO concept; the source uses descriptive
      rather than ontology language.
- name: Ichthyosis
  category: Dermatologic
  description: >-
    Severe ichthyosiform erythroderma covering the whole body but sparing the
    palms in the index patient.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 13-year-old female presented for evaluation of severe ichthyosiform erythroderma affecting her entire body but sparing the palms"
    explanation: Documents the ichthyosiform component of the cutaneous phenotype in the index patient.
  - reference: PMID:21695019
    reference_title: "Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, a prominent skin phenotype has been described in two patients with SC4MOL deficiency, who present with a severe ichthyosiform dermatosis and psoriasiform features."
    explanation: The one SC4MOL-specific sentence in this family-wide cutaneous review confirms the ichthyosiform component.
- name: Failure to thrive
  category: Growth
  description: Poor weight gain with weight and height below the third centile.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Also notable in the patient's medical history are congenital cataracts, mild developmental delay, microcephaly (head circumference 53.5 cm at the age of 13 years, <3rd percentile; 50th percentile for a 7.5-year-old), and failure to thrive."
    explanation: >-
      The index case description records failure to thrive alongside the
      cataract, developmental delay and microcephaly triad.
- name: Delayed skeletal maturation
  category: Skeletal
  description: >-
    Bone age is delayed while bone morphology remains normal. The normal
    morphology is diagnostically useful because it separates this disorder from
    the chondrodysplasia punctata group of sterol defects.
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A skeletal survey showed delayed skeletal maturation, but bone morphology was normal."
    explanation: Skeletal survey in the index patient documents delayed maturation with preserved morphology.
- name: Blepharitis
  category: Ophthalmologic
  description: Lid margin inflammation noted alongside the hair and skin changes.
  phenotype_term:
    preferred_term: Blepharitis
    term:
      id: HP:0000498
      label: Blepharitis
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Note mild microcephaly, lusterless, fine fair hair, and blepharitis."
    explanation: Blepharitis is documented in the clinical description of the index patient.
- name: Hypocholesterolemia
  category: Laboratory
  description: >-
    Low total, HDL and LDL cholesterol in the index patient. Variable and NOT
    obligate across the reported series, so it cannot be used to include or
    exclude the diagnosis.
  phenotype_term:
    preferred_term: Hypocholesterolemia
    term:
      id: HP:0003146
      label: Hypocholesterolemia
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Her serum lipid profile showed a persistently low total cholesterol level (85 mg/dl; normal, 140-176), low HDL (28 mg/dl; normal, 35-75), and low LDL (49 mg/dl; normal, 70-160) but normal triglycerides (84 mg/dl; normal, 50-200)"
    explanation: >-
      Marked PARTIAL because this documents hypocholesterolemia in the index
      patient only; later reported MSMO1 patients have had normal cholesterol,
      so the finding is supportive rather than defining.
- name: Elevated circulating monomethyl sterol concentration
  category: Laboratory
  description: >-
    Roughly 20-fold elevation of 4-monomethylsterols in plasma, part of the
    diagnostic sterol signature.
  phenotype_term:
    preferred_term: Elevated circulating monomethyl sterol concentration
    term:
      id: HP:6000753
      label: Elevated circulating monomethyl sterol concentration
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The profile showed 20- and 500-fold elevation of 4 α-monomethyl sterols and 4, 4 ′-dimethyl sterols, respectively"
    explanation: GC-MS sterol profiling quantifies the monomethylsterol elevation.
- name: Elevated circulating dimethyl sterol concentration
  category: Laboratory
  description: >-
    Roughly 500-fold elevation of 4,4-dimethylsterols in plasma, with
    preferential accumulation in skin.
  phenotype_term:
    preferred_term: Elevated circulating dimethyl sterol concentration
    term:
      id: HP:6000754
      label: Elevated circulating dimethyl sterol concentration
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The profile showed 20- and 500-fold elevation of 4 α-monomethyl sterols and 4, 4 ′-dimethyl sterols, respectively"
    explanation: The same GC-MS profile quantifies the far larger dimethylsterol elevation.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dimethylsterol (peak 6) is most elevated in skin, suggesting the preferential accumulation of 4,4′-dimethylsterols in the patient's skin."
    explanation: Documents preferential cutaneous deposition, the rationale for topical therapy.
histopathology:
- name: Psoriasiform epidermal hyperplasia
  description: >-
    Skin biopsy shows psoriasiform hyperplasia with dilated dermal papillary
    capillaries and neutrophils in the epidermis and stratum corneum, plus
    lipid-laden foamy cells in the dermis. The histology mimics true psoriasis,
    which is the principal reason for diagnostic delay.
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thinning of suprapapillary plate, and neutrophilic epidermal infiltration; these features are characteristic of psoriasis."
    explanation: Describes the psoriasis-like epidermal histology seen on biopsy of affected skin.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The arrow shows the intracellular lipid accumulation in the foamy cells in the dermis."
    explanation: Documents the dermal lipid-laden foamy cells that accompany the psoriasiform epidermal changes.
biochemical:
- name: Plasma C4-methylsterols
  presence: INCREASED
  context: >-
    Diagnostic sterol profile. Marked elevation of 4-monomethyl and
    4,4-dimethylsterols in plasma and skin scales is the biochemical signature
    that distinguishes this disorder from the other post-squalene defects.
  biomarker_term:
    preferred_term: 4,4-dimethylsterol
    term:
      id: CHEBI:143563
      label: 3beta-hydroxy-4,4-dimethylsteroid
  readouts:
  - target: C4-Methylsterol Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Elevated plasma C4-monomethyl and C4-dimethyl sterols report the
      substrate pool accumulating immediately upstream of the MSMO1 block.
    evidence:
    - reference: PMID:28673550
      reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."
      explanation: Blood sterol profiling reads out the accumulated substrate pool.
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantitative sterol analysis of plasma and skin scales from all four patients showed marked elevation of 4α-methyl- and 4, 4'-dimethylsterols, consistent with a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis."
    explanation: Quantitative sterol analysis in patients establishes the diagnostic elevation.
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."
    explanation: Independent confirmation of the same plasma sterol pattern.
genetic:
- name: MSMO1
  gene_term:
    preferred_term: MSMO1
    term:
      id: hgnc:10545
      label: MSMO1
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:33161406
      reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Segregation analysis in all available family members confirmed recessive inheritance of the mutation."
      explanation: Segregation in a consanguineous family confirms recessive transmission of the MSMO1 allele.
  features: >-
    Biallelic missense variants in MSMO1 (also called SC4MOL) reduce
    methylsterol monooxygenase 1 activity. Reported alleles include c.731A>G
    p.Tyr244Cys and c.605G>A p.Gly202Glu in compound heterozygosity, homozygous
    c.81A>C p.Asn27Thr, and homozygous c.548A>C p.Glu183Ala. All reported
    disease alleles to date are missense.
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay."
    explanation: Landmark study identifying SC4MOL/MSMO1 as the causative gene.
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirmed mutations in each allele (c.731A>G, p.Y244C, which is already known, and c.605G>A, p.G202E, which is a novel variant)"
    explanation: Documents compound heterozygous MSMO1 alleles with parental segregation.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81A>C; p.Asn27Thr in MSMO1."
    explanation: Adds a homozygous missense allele identified by exome sequencing.
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed a novel, homozygous c.548A > C, p.(Glu183Ala) variant."
    explanation: Adds a further homozygous missense allele in a consanguineous family.
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols."
    explanation: Summarises the missense-only variant spectrum reported so far.
treatments:
- name: Systemic cholesterol supplementation with statin therapy
  description: >-
    Oral cholesterol supplementation replaces the deficient end product while an
    oral statin reduces flux into the blocked pathway and thereby the toxic
    methylsterol load. Reported regimens have combined systemic cholesterol,
    statin and bile acid. This combination is documented specifically in
    MSMO1-genotyped patients, not extrapolated from the other post-squalene
    disorders.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholesterol
      term:
        id: CHEBI:16113
        label: cholesterol
    - preferred_term: simvastatin
      term:
        id: CHEBI:9150
        label: simvastatin
  target_mechanisms:
  - target: C4-Methylsterol Accumulation
    treatment_effect: INHIBITS
    description: Statin therapy reduces flux into the pathway and lowers the toxic methylsterol pool.
    evidence:
    - reference: PMID:41413001
      reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Topical (2% simvastatin/2% cholesterol cream) and oral statin was commenced to reduce the toxic accumulation of methylsterols, along with cholesterol replacement to replace the downstream deficiency."
      explanation: States the mechanistic rationale of the statin arm in a genotyped MSMO1 patient.
  - target: Impaired Distal Cholesterol Biosynthesis
    treatment_effect: BYPASSES
    description: Exogenous cholesterol supplies the end product that the blocked pathway cannot make.
    evidence:
    - reference: PMID:41413001
      reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Topical (2% simvastatin/2% cholesterol cream) and oral statin was commenced to reduce the toxic accumulation of methylsterols, along with cholesterol replacement to replace the downstream deficiency."
      explanation: States the mechanistic rationale of the cholesterol-replacement arm.
  evidence:
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with oral and topical cholesterol supplements and statins was reported to improve the biochemical, immunological, and cutaneous findings, supporting a potential treatment following the precision diagnosis of MSMO1 deficiency."
    explanation: The disease-specific review summarises improvement of biochemical, immunological and cutaneous findings in MSMO1 patients.
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on previously published treatment algorithms, we initiated a modified dosage regime with systemic cholesterol supplementation, statins and bile acid along with topical application of a cholesterol/statin formulation."
    explanation: Describes the systemic component of the regimen used in genotyped siblings.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement."
    explanation: Independent genotyped siblings improved on the oral plus topical combination.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "After 3 months of cholesterol supplementation, the patient's methylsterol level decreased by about 20%, and the plasma cholesterol level was much improved, reaching a level near the low end of the normal range, but the methylsterol level decreased no further with longer treatment"
    explanation: >-
      Marked PARTIAL because it shows cholesterol supplementation ALONE is
      insufficient: it plateaus at roughly a 20 percent methylsterol reduction,
      which is why the statin substrate-reduction arm is required.
- name: Topical cholesterol and statin formulation
  description: >-
    A compounded cream containing cholesterol and a statin, applied to affected
    skin. In a genotyped MSMO1 infant a 2% simvastatin plus 2% cholesterol cream
    combined with oral statin produced almost complete clearance of a previously
    treatment-refractory psoriasiform eruption, and in two other genotyped
    sibships it improved dermatitis and permitted some hair regrowth.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: simvastatin
      term:
        id: CHEBI:9150
        label: simvastatin
    - preferred_term: cholesterol
      term:
        id: CHEBI:16113
        label: cholesterol
  target_phenotypes:
  - preferred_term: Psoriasiform dermatitis
    term:
      id: HP:0003765
      label: Psoriasiform dermatitis
  target_mechanisms:
  - target: Epidermal and Hematopoietic Cell Overproliferation
    treatment_effect: MODULATES
    description: >-
      Topical cholesterol plus statin targets the cutaneous arm of the disease,
      with near-complete clearance of the psoriasiform eruption reported.
    evidence:
    - reference: PMID:41413001
      reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Improvement in her skin, with almost complete clearance after only after a few months of treatment has been life changing."
      explanation: Documents near-complete cutaneous clearance on the topical plus oral regimen.
  evidence:
  - reference: PMID:41413001
    reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical (2% simvastatin/2% cholesterol cream) and oral statin was commenced to reduce the toxic accumulation of methylsterols, along with cholesterol replacement to replace the downstream deficiency."
    explanation: Specifies the topical formulation used in a genotyped MSMO1 patient.
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This resulted in a marked improvement of psoriasiform dermatitis and some hair growth."
    explanation: Reports the cutaneous and hair response to the combined topical and systemic regimen.
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement."
    explanation: Independent genotyped siblings improved with the topical component of the regimen.
- name: Oral acitretin
  description: >-
    A systemic retinoid used before the metabolic diagnosis was made. It reduced
    skin severity significantly in one genotyped MSMO1 patient but left residual
    inflammatory skin, so it is recorded as partially effective symptomatic
    therapy rather than disease-directed treatment.
  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_phenotypes:
  - preferred_term: Psoriasiform dermatitis
    term:
      id: HP:0003765
      label: Psoriasiform dermatitis
  evidence:
  - reference: PMID:41413001
    reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral acitretin reduced skin severity significantly."
    explanation: >-
      Marked PARTIAL because the same report notes continued impact from
      inflammatory skin afterwards, so acitretin gave incomplete symptomatic
      benefit and did not address the sterol lesion.
- name: Conventional psoriasis-directed therapy
  description: >-
    Standard antipsoriatic treatment does not work in MSMO1 deficiency. In the
    index patient topical corticosteroids, calcipotriene, cyclosporine A,
    etanercept, phototherapy and oral isotretinoin were all tried without
    durable response. Anti-TNF therapy is mechanistically inappropriate because
    serum TNF-alpha is normal in this disorder. Recorded here as negative
    evidence so that the entry documents what NOT to do.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Psoriasiform dermatitis
    term:
      id: HP:0003765
      label: Psoriasiform dermatitis
  evidence:
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, while her skin briefly improved with cyclosporine A, she did not exhibit a long-term response to any of the therapies."
    explanation: >-
      The preceding sentence in the same report lists the therapies tried in the
      index patient (topical corticosteroids, calcipotriene, cyclosporine A,
      etanercept, phototherapy and oral isotretinoin); this sentence records
      that none produced a durable response.
  - reference: PMID:41413001
    reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "This progressed to become erythrodermic despite multiple topical treatments as well as systemic treatments including ciclosporin and zinc supplements."
    explanation: A second genotyped patient likewise progressed on conventional topical and systemic therapy.
- name: Cataract surgery
  description: >-
    Surgical removal of the congenital cataract, performed in reported patients
    in infancy or early childhood. Necessary because the lens opacity is
    structural and is not reversed by metabolic therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Congenital cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: PMID:41413001
    reference_title: P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other syndromic features were apparent from presentation and developed over follow-up with global developmental delay, microcephaly, congenital cataracts corrected age 3, and skeletal abnormalities (inward curving little finger)."
    explanation: Documents surgical correction of the congenital cataracts in a genotyped MSMO1 patient.
diagnosis:
- name: Plasma sterol profiling by gas chromatography-mass spectrometry
  presence: PRESENT
  description: >-
    Quantitative plasma sterol analysis by GC-MS is the definitive biochemical
    test, showing marked elevation of C4-monomethyl and C4-dimethyl sterols.
    Cultured fibroblasts and skin scales are alternative sample types, with
    dimethylsterol accumulating preferentially in skin. Because most MSMO1
    missense alleles are initially reported as variants of uncertain
    significance, the sterol profile also functions as the practical
    functional assay for variant classification.
  evidence:
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme."
    explanation: Blood sterol profiling established the biochemical diagnosis in this patient.
  - reference: PMID:28673550
    reference_title: "A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consequently, we suggest that these two analyses should be performed as soon as possible in all undiagnosed patients affected by bilateral cataracts and developmental delay."
    explanation: Gives the explicit clinical indication for combined sterol profiling and MSMO1 sequencing.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data strongly indicated a block at the step of SMO in the cholesterol synthesis pathway."
    explanation: The sterol profile localises the metabolic block to the SMO step, which is what makes it diagnostic.
- name: MSMO1 sequencing
  presence: PRESENT
  description: >-
    Molecular confirmation by exome sequencing or targeted MSMO1 sequencing.
    Whole-exome sequencing is the current first-line route to diagnosis; all
    reported disease alleles are coding missense variants, so exome coverage is
    adequate.
  evidence:
  - reference: PMID:33161406
    reference_title: New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81A>C; p.Asn27Thr in MSMO1."
    explanation: Exome sequencing established the molecular diagnosis in these siblings.
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed a novel, homozygous c.548A > C, p.(Glu183Ala) variant."
    explanation: Exome sequencing likewise established the diagnosis in an independent family.
animal_models:
- species: Danio rerio
  genotype: msmo1nu81 homozygous loss-of-function
  category: Loss-of-function zebrafish mutant
  description: >-
    A 37-base-pair insertion producing a functional msmo1 null. Homozygotes are
    larval lethal, and lethality is partly relieved by additionally blocking
    lanosterol synthase upstream, genetically separating a cholesterol
    deprivation arm from a toxic sterol intermediate arm. Because complete loss
    is lethal in this model while human patients survive, all human MSMO1
    alleles reported so far are inferred to be hypomorphic.
  genes:
  - preferred_term: MSMO1
    term:
      id: hgnc:10545
      label: MSMO1
  evidence:
  - reference: PMID:32430393
    reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Generated msmo1nu81 knockdown mutation resulted in lethality at larval stage."
    explanation: Establishes the lethality of the complete msmo1 loss-of-function allele.
  - reference: PMID:32430393
    reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results indicate that double lssnu60;msmo1nu81 and single lssnu60 mutants survive significantly longer than msmo1nu81 homozygotes."
    explanation: >-
      Blocking the pathway further upstream partially rescues lethality, the
      cleanest in vivo evidence that accumulated sterol intermediates are toxic
      rather than merely inert markers of the block.
- species: Danio rerio
  genotype: kolibernu7 cis-regulatory msmo1 mutant
  category: Tissue-restricted regulatory zebrafish mutant
  description: >-
    A cis-acting regulatory mutation that removes msmo1 expression specifically
    from pre-hypertrophic chondrocytes, producing a viable late-onset skeletal
    phenotype. No equivalent human regulatory allele has been described.
  genes:
  - preferred_term: MSMO1
    term:
      id: hgnc:10545
      label: MSMO1
  evidence:
  - reference: PMID:32430393
    reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In a forward-genetic approach, we have found that a late-onset skeletal mutant, named kolibernu7 , is the result of a cis-acting regulatory mutation leading to loss of methylsterol monooxygenase 1 (msmo1) expression within pre-hypertrophic chondrocytes."
    explanation: Defines the allele and the tissue in which msmo1 expression is lost.
mechanistic_hypotheses:
- hypothesis_group_id: msmo1_psors9_common_skin_disease
  hypothesis_label: MSMO1 as a PSORS9 candidate and heterozygote susceptibility factor
  status: EMERGING
  description: >-
    MSMO1 lies within the PSORS9 psoriasis susceptibility interval, and
    obligate carriers in the index family had raised plasma methylsterols and,
    in the father, granulocyte activation approaching the proband's. Together
    these raise the hypothesis that a single hypomorphic MSMO1 allele is a
    susceptibility factor for common inflammatory skin disease rather than
    being fully recessive. This is explicitly an unproven hypothesis and is not
    asserted as a mechanism anywhere in the pathophysiology graph.
  evidence:
  - reference: PMID:24144731
    reference_title: The role of sterol-C4-methyl oxidase in epidermal biology.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "SC4MOL is situated within the psoriasis susceptibility locus PSORS9, and may be a genetic risk factor for common skin conditions."
    explanation: States the PSORS9 candidacy as a possibility, not an established association.
  - reference: PMID:21285510
    reference_title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Methylsterol levels were also increased (though less so) in the plasma of the patient's parents (Table 2), particularly the father, who carries the active site H173Q mutation, suggesting a subclinical effect in the heterozygous state."
    explanation: Documents a subclinical biochemical effect in heterozygotes, the observation underpinning the hypothesis.
discussions:
- discussion_id: msmo1_no_mouse_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does any available Msmo1 mouse allele model human MSMO1 deficiency, given
    that every reported human allele is a hypomorphic missense change while the
    available mouse alleles are nulls and gene traps, and zebrafish msmo1 nulls
    are larval lethal?
  attaches_to:
  - pathophysiology#MSMO1 Deficiency
  rationale: >-
    The zebrafish null is lethal, so a mouse null would most plausibly be
    embryonic or perinatal lethal, and an absence of adult phenotypes in a
    knockout pipeline would reflect absent homozygotes rather than a benign
    knockout. No published mouse model reproducing the human microcephaly,
    cataract and psoriasiform dermatitis phenotype was identified. The
    informative mammalian in vivo data come from Nsdhl mice, which model CHILD
    syndrome and are a paralog, not an MSMO1 model.
  proposed_experiments:
  - experiment_id: exp_msmo1_hypomorphic_knockin_mouse
    name: Hypomorphic Msmo1 knock-in mouse
    description: >-
      Generate and characterise a mouse carrying a recurrent human hypomorphic
      allele such as p.Tyr244Cys or p.Gly115Arg, and test whether it reproduces
      the cutaneous, ocular and neurodevelopmental phenotype.
  - experiment_id: exp_msmo1_null_lethality_staging
    name: Staging of Msmo1 null lethality in mouse
    description: >-
      Determine homozygous viability for existing Msmo1 null and gene-trap
      alleles and stage any embryonic or perinatal lethality, so that an absence
      of adult phenotypes is not misread as a benign knockout.
  evidence:
  - reference: PMID:32430393
    reference_title: Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Generated msmo1nu81 knockdown mutation resulted in lethality at larval stage."
    explanation: The lethality of the complete null in zebrafish is what makes a mammalian null a poor model of the hypomorphic human disease.
- discussion_id: msmo1_natural_history_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the natural history of MSMO1 deficiency, and does treatment started
    presymptomatically change neurodevelopmental outcome?
  rationale: >-
    No registry, natural history study, survival analysis or quality-of-life
    measurement exists. All prognostic statements derive from a handful of
    individually reported patients. The cataract and microcephaly appear fixed
    before current diagnosis is possible, which is why the disorder is
    described as only partially treatable, but whether presymptomatic therapy
    following cascade testing of a sibling would alter the neurodevelopmental
    trajectory has never been tested.
  proposed_experiments:
  - experiment_id: exp_msmo1_natural_history_registry
    name: International MSMO1 deficiency registry
    description: >-
      Establish a registry with standardised developmental, ophthalmologic,
      dermatologic and growth outcome measures to build the first natural
      history dataset for this disorder.
  - experiment_id: exp_msmo1_presymptomatic_cascade_treatment
    name: Presymptomatic treatment of cascade-identified siblings
    description: >-
      Systematically offer cascade testing at proband diagnosis and start
      cholesterol plus statin therapy in presymptomatic biallelic siblings,
      with prospective developmental and cutaneous follow-up.
  evidence:
  - reference: PMID:37195326
    reference_title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date."
    explanation: The tiny reported cohort is the reason no natural history evidence exists.
differential_diagnoses:
- name: Smith-Lemli-Opitz syndrome
  description: >-
    The best-known post-squalene cholesterol biosynthesis disorder, caused by
    DHCR7 deficiency at the terminal step. It shares microcephaly, growth
    restriction and intellectual disability with MSMO1 deficiency but is
    distinguished biochemically by elevated 7-dehydrocholesterol with low
    cholesterol rather than accumulated C4-methylsterols, and clinically by
    2-3 toe syndactyly and male genital underdevelopment rather than
    psoriasiform dermatitis with congenital cataract.
  distinguishing_features:
  - Caused by DHCR7 rather than MSMO1
  - Elevated 7-dehydrocholesterol with low cholesterol, not elevated C4-methylsterols
  - 2-3 toe syndactyly and male genital underdevelopment are characteristic
  - Psoriasiform dermatitis and congenital cataract are not core features
  disease_term:
    preferred_term: Smith-Lemli-Opitz syndrome
    term:
      id: MONDO:0010035
      label: Smith-Lemli-Opitz syndrome
  evidence:
  - reference: PMID:23042573
    reference_title: "Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome."
    explanation: >-
      Positions SC4MOL deficiency as a distinct entity within the group of
      post-squalene sterol synthesis disorders that also contains
      Smith-Lemli-Opitz syndrome.
- name: CHILD syndrome
  description: >-
    Congenital hemidysplasia with ichthyosiform erythroderma and limb defects,
    caused by NSDHL variants. NSDHL is the immediate partner of MSMO1 in the
    same C4-demethylation complex and CHILD syndrome is the disorder for which
    topical cholesterol plus statin therapy is best known, so treatment and
    mechanism literature is easily misattributed between the two. CHILD
    syndrome is X-linked dominant with characteristically lateralised skin and
    limb involvement, whereas MSMO1 deficiency is autosomal recessive with
    generalised psoriasiform dermatitis.
  distinguishing_features:
  - Caused by NSDHL, the immediate C4-demethylation partner of MSMO1, rather than MSMO1 itself
  - X-linked dominant with male lethality, not autosomal recessive
  - Strikingly lateralised (hemidysplastic) skin and ipsilateral limb defects
  - Congenital cataract, microcephaly and immune dysfunction are not its defining triad
  - Allelic with CK syndrome - both are NSDHL disorders that accumulate methyl sterols, so the discriminator against CK syndrome is clinical (lateralised cutaneous/limb disease in females) and not biochemical
  disease_term:
    preferred_term: CHILD syndrome
    term:
      id: MONDO:0010621
      label: CHILD syndrome
  evidence:
  - reference: PMID:21695019
    reference_title: "Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, a prominent skin phenotype has been described in two patients with SC4MOL deficiency, who present with a severe ichthyosiform dermatosis and psoriasiform features."
    explanation: >-
      This family-wide cutaneous review separates SC4MOL deficiency from CHILD
      syndrome and the other distal cholesterol disorders it covers.
  - reference: PMID:21129721
    reference_title: Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels."
    explanation: >-
      Establishes that CHILD syndrome and CK syndrome are allelic NSDHL
      disorders sharing methyl sterol accumulation, so the two cannot be
      separated from each other on the accumulating sterol alone.
- name: CK syndrome
  description: >-
    The second, brain-predominant NSDHL disorder. Like CHILD syndrome it is
    caused by variants in NSDHL, the partner of MSMO1 in the same
    C4-demethylation complex, and like MSMO1 deficiency it accumulates methyl
    sterols and presents with intellectual disability - so both the mechanism
    sentences and the sterol-profile sentences of this literature are easy to
    misattribute to MSMO1. It is separated from MSMO1 deficiency by X-linked
    recessive inheritance in males, by cortical brain malformation with an
    asthenic build rather than psoriasiform dermatitis with congenital
    cataract, and by the deficient enzyme being NSDHL (the C4 decarboxylase
    step) rather than MSMO1 (the C4 methyl oxidase step).
  distinguishing_features:
  - Deficient enzyme is NSDHL, not the MSMO1 sterol-C4-methyl oxidase
  - Accumulating sterols are methyl sterols shared with CHILD syndrome, whereas MSMO1 deficiency accumulates both 4-monomethyl and 4,4-dimethylsterols upstream of the NSDHL step
  - X-linked recessive, affecting males, rather than autosomal recessive
  - Cortical brain malformation, dysmorphism and asthenic build dominate; the psoriasiform/ichthyosiform skin phenotype of MSMO1 deficiency is not its presenting feature
  - Separated from its allelic disorder CHILD syndrome by the absence of lateralised ichthyosiform skin and ipsilateral limb defects
  disease_term:
    preferred_term: CK syndrome
    term:
      id: MONDO:0010441
      label: CK syndrome
  evidence:
  - reference: PMID:21129721
    reference_title: Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build."
    explanation: >-
      Gives the inheritance pattern and the brain-predominant clinical core
      that separate CK syndrome from MSMO1 deficiency.
  - reference: PMID:21129721
    reference_title: Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels."
    explanation: >-
      Names the accumulating sterol class in CK syndrome and its allelism with
      CHILD syndrome, the molecular discriminator against both CHILD syndrome
      and MSMO1 deficiency.
  - reference: PMID:23042573
    reference_title: "Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome."
    explanation: >-
      A family-wide review treats SC4MOL deficiency and CK syndrome as the two
      newly described members of the same post-squalene group, which is the
      shared-language setting in which their evidence gets mixed up.
- name: Lathosterolosis
  description: >-
    A post-squalene disorder caused by deficiency of sterol-C5-desaturase
    (SC5D), two steps downstream of the MSMO1 block. Like MSMO1 deficiency it
    is autosomal recessive, is diagnosed on a plasma sterol profile and has
    been treated with a statin, so its therapeutic and biochemical language
    closely parallels this entry. The discriminator is which sterol
    accumulates: lathosterol in lathosterolosis versus 4-monomethyl and
    4,4-dimethylsterols in MSMO1 deficiency.
  distinguishing_features:
  - Deficient enzyme is SC5D (3-beta-hydroxysteroid-delta-5-desaturase / sterol-C5-desaturase), not MSMO1
  - Lathosterol accumulates in plasma and fibroblasts, whereas MSMO1 deficiency accumulates 4-monomethyl and 4,4-dimethylsterols
  - Presents as a Smith-Lemli-Opitz-like malformation syndrome with dysmorphism and multiple congenital anomalies rather than the microcephaly-cataract-psoriasiform-dermatitis triad
  disease_term:
    preferred_term: Lathosterolosis
    term:
      id: MONDO:0011816
      label: lathosterolosis
  evidence:
  - reference: PMID:24142275
    reference_title: "Lathosterolosis: a disorder of cholesterol biosynthesis resembling smith-lemli-opitz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lathosterolosis is an inborn error of cholesterol biosynthesis due to deficiency of the enzyme 3-beta-hydroxysteroid-delta-5-desaturase (or sterol-C5-desaturase or SC5D)."
    explanation: Names the deficient enzyme and gene that separate lathosterolosis from MSMO1 deficiency.
  - reference: PMID:24142275
    reference_title: "Lathosterolosis: a disorder of cholesterol biosynthesis resembling smith-lemli-opitz syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a patient with dysmorphism, multiple congenital anomalies, and developmental delay, initially suspected to have Smith-Lemli-Opitz syndrome, who was later found to have elevated levels of lathosterol in both plasma and fibroblasts."
    explanation: >-
      Documents the accumulating sterol in a genotyped patient - the
      biochemical discriminator on the same sterol profile used to diagnose
      MSMO1 deficiency.
  - reference: PMID:21695019
    reference_title: "Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although the PI is unaware of lathosterolosis cases in the US, several patients have been described in Europe, and all have prominent ichthyosis."
    explanation: >-
      Lathosterolosis shares prominent ichthyosis with MSMO1 deficiency, so the
      cutaneous phenotype does not separate them and the sterol profile must.
- name: Desmosterolosis
  description: >-
    A post-squalene disorder caused by deficiency of
    3beta-hydroxysterol-Delta24-reductase (DHCR24). It sits in the same
    autosomal recessive, sterol-profile-diagnosed group as MSMO1 deficiency and
    is routinely tabulated alongside it, but desmosterol rather than
    C4-methylsterol is the accumulating species, and it presents with prominent
    congenital anomalies and minimal skin disease - close to the inverse of the
    MSMO1 cutaneous-predominant phenotype.
  distinguishing_features:
  - Deficient enzyme is DHCR24 (3beta-hydroxysterol Delta24-reductase), not MSMO1
  - Desmosterol accumulates in plasma, tissue and cultured cells, whereas MSMO1 deficiency accumulates 4-monomethyl and 4,4-dimethylsterols
  - Prominent congenital anomalies with minimal skin abnormality, the opposite emphasis to the severe ichthyosiform/psoriasiform dermatitis of MSMO1 deficiency
  disease_term:
    preferred_term: Desmosterolosis
    term:
      id: MONDO:0011217
      label: desmosterolosis
  evidence:
  - reference: PMID:11519011
    reference_title: Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with desmosterolosis have elevated levels of the cholesterol precursor desmosterol, in plasma, tissue, and cultured cells; this abnormality suggests a deficiency of the enzyme 3beta-hydroxysterol Delta24-reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Delta24 double bond of sterol intermediates."
    explanation: >-
      Gives both halves of the molecular discriminator - the deficient enzyme
      and the accumulating sterol.
  - reference: PMID:21695019
    reference_title: "Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, a US kindred38 and several additional patients in Europe14 have been described with desmosterolosis, a disorder that displays prominent congenital anomalies, but minimal evidence of skin abnormalities."
    explanation: >-
      The cutaneous contrast against the severe ichthyosiform dermatosis
      described for SC4MOL deficiency in the same review.
references:
- reference: PMID:37195326
  title: "MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly."
  findings: []
- reference: PMID:21285510
  title: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.
  findings: []

📚

References & Deep Research

References

2

PMID:37195326

MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly.

No top-level findings curated for this source.

PMID:21285510

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 28 citations 2026-08-01T00:53:30.342973

1. Disease Information

Overview

MSMO1 deficiency is an autosomal recessive inborn error of the distal (post-squalene) cholesterol biosynthesis pathway, caused by biallelic loss-of-function (predominantly missense) variants in MSMO1 (formerly SC4MOL), encoding methylsterol monooxygenase 1 / sterol-C4-methyl oxidase (SMO). The enzymatic block at the first step of sterol C4-demethylation causes accumulation of 4α-monomethylsterols and 4,4′-dimethylsterols — a class that includes the biologically active meiosis-activating sterols (MAS) — with variably reduced cholesterol synthesis.

The core clinical picture is the triad of microcephaly, congenital cataract, and psoriasiform dermatitis, plus growth and developmental delay and immune dysregulation. Importantly, it is one of the few neurodevelopmental disorders that is partially treatable by pathway-directed therapy (cholesterol supplementation + statin, oral and topical).

"Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined." — He et al. 2011, J Clin Invest (PMID:21285510; DOI 10.1172/JCI42650)

"MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date. The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols." — Tkemaladze et al. 2023, Clin Dysmorphol (PMID:37195326; DOI 10.1097/MCD.0000000000000461)

Key identifiers

Resource	Identifier
MONDO	MONDO:0014793 — "microcephaly-congenital cataract-psoriasiform dermatitis syndrome" (verified via OLS4)
OMIM (phenotype)	616834 — MICROCEPHALY, CONGENITAL CATARACT, AND PSORIASIFORM DERMATITIS; MCCPD
OMIM (gene)	607545 — MSMO1 (SC4MOL)
Orphanet	ORPHA:488168 — Microcephaly-congenital cataract-psoriasiform dermatitis syndrome
MedGen	UID 1798933 / Concept ID C5567510
UMLS	C5567510
GARD	0017886 (rarediseases.info.nih.gov/diseases/17886)
HGNC	HGNC:10545 (`hgnc:10545`)
NCBI Gene	6307
Ensembl gene	ENSG00000052802
UniProt	Q15800 (ERG25_HUMAN / MSMO1)
EC number	EC 1.14.18.9 (methylsterol monooxygenase)
ICD-10	No specific code. Best fit E78.7 "Disorders of bile acid and cholesterol metabolism" (generic bucket for cholesterol biosynthesis defects). Not independently confirmed as an official Orphanet mapping — flag as inferred.
ICD-11	No specific code identified. Not available.
MeSH	No dedicated descriptor identified. Not available.

Synonyms and alternative names

Microcephaly, congenital cataract, and psoriasiform dermatitis (MCCPD)
SC4MOL deficiency
SMO deficiency / sterol-C4-methyl oxidase deficiency
Methylsterol monooxygenase 1 deficiency
Microcephaly with congenital cataract and psoriasiform dermatitis
Gene aliases: SC4MOL, ERG25, DESP4, MCCPD

Provenance of the information

Disease-level aggregated resources (OMIM, Orphanet, MedGen, GARD, HPO) are derived almost entirely from individual published case reports, not EHR cohorts or registries. The HPO annotation set for OMIM:616834 is dominated by a single source (PMID:21285510, the index patient), with frequencies recorded as literal 1/1. There is no disease registry, natural history study, or EHR-derived cohort for MSMO1 deficiency.

2. Etiology

Disease causal factors

Purely genetic (monogenic, autosomal recessive). Biallelic pathogenic variants in MSMO1 (4q32.3) abolish or severely reduce sterol-C4-methyl oxidase activity. No infectious, environmental, or acquired etiology exists.

Mechanistically, the causal factor is a metabolic block at the first of three enzymatic steps of C4-demethylation in the post-squalene cholesterol pathway, producing a dual insult: (i) substrate accumulation of bioactive methylsterols, and (ii) product deficiency of cholesterol.

Risk factors

Genetic: - Biallelic MSMO1 pathogenic variants — necessary and sufficient (see §4). Relationship type: CAUSAL. - Consanguinity — a demonstrated major risk factor. Homozygous variants were reported in a consanguineous Turkish family (Kalay Yildizhan et al. 2020, PMID:33161406) and a consanguineous Georgian family (Tkemaladze et al. 2023, PMID:37195326). - Carrier (heterozygous) status — carriers are clinically unaffected but are not biochemically silent: "Methylsterol levels were also increased (though less so) in the plasma of the patient's parents" (He et al. 2011). Strikingly, the index patient's father showed granulocyte activation phenotypes approaching the proband's: "activated CD16+ granulocytes ... were increased 30- and 20-fold in the patient and her father, respectively" (PMID:21285510). This raises a genuinely open question about a heterozygote phenotype (possible risk factor for common inflammatory skin disease) — see §4 modifier discussion.

Environmental / non-genetic modifiers of expression (not of occurrence): - Cold/winter season and psychological stress worsened dermatitis in the index patient: "Dermatitis worsened in winter or with stress" (PMID:21285510). This is an exacerbating factor, not a disease-risk factor. - Dietary cholesterol intake — theoretically modifies substrate/product balance; there is no published evidence that dietary cholesterol status modifies disease onset. - No toxin, radiation, occupational, or infectious risk factor has been reported.

Protective factors

Genetic protective factors: none identified. No modifier alleles or protective variants have been described.
Environmental protective factors: exogenous cholesterol supplementation is therapeutic (see §12) rather than preventive; it does not prevent disease onset in a genetically affected individual but reduces methylsterol burden and cutaneous/immune manifestations.
Note a mechanistically interesting pharmacologic observation: metabolic blockade upstream of MSMO1 is protective at the cellular level. "Metabolic blocks upstream of SC4MOL with ketoconazole rescued viability and EGFR degradation" (Sukhanova et al. 2013, Cancer Discov, PMID:23125191; DOI 10.1158/2159-8290.CD-12-0031). This is the conceptual rationale for statin co-therapy in patients (reduce flux into the blocked step).

Gene–environment interactions

The clearest GxE interaction in this disorder is pharmacological: the genetic block interacts with (a) exogenous cholesterol and (b) HMG-CoA reductase inhibition to determine methylsterol burden. He et al. 2014 documented a dose/regimen interaction:

Cholesterol supplementation (100 mg/kg/day) alone reduced methylsterol levels by ~20%; addition of "oral statin (10 mg/day) plus bile acids (30 mg/kg/day) along with cholesterol normalized" methylsterol levels. — He et al. 2014, BBA (PMID:24144731; DOI 10.1016/j.bbalip.2013.10.009)

A second GxE axis is azole/vitamin D analog drug metabolism: MSMO1 participates in hepatic metabolism of the anti-osteoporosis vitamin D analog eldecalcitol (Yasuda et al. 2015, PMID:26038696), implying potential altered handling of such compounds in deficient patients — theoretical, no clinical data.

3. Phenotypes

3.1 HPO annotation set for OMIM:616834 (retrieved from the HPO/JAX API, August 2026)

All frequencies are literal counts from the annotation file; 1/1 reflects the single index patient (PMID:21285510), not a population frequency.

HPO ID	Label	Category	HPO frequency	Source
HP:0000252	Microcephaly	Head/neck	1/1	PMID:21285510
HP:0000519	Developmental cataract	Eye	1/1	PMID:21285510
HP:0003765	Psoriasiform dermatitis	Immunology/skin	1/1	PMID:21285510
HP:0008064	Ichthyosis	Skin	1/1	PMID:21285510
HP:0000498	Blepharitis	Head/neck	1/1	PMID:21285510
HP:0001263	Global developmental delay	Nervous system	1/1	PMID:21285510
HP:0001256	Mild intellectual disability	Nervous system	—	OMIM:616834
HP:0001508	Failure to thrive	Growth	1/1	PMID:21285510
HP:0004322	Short stature	Growth	1/1	PMID:21285510
HP:0002750	Delayed skeletal maturation	Skeletal	1/1	PMID:21285510
HP:0000823	Delayed puberty	Endocrine	—	OMIM:616834
HP:0002829	Arthralgia	Musculoskeletal	—	OMIM:616834
HP:0003146	Hypocholesterolemia	Lab	1/1	PMID:21285510
HP:0003233	Decreased circulating HDL-C concentration	Lab	1/1	PMID:21285510
HP:0003563	Decreased circulating LDL-C concentration	Lab	1/1	PMID:21285510
HP:6000753	Elevated circulating monomethyl sterol concentration	Lab	1/1	PMID:21285510
HP:6000754	Elevated circulating dimethyl sterol concentration	Lab	1/1	PMID:21285510
HP:6001113	Elevated circulating methysterol concentration	Lab	—	OMIM:616834
HP:0011463	Childhood onset	Clinical course	1/1	PMID:21285510
HP:0000007	Autosomal recessive inheritance	Inheritance	—	PMID:21285510

Curation note: HP:6000753 / HP:6000754 / HP:6001113 are the disease-defining biochemical HPO terms and are the highest-value annotations for this entry. Note HP:6001113's label is spelled "methysterol" in HPO (sic) — reproduce exactly in term.label.

3.2 Phenotypes reported in the literature but not yet in the HPO annotation set

These come from patients published after the HPO annotation was created. Each needs its own evidence item.

Feature	HPO suggestion (verified where marked ✓)	Reported in
Alopecia / hair changes	HP:0001596 Alopecia ✓ (OLS-verified)	Tkemaladze 2023 (PMID:37195326); He 2014 "hair changes" (PMID:24144731)
Polydactyly	HP:0010442 Polydactyly ✓ (OLS-verified); postaxial subtype HP:0100259 ✓	Tkemaladze 2023 (PMID:37195326)
Spasticity / spastic quadriplegia	HP:0001257 Spasticity; HP:0002510 Spastic tetraplegia (unverified — check with OAK)	Tkemaladze 2023; Hassas 2026 (PMID:41718295)
Nystagmus	HP:0000639 Nystagmus (unverified)	Kalay Yildizhan 2020 (PMID:33161406); Morales 2022
Optic nerve hypoplasia	HP:0000609 Optic nerve hypoplasia (unverified)	Kalay Yildizhan 2020 (PMID:33161406)
Myopia	HP:0000545 Myopia (unverified)	Kalay Yildizhan 2020
Strabismus	HP:0000486 Strabismus (unverified)	Kalay Yildizhan 2020
Severe intellectual disability	HP:0010864 (unverified)	Kalay Yildizhan 2020
Autism spectrum disorder	HP:0000717 Autism (unverified)	Morales, Curry & Enns 2022 (DOI 10.20517/jtgg.2022.01)
Behavioral abnormality	HP:0000708 (unverified)	Frisso 2017 (PMID:28673550)
Joint contractures	HP:0034392 / HP:0001371 (unverified)	He 2014, patient 2 (PMID:24144731)
Cerebral white matter volume loss / T2-FLAIR hyperintensity	HP:0012429 Cerebral white matter atrophy; HP:0002500 Abnormal cerebral white matter morphology (unverified)	Hassas 2026 (PMID:41718295)
Genu valgum	HP:0002857 (unverified)	Morales 2022
Segmental hyperpigmentation	HP:0011821 / HP:0001000 (unverified)	Hassas 2026
Erythroderma / ichthyosiform erythroderma	HP:0001019 Erythroderma (unverified)	He 2011 (PMID:21285510)
Immune dysregulation / recurrent infection	HP:0002721 Immunodeficiency; HP:0002960 Autoimmunity (unverified)	He 2011, He 2014
Scalp scaling / dandruff	(no precise HPO; consider HP:0011368 Eczematoid dermatitis or HP:0001051 seborrheic-type)	Frisso 2017 — "abundant scalp dandruff, without other skin manifestations"

3.3 Phenotype characteristics by domain

Dermatologic — psoriasiform dermatitis (the most distinctive feature) - Type: physical manifestation / clinical sign. - Onset: typically infancy to early childhood, but not congenital. In the index patient: "She did not show signs of dermatitis at birth; it was first noted around her umbilicus at the age of 2" and "subsequently progressed to her back, trunk, and then the remainder of her body by the age of 6" (PMID:21285510). Patients 3 and 4 had "severe skin manifestations similar to patient one beginning in early infancy" (PMID:24144731). - Severity: highly variable — from full-body ichthyosiform erythroderma sparing only the palms (index patient), to isolated scalp dandruff (Frisso 2017), to transient perianal dermatitis (Morales 2022), to absent ("her skin is dry but has never demonstrated a marked psoriasiform rash," He 2014 patient 2), to no dermatitis at all (Hassas 2026). - Progression: chronic, fluctuating/relapsing with seasonal and stress triggers. - Frequency: roughly 6–8 of ~11 reported individuals. Defensible band: FREQUENT (with explicit evidence quote), or omit. - QoL impact: substantial — pruritus, disfigurement, thermoregulatory and barrier compromise, and refractoriness to conventional psoriasis therapy (steroids, calcipotriene, cyclosporine, etanercept, phototherapy, isotretinoin all failed in the index patient). No formal QoL instrument (DLQI, EQ-5D, PROMIS) has ever been applied in this disease — not available.

Ocular — congenital/infantile cataract - Type: physical manifestation. - Onset: congenital or within the first year. Diagnosed at 8 months in Hassas 2026; requiring lensectomy at 7 months in Morales 2022. - Laterality: bilateral in all reported cases. - Severity: vision-threatening; requires surgery. Hassas 2026: "diffuse cataracts bilaterally with scattered, white fleck-like opacities in the anterior lens," with "intumescent appearance with significant lenticular liquefaction"; post-operatively only "perception to light." - Progression: progressive opacification; not reversible by metabolic therapy — the critical period has passed by diagnosis. - Frequency: present in essentially every reported patient — the most consistent feature. Defensible band: VERY_FREQUENT. - QoL impact: severe and permanent; drives lifelong low vision, compounding developmental delay. - Associated ocular findings: blepharitis, nystagmus, optic nerve hypoplasia, myopia, strabismus.

Neurologic — microcephaly, developmental delay, intellectual disability - Onset: congenital (microcephaly) to infantile (developmental delay). - Severity: variable — "mild developmental delay" and mild ID in the index patient; "severe intellectual disability" in the Turkish siblings; non-verbal, non-ambulatory with spastic quadriplegia in Hassas 2026; ASD with normal head circumference in the mildest case (Morales 2022). - Progression: static/non-progressive developmental impairment in most; spasticity may be progressive. No neurodegeneration has been documented. - Microcephaly frequency: not universal — explicitly absent in Frisso 2017 ("but not microcephaly") and Morales 2022 ("Normal head circumference (unlike typical MCCPD triad cases)"). Defensible band: FREQUENT, not obligate. - QoL: dominant driver of lifelong dependency in severe cases.

Growth and endocrine - Failure to thrive, short stature, delayed skeletal maturation with normal bone morphology (PMID:21285510), delayed puberty. Index patient at age 13: height 140 cm (<3rd centile; 50th centile for a 10.5-year-old); weight 28.6 kg (<3rd centile; 50th centile for a 9-year-old); OFC 53.5 cm (<3rd centile). - Onset: infancy/childhood; progressive relative to peers; partially treatment-responsive.

Immunologic - Type: laboratory abnormality + clinical immune dysregulation. - Granulocyte and T-cell abnormalities (detailed in §6). Elevated serum GM-CSF, IL-6, IL-8; normal TNF-α — which correctly predicted etanercept failure. - Onset: presumably congenital; detected only on specialized flow cytometry.

Laboratory / biochemical (the diagnostic core) - Elevated 4α-monomethylsterols (~20-fold) and 4,4′-dimethylsterols (~500-fold) in plasma; dimethylsterol preferentially accumulates in skin scales. - Cholesterol is variably low — index patient total cholesterol 85 mg/dL (nl 140–176), HDL 28 (nl 35–75), LDL 49 (nl 70–160), triglycerides normal at 84. He 2014 patient 2: ~90 mg/dL. But patients 3, 4 had normal cholesterol, and Morales 2022 reported "Normal total cholesterol levels throughout." Hassas 2026 reported "Normal serum lipid measurements." - Curation implication: hypocholesterolemia is a supportive, not obligate, finding. Methylsterol elevation is the obligate biochemical signature. Do not model normal cholesterol as excluding the diagnosis.

4. Genetic / Molecular Information

Causal gene

MSMO1 (methylsterol monooxygenase 1), formerly SC4MOL.

Attribute	Value
HGNC	`hgnc:10545`
Cytoband	4q32.3
GRCh38 coordinates	NC_000004.12: 165,327,669–165,343,164
Exons	6
Canonical RefSeq	NM_006745.5 → NP_006736.1 (isoform 1, 293 aa)
Other transcripts	NM_001440534.1 (isoform 1); NM_001017369.3 → NP_001017369.1 (isoform 2)
OMIM gene	607545
UniProt	Q15800
Protein family	Sterol desaturase family (fatty acid hydroxylase superfamily)
Topology	ER membrane, multi-pass; three helical TM segments at aa 55–75, 100–120, 199–219
Cofactor	Fe cation (non-heme di-iron); electron donor Fe(II)-cytochrome b5
Expression	Broad; highest in liver (RPKM 94.8), then brain (RPKM 43.2), plus ~20 other tissues (NCBI Gene); UniProt notes "Enhanced expression in liver"

Reported pathogenic variants (all published cases)

All disease-causing variants reported to date are missense; no truncating, splice, or structural variant has been reported as causal. This is consistent with the gene being intolerant of complete loss of function (see constraint below and the zebrafish/mouse data in §15) — i.e., human MSMO1 deficiency likely represents hypomorphic residual activity, not a true null state.

cDNA (NM_006745.5)	Protein	Zygosity / origin	Family / ethnicity	Reference
c.519T>A	p.His173Gln	compound het (paternal)	Family 1 (index)	He 2011, PMID:21285510
c.731A>G	p.Tyr244Cys	compound het (maternal)	Family 1	He 2011, PMID:21285510
c.343G>A	p.Gly115Arg	homozygous	Family 2 (Hispanic)	He 2014, PMID:24144731
c.605G>A	p.Gly202Glu (novel at the time)	compound het (maternal)	Family 5 (Italian)	Frisso 2017, PMID:28673550
c.731A>G	p.Tyr244Cys	compound het (paternal)	Family 5 (Italian)	Frisso 2017, PMID:28673550
c.81A>C	p.Asn27Thr	homozygous	Family 6 (consanguineous Turkish)	Kalay Yildizhan 2020, PMID:33161406
c.536C>T	p.Pro179Leu (VUS)	compound het (maternal)	Family 7	Morales/Curry/Enns 2022, DOI 10.20517/jtgg.2022.01
c.731A>G	p.Tyr244Cys (likely pathogenic)	compound het (paternal)	Family 7	Morales 2022
c.548A>C	p.Glu183Ala (novel)	homozygous	Family 8 (consanguineous Georgian)	Tkemaladze 2023, PMID:37195326
c.343G>A	p.Gly115Arg	homozygous	Family 9	Hassas 2026, PMID:41718295

Recurrent alleles: c.731A>G (p.Tyr244Cys) has now been seen in three unrelated families (US, Italy, US) and c.343G>A (p.Gly115Arg) in two — these are the two candidate recurrent/founder-like alleles. No formal founder haplotype study exists.

Structure–function. Both original variants hit conserved metal-binding motifs: "Both positions encode amino acids that occur in highly conserved metal-binding domains in SMO," and "H173Q alters a predicted active site encompassing the second iron-binding motif" (PMID:21285510). PolyPhen scored Y244C at 2.5 and H173Q at 3.2 — both "probably damaging."

Variant classification (ACMG/AMP) — worked example

For c.343G>A (p.Gly115Arg), Hassas et al. 2026 reclassified from VUS to likely pathogenic:

"Based on its computational predictions, rarity in the population, and presence in the homozygous state in multiple individuals with suspected MSMO1 deficiency, re-assessment of the variant's clinical significance by the study team was consistent with a classification as likely pathogenic (ACMG-AMP criteria applied: PP3_Strong, PM3, and PM2_Supporting)." — PMID:41718295

Supporting criteria detail: "The amino acid substitution is strongly predicted by AlphaMissense to be damaging to protein function (score = 0.9933)" (PP3_Strong); "It is in gnomAD v4.1 in just two heterozygous individuals" (PM2_Supporting).

Allele frequency / population data

c.343G>A (p.Gly115Arg): 2 heterozygotes in gnomAD v4.1 (PMID:41718295). No homozygotes.
Population frequencies for the other alleles are not published; all are ultra-rare.
No founder mutation, no carrier-frequency estimate, and no population-specific screening data exist.

Gene-level constraint (ClinGen/gnomAD v4.0, retrieved August 2026)

Metric	Value	Interpretation
pLI	0	Not LoF-intolerant in the heterozygous state (expected for a recessive gene)
LOEUF	0.9	Moderate LoF constraint
DECIPHER %HI	44.79	Low haploinsufficiency likelihood
ClinGen gene-disease validity	0 classifications — "ClinGen has not yet published curations for MSMO1 (HGNC:10545)"	Curation gap — no CGGV assertion available to cite
ClinGen dosage sensitivity	0 classifications	—

Curation note: because ClinGen has no MSMO1 curation, a CGGV: structured-source evidence item is not available for this entry. Gene-disease validity must be argued from primary literature (multiple unrelated families + biochemical concordance + functional data), which would support a "Definitive"-equivalent argument if curated.

ClinVar

A gene-level ClinVar query (MSMO1[gene], August 2026) returned on the order of 50 variation records across all classifications; the great majority are VUS or benign/likely benign, with the literature-reported missense alleles above carrying pathogenic/likely-pathogenic assertions. I was unable to reliably enumerate per-variant ClinVar classifications through the accessible interfaces — verify individual variant IDs directly before asserting classifications in the KB.

Somatic vs germline

All disease-causing variants are germline. MSMO1 is, however, of considerable somatic/oncologic interest as an expression-level driver rather than a mutational target (see §6 and §12): upregulation in cervical cancer associates with poor survival, and MSMO1 modulates breast-cancer chemosensitivity via T-MAS/PERK signaling (iScience 2026, DOI 10.1016/j.isci.2026.112...; ScienceDirect PII S2589004226001653). No recurrent somatic MSMO1 mutation is reported in COSMIC/TCGA as an oncogenic driver.

Functional consequence

Loss of function (hypomorphic). Missense substitutions in iron-coordinating/active-site residues reduce catalytic activity. No gain-of-function or dominant-negative mechanism has been proposed. Heterozygotes show intermediate biochemistry (elevated but sub-diagnostic methylsterols) — consistent with a gene-dosage-sensitive enzymatic step, though clinically unaffected.

Modifier genes

None established. Two mechanistically plausible candidates, untested: - NSDHL and HSD17B7 — the other two members of the sterol C4-demethylation complex. Combined partial deficiency would be expected to be additive. - CYP51A1 and HMGCR — upstream flux controllers; genotype-determined flux may modify substrate accumulation (this is the pharmacological premise of statin therapy).

An intriguing, unresolved candidate-modifier observation is the heterozygous father's immune phenotype (PMID:21285510), suggesting that a single hypomorphic MSMO1 allele may be a susceptibility factor rather than fully recessive.

Epigenetics

No data. No DNA methylation, histone modification, chromatin, or episignature study of MSMO1 deficiency exists. There is no published MSMO1 episignature in the DNA-methylation-signature literature for Mendelian disorders. Not available.

Chromosomal abnormalities

None reported. No aneuploidy, translocation, inversion, or CNV involving 4q32.3 has been reported as a cause of MSMO1 deficiency. CMA is not a diagnostic modality for this disorder.

5. Environmental Information

Environmental factors: none causal. No toxicant, pollutant, radiation, or occupational exposure is implicated. CTD lists MSMO1 as chemically responsive (notably to azoles and sterol-pathway drugs), but this is expression modulation, not disease etiology.
Lifestyle factors: none causal. Cold weather and stress exacerbate the dermatitis (PMID:21285510). Dietary cholesterol is therapeutically relevant, not etiologic.
Infectious agents: not applicable. No pathogen causes or triggers MSMO1 deficiency. However, the documented immune dysregulation (granulocyte activation, TLR-2/TLR-4 dysregulation, reduced CD16b) raises a theoretical concern for altered infection susceptibility — clinically undocumented.

6. Mechanism / Pathophysiology

6.1 The enzymatic lesion

Cholesterol synthesis from lanosterol requires removal of three methyl groups. CYP51A1 removes the 14α-methyl. The two C4 methyls are removed by two successive rounds of a three-enzyme sterol C4-demethylation complex on the ER membrane:

MSMO1 / SC4MOL — sterol-C4-methyl oxidase; performs three sequential monooxygenations of the 4α-methyl group (methyl → hydroxymethyl → aldehyde → carboxylate), using Fe(II)-cytochrome b5 as electron donor and a non-heme di-iron center (EC 1.14.18.9).
NSDHL — 3β-hydroxysteroid dehydrogenase / C4-decarboxylase.
HSD17B7 — 3-ketosteroid reductase.

MSMO1 catalyzes the rate-limiting first step, and in the UniProt pathway annotation performs step 3 of 6 in zymosterol biosynthesis from lanosterol.

"SC4MOL deficiency is the first autosomal recessive disorder identified in the sterol demethylation complex." — He et al. 2014 (PMID:24144731)

(NSDHL deficiency causes CHILD syndrome and CK syndrome; the C4-demethylation complex is thus responsible for at least two distinct Mendelian disorders — useful for module/grouping design.)

6.2 Accumulating metabolites — the meiosis-activating sterols

The block causes accumulation of the immediate substrates:

Metabolite	Chemistry	CHEBI
T-MAS (testis meiosis-activating sterol) = 14-demethyllanosterol = 4,4-dimethyl-5α-cholesta-8,24-dien-3β-ol	4,4-dimethylsterol	CHEBI:18364 ✓ (OLS-verified: "A 3β-sterol formed formally by loss of a methyl group from the 14-position of lanosterol")
FF-MAS (follicular fluid MAS) = 4,4-dimethyl-5α-cholesta-8,14,24-trien-3β-ol	4,4-dimethylsterol	CHEBI:17813 ✓ (OLS-verified)
4α-monomethylsterols	monomethylsterol	(no single CHEBI class; use the HPO lab term HP:6000753)
Cholesterol (deficient product)	—	CHEBI:16113 ✓ (OLS-verified)
Lanosterol (upstream)	—	CHEBI:16521 (unverified — confirm with OAK)

These are not inert:

"C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. ... MASs serve as ligands for liver X receptors α and β (LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity." — He et al. 2011 (PMID:21285510)

This dual-signaling identity (MAS = mitogenic/meiotic signal and LXR ligand) is the mechanistic key to the disease being far more than a cholesterol-deficiency phenotype.

6.3 Causal chain (upstream → downstream)

Node 1 (MOLECULAR) — MSMO1 loss-of-function missense variant. Substitution in an iron-binding/active-site residue reduces sterol-C4-methyl oxidase catalytic activity. ↓ Node 2 (MOLECULAR) — Block of sterol C4-demethylation. GO:0000254 C-4 methylsterol oxidase activity ✓ (DECREASED); GO:0006695 cholesterol biosynthetic process ✓ (DECREASED). ↓ (branches into two arms)

Arm A — Substrate accumulation (dominant arm)

Node 3A (MOLECULAR) — Methylsterol/MAS accumulation. 4α-monomethylsterols ↑ ~20-fold; 4,4′-dimethylsterols ↑ ~500-fold in plasma; dimethylsterol preferentially deposits in skin (PMID:21285510, PMID:24144731). Also demonstrated in patient fibroblasts: "Methylsterols were indeed markedly elevated in the patient's fibroblasts, but not any of the controls." ↓ (three parallel downstream effectors)

Node 4A-i (CELLULAR) — LXRα/β dysregulation. MAS are LXR ligands. He 2011 proposes: "the reduction of TLR-4 expression in SMO deficiency may be related to inhibition of LXR by T-MAS, which is structurally similar to FF-MAS," noting "activated LXR binds to TLR-4 promoter through an LXRE site to regulate TLR-4 expression" and "The promoter region of ABCA1 also has an LXRE site, which is strongly inhibited by TLR-4 signaling." Consequence: dysregulated epidermal lipid transport and innate immune tone. Independent confirmation of the MAS→LXR→ABCA1/ABCG1/LDLR axis comes from Gabitova et al. 2015 (PMID:26344763): "Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α."
Node 4A-ii (CELLULAR) — Cell-cycle activation / hyperproliferation. "The S-G2-M to G0-G1 ratio in patient skin fibroblasts was 3-fold higher than in control cells" in cholesterol-restricted medium; "This ratio peaked after 2–3 days growth in the cholesterol-restricted medium and corresponded with peaks of cellular methylsterols and total protein." Pharmacologic phenocopy: the SMO inhibitor ATZ increased the ratio 3-fold in normal lymphoblasts, whereas simvastatin and fluconazole did not — establishing that it is methylsterol accumulation, not cholesterol deficiency, that drives proliferation (PMID:21285510). GO:0008284 positive regulation of cell population proliferation (unverified).
Node 4A-iii (CELLULAR) — Impaired EGFR endosomal trafficking. "SC4MOL is required for effective endosomal trafficking of EGFR." Silencing MSMO1 prevents EGFR association with RAB11 recycling endosomes and shifts it toward RAB7 late endosomes; patient fibroblasts show "diminished EGFR signaling" with reduced downstream ERK phosphorylation despite elevated EGFR phosphorylation (PMID:24144731). Corroborated in the cancer setting: "Bioinformatics modeling revealed an unexpected role for these genes in controlling EGFR signaling, trafficking, and degradation" and "Analysis of Nsdhl-deficient mice confirmed dramatic loss of internalized growth factor receptors in fibroblasts and reduced activation of EGFR signaling in NSDHL-lacking skin regions" (Sukhanova 2013, PMID:23125191).

Arm B — Product deficiency

Node 3B (ORGANISM) — Reduced cholesterol availability. Hypocholesterolemia (variable, ~50% of patients): total cholesterol 85–90 mg/dL, low HDL and LDL. Consequences relevant to affected organs: membrane raft composition (lens fiber cells, neurons), myelination, and Sonic hedgehog signaling (SHH requires cholesteroylation) — the last is the standard explanation for developmental malformation in cholesterol-synthesis defects, though it has not been directly demonstrated in MSMO1 deficiency (an explicit knowledge gap).

Convergent downstream tissue phenotypes

Skin (Node 5, TISSUE): MAS-driven keratinocyte/fibroblast hyperproliferation + LXR-mediated barrier-lipid dysregulation + constitutive IL-6 → psoriasiform epidermal hyperplasia and inflammation. "Cultures of patient skin fibroblasts showed constitutive production of IL-6 compared with control fibroblasts"; after 24 h of simvastatin, "IL-6 production by patient fibroblasts was significantly decreased" (PMID:21285510) — the direct in-vitro rationale for statin therapy.
Immune system (Node 5, CELLULAR/ORGANISM): see 6.4.
Lens (Node 5, TISSUE): "the mechanism of early lens opacification is thought to result from impaired cholesterol synthesis, altering the lipid composition of the lens membrane" (Hassas 2026, PMID:41718295). The lens is uniquely vulnerable because it is avascular and cannot import LDL cholesterol, relying on local de novo synthesis — hence cataract in nearly every distal cholesterol-synthesis defect.
Brain (Node 5, ORGAN): microcephaly, DD, white matter loss. The brain likewise depends on local cholesterol synthesis (blood–brain barrier excludes lipoprotein cholesterol), explaining why systemic cholesterol supplementation does not rescue neurologic features.
Skeleton (Node 5, TISSUE): delayed skeletal maturation with normal morphology; zebrafish data implicate hypertrophic chondrocyte patterning (see §15).

6.4 Immune system involvement (detailed)

From He et al. 2011 (PMID:21285510), all human in vivo flow cytometry:

Granulocytes: "activated CD16+ granulocytes (identified by CD25+CD69+ and CD86+HLA-DR+ subsets) were increased 30- and 20-fold in the patient and her father, respectively"; "30- and 15-fold increases in the numbers of TLR-2+TLR-4– granulocytes in the patient and her father"; "CD16b isoform was also markedly downregulated in both the patient and her father."
T cells: "both patient and father had a significantly higher proportion of CD8dim T cells that were also CD28–CD56+" — a senescent/NK-like effector phenotype.
Monocytes: "No significant differences were observed in the monocyte population."
Cytokines: serum GM-CSF, IL-6, IL-8 increased; TNF-α normal — explaining etanercept failure.
Pharmacologic phenocopy in normal cells: SMO inhibition with ATZ produced "a greater than 6-fold increase in the TLR-2+TLR-4– granulocyte population" and a "2-fold decrease in CD8 expression" — establishing causality rather than mere association.

This is a sterol-driven innate-immune reprogramming phenotype (TLR-2 high / TLR-4 low), which is notable because the TLR-2^high^ granulocyte pattern is "typical of psoriasis patients" (PMID:24144731) — providing a mechanistic bridge from a rare metabolic disease to common inflammatory skin disease.

6.5 Link to common disease — PSORS9

"SC4MOL is situated within the psoriasis susceptibility locus PSORS9, and may be a genetic risk factor for common skin conditions." — He et al. 2014 (PMID:24144731)

PSORS9 (OMIM 607857) maps to 4q31–4q32, encompassing MSMO1 at 4q32.3. Note that the historically favored PSORS9 candidate in Han Chinese linkage studies has been IL15 at 4q31.2; the MSMO1 candidacy remains a hypothesis (appropriate for a mechanistic_hypotheses entry with status: EMERGING, not an asserted mechanism).

6.6 Oncologic mechanism (adjacent, for completeness)

MSMO1/NSDHL inactivation sensitizes tumors to EGFR inhibitors: "We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL and NSDHL, sensitized tumor cells to EGFR inhibitors. ... SC4MOL inactivation sensitized A431 xenografts to cetuximab." (PMID:23125191)
LXR-dependent anti-tumor effect: "Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling." (PMID:26344763)
Chemoresistance (2026): MSMO1 modulates breast-cancer sensitivity to paclitaxel, carboplatin, and epirubicin by tuning its substrate T-MAS, which regulates ER stress and apoptosis via the PERK/eIF2α/ATF4/CHOP axis; plasma exosomal MSMO1 proposed as a predictive biomarker (iScience, Jan 2026, ScienceDirect PII S2589004226001653). PMID not confirmed — verify before citing.
MSMO1 upregulation associates with poor survival in cervical cancer (PMC11543037).

6.7 Molecular profiling in patients

Transcriptomics: no patient-derived RNA-seq study published. Not available.
Proteomics: none. Not available.
Metabolomics/sterolomics: this is the diagnostic modality — GC/MS sterol profiling of plasma, fibroblasts, and skin scales (see §10). This is the richest omics layer for the disease.
Lipidomics: the skin-scale sterol data constitute a targeted lipidomic finding (preferential dimethylsterol deposition in cutaneous tissue), but no untargeted lipidomics has been reported.
Single-cell / spatial transcriptomics: none. Not available.
Functional genomics screens: MSMO1 appears in CRISPR/RNAi screens as an EGFR-inhibitor sensitizer (Sukhanova 2013, PMID:23125191). DepMap data exist at the cell-line level but have not been analyzed in a disease context.

6.8 Ontology term suggestions for pathophysiology nodes

GO biological processes / molecular functions: | GO ID | Label | Verification | |---|---|---| | GO:0000254 | C-4 methylsterol oxidase activity | ✓ OLS-verified | | GO:0006695 | cholesterol biosynthetic process | ✓ OLS-verified | | GO:0016126 | sterol biosynthetic process | unverified | | GO:0008203 | cholesterol metabolic process | unverified | | GO:0005506 | iron ion binding | unverified | | GO:0008284 | positive regulation of cell population proliferation | unverified | | GO:0032456 | endocytic recycling | unverified | | GO:0007173 | epidermal growth factor receptor signaling pathway | unverified | | GO:0006954 | inflammatory response | unverified | | GO:0002224 | toll-like receptor signaling pathway | unverified |

GO cellular components: GO:0005789 endoplasmic reticulum membrane; GO:0055037 recycling endosome; GO:0005770 late endosome (all unverified — confirm with OAK).

CL cell types: | CL ID | Label | Verification | |---|---|---| | CL:0011004 | lens fiber cell | ✓ OLS-verified | | CL:0002224 | lens epithelial cell | ✓ OLS-verified | | CL:0000312 | keratinocyte | unverified | | CL:0000057 | fibroblast | unverified | | CL:0000775 | neutrophil | unverified | | CL:0000625 | CD8-positive, alpha-beta T cell | unverified | | CL:0000138 | chondrocyte (hypertrophic: CL:0000743) | unverified |

UBERON anatomical sites: UBERON:0002097 skin of body; UBERON:0000965 lens of camera-type eye; UBERON:0000955 brain; UBERON:0002107 liver; UBERON:0000473 testis; UBERON:0000992 ovary; UBERON:0002481 bone tissue (all unverified — confirm with OAK).

7. Anatomical Structures Affected

Organ level

Primary organs (directly affected): - Skin (UBERON:0002097) — psoriasiform dermatitis, ichthyosis, erythroderma, alopecia; the tissue with the highest measured dimethylsterol accumulation. - Lens of the eye (UBERON:0000965) — bilateral congenital/infantile cataract. - Brain (UBERON:0000955) — microcephaly, cerebral white matter volume reduction with T2-FLAIR hyperintensity (Hassas 2026). - Eyelid / ocular adnexa — blepharitis.

Secondary / systemic involvement: - Immune system — granulocyte and T-cell dysregulation (bone marrow–derived, systemically distributed). - Skeletal system — delayed skeletal maturation with normal bone morphology; genu valgum; polydactyly (developmental, therefore arguably primary). - Joints — arthralgia; joint contractures (lower extremities, He 2014 patient 2). - Endocrine / reproductive — delayed puberty. Note: MAS are physiologically concentrated in testis and ovary (PMID:21285510), so gonadal involvement is mechanistically expected, but no fertility or gonadal-histology data exist in patients — a notable knowledge gap. - Liver — the highest-expressing tissue for MSMO1 (RPKM 94.8); no hepatic phenotype has been reported, which is itself mechanistically interesting.

Body systems: integumentary, nervous, visual/special sense, immune/hematologic, musculoskeletal, endocrine.

Tissue and cell level

Epidermis / stratum corneum — hyperproliferative keratinocytes (CL:0000312); scale contains the highest dimethylsterol.
Dermal fibroblasts (CL:0000057) — the primary patient-derived experimental cell type; show elevated methylsterols, 3-fold increased S-G2-M/G0-G1 ratio, constitutive IL-6.
Lens fiber cells (CL:0011004 ✓) and lens epithelial cells (CL:0002224 ✓) — opacification.
Granulocytes/neutrophils (CL:0000775) — CD16+, activated (CD25+CD69+, CD86+HLA-DR+), TLR-2^+^TLR-4^−^, CD16b down.
CD8 T cells (CL:0000625) — CD8^dim^CD28^−^CD56^+^ subset expanded.
B cells (CL:0000236) — He 2014 states immunologic analyses covered "granulocytes and B cells" and indicated "dysregulation of immune-related receptors"; specific B-cell findings not detailed in the accessible text.
Monocytes — explicitly unaffected ("No significant differences were observed in the monocyte population").
Pre-hypertrophic / hypertrophic chondrocytes — the cell type identified by the zebrafish model (see §15).

Subcellular level

Endoplasmic reticulum membrane (GO:0005789) — the site of MSMO1 catalysis; "localized to the endoplasmic reticulum membrane" with three TM helices.
Recycling endosome (RAB11+) and late endosome (RAB7+) — the trafficking compartments whose EGFR partitioning is disrupted.
Plasma membrane / lipid rafts — the downstream target of altered sterol composition (lens fiber membranes, immune receptor platforms).

Localization and lateralization

Cataract: bilateral in all reported cases.
Dermatitis: generalized/diffuse, characteristically sparing the palms in the index patient ("affecting the entire body except palms"); umbilical onset with centrifugal spread. Perianal-limited in the mild case; scalp-limited (dandruff) in Frisso's patient.
Note the contrast with CHILD syndrome (NSDHL, the adjacent enzyme in the same complex), which is characteristically strikingly unilateral/lateralized due to X-inactivation mosaicism. MSMO1 deficiency is autosomal and therefore symmetric/generalized — a clinically useful discriminator.

8. Temporal Development

Onset

Congenital: cataract (present at birth or detected in the first months), microcephaly, polydactyly.
Infantile (1–23 months, per GARD): growth failure, developmental delay, early-onset dermatitis in the severe cases.
Early childhood: dermatitis in the index patient began at age 2 at the umbilicus and generalized by age 6.
Onset pattern: insidious/chronic, not acute. There is no metabolic decompensation phenotype — this disorder does not conform to the metabolic_intoxication_decompensation module. No crises, no catabolic triggers, no acute encephalopathy.
HPO clinical-course annotation: HP:0011463 Childhood onset (from PMID:21285510) — but this reflects the dermatitis onset in the index case and understates the congenital ocular/head-size features.

Progression

Neurologic: static developmental impairment. No documented neurodegeneration. Spasticity may worsen with growth (as in cerebral palsy–like static encephalopathy).
Ocular: cataract is progressive until surgically removed; irreversible.
Dermatologic: chronic relapsing–remitting with seasonal (winter) and stress-related flares; the index patient's skin "once almost completely normalized."
Growth: progressive falling away from centiles through childhood; delayed skeletal maturation and delayed puberty imply a prolonged growth window.
Overall course: chronic, lifelong, non-lethal in reported cases. Reported patients have survived into the third decade (index patient was 20 at the 2014 report; the Italian patient was 19).
Disease staging: no formal staging system exists. Not available.

Patterns

Remission: dermatologic remission is treatment-induced (cholesterol/statin) and, less durably, spontaneous. Metabolic remission (normalized methylsterols) is achievable with combined oral cholesterol + statin + bile acid (PMID:24144731). Neurologic and ocular deficits do not remit.
Critical periods — the central prognostic issue:
The prenatal/perinatal window determines microcephaly and lens clarity. Both are essentially fixed before diagnosis is currently made. This is why the disorder is "potentially partially treatable" (PMID:37195326) rather than treatable.
The postnatal window governs dermatitis, immune dysregulation, growth, and — suggestively — some developmental gain. Morales 2022 reported "Marked language improvements within 6 months of treatment initiation," and Tkemaladze 2023 reported treatment "resulted in a marked improvement of psoriasiform dermatitis and some hair growth."
Implication for prevention/screening: any meaningful reduction in the neuro-ophthalmic burden requires pre-symptomatic (newborn or prenatal) identification — currently not performed anywhere.

9. Inheritance and Population

Epidemiology

Prevalence: <1 / 1,000,000 — Orphanet-class BELOW_1_IN_1000000; realistically "not yet documented." With ~11 individuals ever reported worldwide, the observed prevalence is on the order of 10⁻⁹. Recommended structured curation:
measure_type: POINT_PREVALENCE, prevalence_class: BELOW_1_IN_1000000 (or NOT_YET_DOCUMENTED), population: Worldwide
Plus a measure_type: CASES_IN_LITERATURE record with notes recording the count.
Incidence: not available.
Case count discrepancy — flag this. Published tallies conflict: He 2014 reported "four patients from three different families"; Kalay Yildizhan 2020 stated "5 patients from 4 unrelated families ... reported to date"; Tkemaladze 2023 stated "only five cases reported to date" — which appears to undercount, since He (4) + Frisso (1) + Kalay Yildizhan (2) + Morales (1) = 8 before their own 2 siblings. My reconstruction from primary sources is ~11 individuals across ~9 families. Curate the count with an explicit caveat rather than repeating any single paper's figure.

Inheritance

Pattern: Autosomal recessive (HP:0000007). Annotated to OMIM:616834 from PMID:21285510. Both compound heterozygous and homozygous states are documented, with confirmed parental segregation in multiple families ("The 519T→A mutation was carried by the patient's father, and the 731A→G mutation was present in the mother"; "Segregation analysis in all available family members confirmed recessive inheritance of the mutation," PMID:33161406).
Not digenic/oligogenic. No multi-locus inheritance has been reported.
Penetrance: appears complete in biallelic individuals, though with only ~11 cases this is weakly established.
Expressivity: markedly variable — the single most important genetic-counseling point. The same disorder spans severe non-ambulatory spastic quadriplegia with erythroderma to a boy with normal head circumference, ASD, and transient perianal dermatitis described as "the mildest case of SC4MOL deficiency to date" (Morales 2022). Even within a genotype: c.343G>A homozygotes include He's patient 2 (no psoriasiform rash) and Hassas's patient (spastic quadriplegia, no dermatitis) — arguing for genotype-independent modifiers.
Genetic anticipation: not applicable (no repeat expansion).
Germline mosaicism: not reported.
Founder effects: none established. Two recurrent alleles (p.Tyr244Cys ×3 families; p.Gly115Arg ×2 families) warrant haplotype investigation but have not been shown to be founder alleles.
Consanguinity: a clear contributor. Homozygosity in consanguineous Turkish and Georgian families; the Georgian family's variant was found by WES in a consanguineous pedigree.
Carrier frequency: not available. Not on any carrier-screening panel; no gnomAD-derived estimate published. Given that all known pathogenic alleles are private/near-private missense variants, a reliable carrier-frequency estimate cannot currently be computed.
Heterozygote biochemical phenotype: carriers have mildly elevated plasma methylsterols and (in one father) markedly abnormal granulocyte activation markers — clinically silent but a research-relevant intermediate phenotype.

Population demographics

Reported ancestries: United States (index family, ancestry not specified), Hispanic, Italian, Turkish (consanguineous), Georgian (consanguineous), plus two additional US families. No ethnic predilection has been established — the distribution most likely reflects ascertainment (specialist metabolic centers, WES availability, consanguinity).
Geographic distribution: cases reported from North America, Western Europe (Italy), and Western Asia/Caucasus (Turkey, Georgia). No endemic region.
Geographic distribution of specific variants: p.Tyr244Cys reported in US and Italian families; p.Asn27Thr in Turkey; p.Glu183Ala in Georgia. Too few observations to establish geographic clustering.
Sex ratio: both sexes affected, consistent with autosomal recessive inheritance. Reported individuals include at least 4 females and at least 4 males. No sex bias; ratio effectively 1:1 but the sample is far too small to state formally.
Age distribution: all reported individuals identified in childhood or adolescence, with the oldest reported at ~20 years. No adult-diagnosed or elderly patients reported — reflecting the era of WES availability rather than mortality.

10. Diagnostics

10.1 Laboratory / biochemical testing — the diagnostic cornerstone

Plasma sterol profiling by GC/MS is the definitive biochemical test and the single most important diagnostic recommendation for this disease.

Diagnostic signature: marked elevation of 4α-monomethylsterols (~20-fold) and 4,4′-dimethylsterols (~500-fold), with normal proximal cholesterol precursors. Morales 2022 explicitly noted "Normal proximal cholesterol precursors," which localizes the block distally.
Total cholesterol may be low OR normal — it is not a screening test.
Standard lipid panel in the index patient: TC 85 mg/dL (nl 140–176), HDL 28 (nl 35–75), LDL 49 (nl 70–160), TG 84 (nl 50–200).
Alternative sample types: cultured skin fibroblasts (methylsterols "markedly elevated in the patient's fibroblasts, but not any of the controls") and skin scales (where dimethylsterol accumulation is greatest). Skin-scale sterol analysis is a nearly disease-specific, non-invasive test that deserves wider use.
LOINC: no dedicated LOINC codes exist for 4-monomethylsterol or 4,4-dimethylsterol quantification. Not available — sterol profiling is reported as a specialty-lab panel.

Frisso et al. 2017 make the explicit clinical recommendation:

"we suggest that these two analyses should be performed as soon as possible in all undiagnosed patients affected by bilateral cataracts and developmental delay." (PMID:28673550)

10.2 Biomarkers

Diagnostic biomarkers: plasma/fibroblast/skin-scale 4α-monomethylsterols and 4,4′-dimethylsterols (T-MAS, FF-MAS).
Treatment-response biomarker: serial plasma methylsterol concentration — used in every treated case to titrate therapy. Morales 2022 tracked methylsterols longitudinally, observing an initial fall on statin and later "upward trend" prompting dose escalation.
Inflammatory biomarkers: serum GM-CSF, IL-6, IL-8 elevated; TNF-α normal — the normal TNF-α is a useful negative predictor for anti-TNF therapy.
Immunophenotyping biomarkers (research): CD16+CD25+CD69+ and CD86+HLA-DR+ granulocyte fractions; TLR-2^+^TLR-4^−^ granulocytes; CD16b expression; CD8^dim^CD28^−^CD56^+^ T cells.
No FDA-qualified biomarker exists for this disease.

10.3 Imaging

Brain MRI: recommended. Findings reported: "diffuse white matter volume reduction, T2 FLAIR hyperintensity" (Hassas 2026, PMID:41718295). Not specific; used to characterize the neurologic phenotype and exclude alternatives.
Ocular examination / slit lamp / B-scan: essential for cataract characterization. Described morphology: "diffuse cataracts bilaterally with scattered, white fleck-like opacities in the anterior lens," "intumescent appearance with significant lenticular liquefaction."
Skeletal survey / bone age: documents delayed skeletal maturation with normal bone morphology (PMID:21285510) — the normal morphology is diagnostically informative because it distinguishes MSMO1 deficiency from the chondrodysplasia-punctata group (CDPX2, CHILD, HEM/Greenberg), where stippled epiphyses are characteristic.
No disease-specific imaging biomarker.

10.4 Functional tests and electrophysiology

Not established. No pulmonary, cardiac, EEG, EMG, ECG, or NCS abnormality is characteristic. VEP/ERG may be used in the ophthalmologic workup of infantile cataract but is not disease-specific. Not applicable / not available.

10.5 Biopsy and histopathology

Skin biopsy shows psoriasiform epidermal hyperplasia (consistent with the clinical descriptor "psoriasiform dermatitis"); it is non-diagnostic — the histology mimics true psoriasis, which is exactly why the disorder is misdiagnosed. Detailed histopathologic and immunohistochemical characterization has not been systematically published. Largely not available — a genuine curation gap.
No other tissue biopsy plays a diagnostic role.

10.6 Genetic testing

Recommended approach: the diagnosis is now most often made by exome or genome sequencing, with confirmatory sterol profiling; the reverse order (biochemical first, gene second) was used in the earlier cases.

Modality	Utility for MSMO1 deficiency
Whole exome sequencing (WES)	High — the current first-line modality. Diagnostic in Kalay Yildizhan 2020 ("We undertook whole-exome sequencing and identified a new homozygous missense mutation") and Tkemaladze 2023 ("Whole-exome sequencing revealed a novel, homozygous c.548A>C, p.(Glu183Ala) variant"). Because all known variants are missense in coding exons, WES coverage is excellent.
Whole genome sequencing (WGS)	Useful; adds little over WES for this gene given the coding-missense spectrum, but would capture regulatory variants — note the zebrafish kolibernu7 allele is a cis-regulatory mutation abolishing tissue-specific expression, raising the possibility of undiscovered human regulatory alleles missed by WES.
Gene panels	MSMO1 is included on cholesterol/sterol biosynthesis disorder panels, congenital cataract panels, and ichthyosis/inherited skin disorder panels. Panel testing is appropriate when the biochemical phenotype is already known. Available tests are registered in GTR under gene 6307.
Single-gene testing	Appropriate only after a diagnostic sterol profile, or for cascade/carrier testing of relatives once the familial variants are known.
Chromosomal microarray	Not indicated — no CNV etiology reported.
Karyotype / FISH	Not indicated.
Mitochondrial DNA testing	Not applicable.
Repeat expansion testing	Not applicable.

Key interpretive challenge: most MSMO1 missense variants are initially reported as VUS. Reclassification depends on (i) sterol profiling as a functional assay, (ii) in-silico support (AlphaMissense), and (iii) homozygosity in additional affected individuals — exactly the PP3_Strong + PM3 + PM2_Supporting pathway used by Hassas 2026. Biochemical testing is therefore not merely confirmatory; it is the practical route to variant classification for this gene.

10.7 Omics-based diagnostics

Metabolomics/sterolomics: the primary diagnostic omics layer (see 10.1). GC/MS.
RNA sequencing: not established diagnostically; could in principle detect a regulatory/expression-null allele.
Proteomics, epigenomics, liquid biopsy: not applicable / not available for diagnosis.

10.8 Clinical criteria and differential diagnosis

There are no formal consensus diagnostic criteria (no society guideline, no DSM/ICD-based criteria). Diagnosis rests on: compatible phenotype + diagnostic sterol profile + biallelic MSMO1 variants.

Differential diagnosis — post-squalene cholesterol biosynthesis disorders (discriminated by sterol profile):

Disorder	Gene	Accumulating sterol	Distinguishing features
MSMO1 deficiency (MCCPD)	MSMO1	4α-methyl- and 4,4-dimethylsterols (T-MAS/FF-MAS)	Microcephaly + congenital cataract + symmetric psoriasiform dermatitis; normal bone morphology
Smith–Lemli–Opitz syndrome	DHCR7	7-dehydrocholesterol	2-3 toe syndactyly, genital anomalies, characteristic facies
Desmosterolosis	DHCR24	desmosterol	Nonspecific; "difficult to suspect clinically"
Lathosterolosis	SC5D	lathosterol	SLOS-like; liver disease
CHILD syndrome	NSDHL (same C4-demethylation complex)	4-methylsterols	X-linked dominant, strikingly unilateral/lateralized ichthyosiform nevus + ipsilateral limb defects
CK syndrome	NSDHL	—	X-linked recessive; ID, seizures, cortical malformation
CDPX2 (Conradi–Hünermann–Happle)	EBP	8(9)-cholestenol, 8-dehydrocholesterol	X-linked dominant; chondrodysplasia punctata, Blaschkoid ichthyosis, cataract
HEM / Greenberg dysplasia	LBR	cholesta-8,14-dien-3β-ol	Lethal; hydrops, "moth-eaten" skeletal dysplasia
Antley–Bixler / POR deficiency	POR	lanosterol, dihydrolanosterol	Craniosynostosis, disordered steroidogenesis

Non-metabolic differentials to exclude: true psoriasis/psoriasis vulgaris (the most common misdiagnosis — the index patient failed steroids, calcipotriene, cyclosporine, etanercept, phototherapy, and isotretinoin before diagnosis); congenital ichthyoses; other syndromic congenital cataract (e.g., Lowe, galactosemia, peroxisomal disorders); other syndromic microcephaly with ID.

A useful clinical rule derived from this literature: psoriasiform dermatitis refractory to conventional psoriasis therapy, in a child with congenital cataract and/or microcephaly, should prompt plasma sterol profiling.

10.9 Screening

Newborn screening: MSMO1 deficiency is not on any newborn screening panel anywhere (not on the US RUSP). Standard MS/MS acylcarnitine/amino-acid NBS would not detect it — detection would require sterol-specific methodology. Given the treatability of the cutaneous/immune/growth arm and the fixed nature of the neuro-ocular arm, this is a legitimate (though currently impractical) NBS candidate discussion point.
Carrier screening: MSMO1 is not on expanded carrier screening panels.
Cascade screening: appropriate for at-risk siblings once familial variants are known — and is arguably time-critical, since presymptomatic treatment is the only route to preventing the cutaneous/growth phenotype.

11. Outcome / Prognosis

Global caveat: there is no natural history study, registry, or survival analysis for MSMO1 deficiency. Everything below is inferred from ≤11 individually reported patients. Any quantitative prognostic statement should be curated as low-confidence.

Survival and mortality

Survival rate (5-/10-year/overall): not available. No deaths have been reported among published patients.
Life expectancy: not established, but the disorder is not known to be life-limiting. Patients have been reported alive at 19 and 20 years. Contrast with the lethal end of the cholesterol-synthesis spectrum (HEM/Greenberg, severe SLOS).
Mortality rate / disease-specific mortality: not available.
The zebrafish and mouse data (§15) show that complete Msmo1 loss is lethal, implying that human survivors necessarily carry hypomorphic alleles with residual activity — a true human null may be embryonic-lethal and therefore unascertained. This is an important, curatable inference.

Morbidity and function

Dominant sources of morbidity: (1) visual impairment from bilateral cataract — permanent, sometimes profound ("perception to light" post-surgery in Hassas 2026); (2) intellectual disability / developmental delay — ranging from mild to severe with non-ambulatory spastic quadriplegia; (3) chronic disfiguring, pruritic dermatitis; (4) short stature and delayed puberty.
Disability outcomes: the severe end entails lifelong total care dependency (non-verbal, non-ambulatory). The mild end is compatible with mainstream functioning with ASD-related support needs.
Quality of life measures: no EQ-5D, SF-36, PROMIS, DLQI, or disease-specific instrument has ever been applied. Complete evidence gap.

Disease course and complications

Complications: post-cataract-surgery complications (aphakia/pseudophakia management, amblyopia, nystagmus); joint contractures; growth failure; refractory dermatitis with barrier compromise; potential infection susceptibility from immune dysregulation (theoretical).
Recovery potential — the key prognostic distinction:
Reversible/improvable with treatment: psoriasiform dermatitis (marked improvement), plasma methylsterol levels (normalizable), immune dysregulation ("partially corrected with cholesterol and statin supplements," per OMIM/MedGen), growth, hair growth, and — suggestively — language/developmental gains ("Marked language improvements within 6 months of treatment initiation," Morales 2022).
Irreversible: congenital cataract (structural, requires surgery), microcephaly, established structural brain changes, and fixed neurodevelopmental deficit.
The framing in the title of Tkemaladze 2023 — "a potentially partially treatable, ultrarare neurodevelopmental disorder" — is the most accurate one-line prognostic statement available and is worth quoting directly in the KB.

Prognostic factors

Inferred, not statistically established: - Age at diagnosis and treatment initiation — the strongest presumed determinant, given the critical-period argument. - Presence and severity of microcephaly — the mildest reported patient had a normal head circumference; the most severe had microcephaly with spastic quadriplegia. Head circumference appears to track with neurodevelopmental outcome. - Residual enzyme activity (inferred from methylsterol elevation magnitude) — plausible but untested. - Treatment responsiveness of plasma methylsterols — biochemical response has tracked with cutaneous response in every treated case. - Genotype: poor predictor. The same c.343G>A homozygous genotype produced markedly different phenotypes in two patients.

Prognostic biomarkers: none validated. Serial plasma methylsterol is the only candidate.

12. Treatment

12.1 Overall strategy — pathogenesis-based dual therapy

The therapeutic logic is the standard "substrate reduction + product replacement" model used across distal cholesterol-synthesis defects, delivered both systemically and topically:

Cholesterol supplementation — replaces the deficient product, and via feedback suppresses SREBP-driven flux into the blocked step.
HMG-CoA reductase inhibition (statin) — reduces flux into the pathway upstream of the block, lowering methylsterol accumulation. This is the substrate-reduction arm and is what distinguishes therapy here from simple cholesterol replacement (statins are conventionally counterintuitive in a hypocholesterolemic patient).
Bile acid supplementation — a third flux-modulating component used in the reported regimen.
Topical cholesterol/statin ointment — targets the skin directly, where dimethylsterol accumulation is greatest and where systemic delivery is least effective. Directly borrowed from the well-established CHILD syndrome protocol (topical 2% lovastatin/simvastatin + 2% cholesterol), which is the mechanistic sibling disorder (NSDHL, same C4-demethylation complex).

12.2 Published regimens and outcomes

He et al. 2011 — cholesterol monotherapy (index patient, 3 months):

"methylsterol level decreased by about 20%, and the plasma cholesterol level was much improved, reaching a level near the low end of the normal range, but the methylsterol level decreased no further with longer treatment" (PMID:21285510)

→ Conclusion: cholesterol alone is insufficient.

He et al. 2014 — the reference combination algorithm:

Cholesterol supplementation 100 mg/kg/day alone reduced methylsterol levels ~20%; addition of "oral statin (10 mg/day) plus bile acids (30 mg/kg/day) along with cholesterol normalized" methylsterol levels. (PMID:24144731)

→ This is the "previously published treatment algorithm" that later authors follow.

Kalay Yildizhan et al. 2020 (Turkish siblings):

"The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement. This study demonstrates how genomics-based diagnosis and therapy can be helpful in clinical practice." (PMID:33161406) (Exact doses are behind a paywall and could not be verified — do not assert specific doses from this paper.)

Morales, Curry & Enns 2022 (mildest case): - Simvastatin 0.3 mg/kg/day, escalated to 10 mg/day - Pravastatin 4 mg/day added at age 6.4 years - Coenzyme Q10 50 mg/day (standard statin adjunct) - Topical cholesterol/simvastatin combination for perianal dermatitis - Outcomes: marked language improvement within 6 months; perianal dermatitis resolved; mild myalgia the only adverse effect - Note: statin therapy was used despite normal total cholesterol — because the target is methylsterol reduction, not cholesterol lowering.

Tkemaladze et al. 2023 (Georgian siblings):

"Based on previously published treatment algorithms, we initiated a modified dosage regime with systemic cholesterol supplementation, statins and bile acid along with topical application of a cholesterol/statin formulation. This resulted in a marked improvement of psoriasiform dermatitis and some hair growth." (PMID:37195326)

12.3 Treatments that FAILED (important negative evidence)

In the index patient, all of the following were tried without durable benefit (PMID:21285510): - Topical corticosteroids - Calcipotriene - Cyclosporine A — "her skin briefly improved with cyclosporine A, she did not exhibit a long-term response" - Etanercept (TNF-α inhibitor) — ineffective, consistent with the patient's normal serum TNF-α - Phototherapy - Oral isotretinoin

→ Curatable clinical rule: conventional psoriasis therapy fails; anti-TNF biologics are mechanistically inappropriate here (normal TNF-α; the driver is IL-6/GM-CSF/IL-8 with MAS-driven hyperproliferation).

12.4 Supportive, surgical, and rehabilitative care

Cataract surgery: lensectomy ± anterior vitrectomy with intraocular lens implantation. Performed at 7 months (Morales 2022) and in Hassas 2026 ("The patient underwent lensectomy and anterior vitrectomy with intraocular lens implantation"). Early surgery is the standard of care for bilateral infantile cataract to prevent deprivation amblyopia.
Low-vision rehabilitation, refractive correction/aphakia management, amblyopia therapy.
Developmental therapies: physical, occupational, and speech therapy; special education.
Spasticity management: as for static encephalopathy (PT, orthotics, tone management) — no disease-specific protocol.
Nutritional support for failure to thrive.
Dermatologic supportive care: emollients, barrier repair.
Genetic counseling for the family (25% recurrence risk; prenatal/PGT options).

12.5 Advanced therapeutics

Gene therapy, gene editing, cell therapy, RNA therapies (ASO/siRNA/mRNA), targeted therapy, immunotherapy: none exist, none in development, no preclinical program identified. Complete gap.
Note conceptually: MSMO1 deficiency is a loss-of-function enzymopathy in a small, ubiquitously expressed ER protein — nominally a good AAV gene-replacement or mRNA-therapy candidate — but the key affected tissues (brain, lens) are affected prenatally, which limits postnatal benefit. No published program.

12.6 Clinical trials

No clinical trial of any kind has ever been registered for MSMO1 deficiency / SC4MOL deficiency / MCCPD on ClinicalTrials.gov. All treatment evidence is uncontrolled single-patient/sibship experience (n≤2 per report). No NCT identifier is available to cite.

12.7 Pharmacogenomics

No disease-specific PGx. However, because statins are the backbone of therapy, standard statin PGx applies: CPIC guideline for SLCO1B1 (and ABCG2, CYP2C9) and statin-associated musculoskeletal symptoms. SLCO1B1 decreased-function alleles (c.521T>C, rs4149056) increase simvastatin myopathy risk — directly relevant since myalgia was the only reported adverse effect (Morales 2022). SLCO1B1 genotyping is a reasonable, evidence-supported adjunct for patients on long-term simvastatin.
No PharmGKB/CPIC record exists for MSMO1 itself (ClinGen: "CPIC/PharmGKB Records: 0 / 0").

12.8 Adverse events

Statins: myalgia (reported), rhabdomyolysis (theoretical), transaminitis; requires CK/LFT monitoring, especially in a growing child on long-term therapy for a non-cardiovascular indication.
Oral cholesterol: generally well tolerated; GI upset.
Bile acids: diarrhea, hepatotoxicity at high dose.
Topical statin/cholesterol: well tolerated in the CHILD-syndrome literature; minimal systemic absorption.
No FAERS signal specific to this indication (off-label, ultra-rare).

12.9 NCIT term suggestions for treatments

All NCIT IDs below are suggestions requiring OAK verification (uv run runoak -i sqlite:obo:ncit info <ID>) before entry, per the dismech anti-hallucination SOP.

Treatment	`treatment_term` (NCIT action)	`therapeutic_agent`	`therapeutic_modality`
Oral cholesterol supplementation	NCIT:C15433 Nutritional Support or NCIT:C15986 Pharmacotherapy	CHEBI:16113 cholesterol ✓	`SMALL_MOLECULE` (not BEHAVIORAL — see the CLAUDE.md guardrail on NCIT:C15433)
Oral simvastatin	NCIT:C15986 Pharmacotherapy	CHEBI:9150 simvastatin (verify)	`SMALL_MOLECULE`
Oral pravastatin	NCIT:C15986 Pharmacotherapy	CHEBI:63618 pravastatin (verify)	`SMALL_MOLECULE`
Bile acid supplementation	NCIT:C15986 Pharmacotherapy	CHEBI:16359 chenodeoxycholic acid / CHEBI:9907 ursodeoxycholic acid (the specific bile acid is not stated in PMID:24144731 — do not over-specify)	`SMALL_MOLECULE`
Topical cholesterol/statin ointment	NCIT:C15986 Pharmacotherapy	cholesterol + lovastatin/simvastatin	`SMALL_MOLECULE`
Coenzyme Q10	NCIT:C15433 Nutritional Support	CHEBI:46245 ubiquinone-10 (verify)	`SMALL_MOLECULE`
Cataract extraction (lensectomy + IOL)	NCIT:C15329 Surgical Procedure (or a cataract-specific NCIT procedure term if one exists)	—	`SURGERY`
Physical therapy	NCIT:C15302 Physical Therapy	—	`BEHAVIORAL`
Speech therapy	NCIT:C159273 Speech Therapy	—	`BEHAVIORAL`
Occupational therapy	NCIT:C121351 Occupational Therapy	—	`BEHAVIORAL`
Genetic counseling	NCIT:C15240 Genetic Counseling	—	(omit — not platform-classifiable)
Low-vision rehabilitation	NCIT:C15315 Rehabilitation	—	`BEHAVIORAL`

target_mechanisms pattern (recommended): - Statin → INHIBITS the "Methylsterol/MAS Accumulation" node (reduces upstream flux into the block). - Oral/topical cholesterol → ACTIVATES/replaces at the "Reduced Cholesterol Availability" node.

This makes MSMO1 deficiency a clean worked example of the substrate-reduction + product-replacement drug pattern in a mechanism-module sense.

13. Prevention

Primary prevention

Not possible for an affected fetus — the disease is fully determined at conception. Primary prevention operates only at the reproductive level: - Genetic counseling with 25% recurrence risk per pregnancy for carrier couples. - Preimplantation genetic testing (PGT-M) once familial variants are known. - Prenatal diagnosis by CVS/amniocentesis molecular testing. In principle, amniotic-fluid sterol profiling could also be diagnostic (as it is for SLOS), but prenatal sterol diagnosis has never been reported for MSMO1 deficiency — this is an untested but plausible approach worth flagging as a knowledge gap. - Consanguinity counseling in populations where it is common — the two homozygous-variant families were consanguineous. - No vaccination, no risk-factor modification, no environmental intervention is applicable.

Secondary prevention (early detection)

This is where the largest unrealized opportunity lies: - Newborn screening: not currently performed anywhere and not detectable by standard MS/MS panels. Detection would require sterol-specific methodology. - Targeted diagnostic screening is the practical substitute, and Frisso et al. 2017's recommendation is the actionable one: perform plasma sterol profiling + MSMO1 sequencing in every undiagnosed child with bilateral congenital/infantile cataract + developmental delay. Given that congenital cataract has a well-defined incidence (~1–6/10,000 births) and is nearly universally investigated genetically, this is a realistic ascertainment pathway. - Cascade testing of siblings at the time of proband diagnosis is the single highest-yield secondary-prevention action — a presymptomatic biallelic sibling could begin cholesterol/statin therapy before dermatitis and growth failure develop.

Tertiary prevention (preventing complications in affected individuals)

This is where the evidence is strongest and should anchor the KB's prevention section: - Early cataract surgery to prevent deprivation amblyopia — the most time-critical intervention. - Early initiation of cholesterol + statin (± bile acid) therapy to prevent/limit dermatitis, growth failure, and immune dysregulation. - Topical cholesterol/statin to prevent progression of cutaneous disease and its barrier complications. - Avoid ineffective immunosuppression (cyclosporine, anti-TNF) — prevents iatrogenic harm and diagnostic delay. - Statin safety monitoring (CK, LFTs) and consideration of SLCO1B1 genotyping. - Early developmental intervention — the language response reported by Morales 2022 argues for aggressive early therapy. - Routine ophthalmologic, growth, pubertal, and developmental surveillance. No published surveillance guideline exists — this would be a valuable contribution.

Public health and environmental interventions

Not applicable. No sanitation, vector-control, health-education, or environmental measure is relevant to a monogenic recessive enzymopathy.

14. Other Species / Natural Disease

Taxonomy and orthologs

Species	NCBI Taxon	Gene	Database ID
Homo sapiens	NCBITaxon:9606	MSMO1	NCBI Gene 6307; HGNC:10545
Mus musculus	NCBITaxon:10090	*Msmo1*	MGI:1913484; Chr 8: 65,171,173–65,186,826 (− strand)
Rattus norvegicus	NCBITaxon:10116	Msmo1	RGD:620281
Danio rerio	NCBITaxon:7955	msmo1	ZFIN (see §15)
Saccharomyces cerevisiae	NCBITaxon:4932	*ERG25*	SGD — the founding ortholog; the human gene alias ERG25 derives from it

The gene is deeply conserved from yeast to human — ERG25 performs the identical C4-methyl oxidation in ergosterol biosynthesis. This makes the pathway an excellent evolutionary-conservation example and underpins the antifungal relevance of the sterol pathway.

Natural disease in other species

None reported. A search of OMIA (Online Mendelian Inheritance in Animals) for MSMO1 returned no phenes — there is no naturally occurring MSMO1 disorder documented in companion animals, livestock, or wildlife.

Veterinary relevance: none currently. Not applicable.
This contrasts with several other cholesterol-pathway genes that do have OMIA entries, so the absence is likely genuine rather than an ascertainment gap in small animals — though naturally-occurring congenital cataract in dogs remains a plausible place to look.

Breed

Not applicable — no VBO breed association exists.

Comparative biology

Evolutionary conservation: high. The three-step C4-methyl oxidation and its di-iron/cytochrome-b5 chemistry are conserved from S. cerevisiae (Erg25p) through zebrafish to human, as is the three-enzyme C4-demethylation complex architecture.
Comparative pathology: the striking cross-species observation is that complete loss of function is lethal in zebrafish (larval death by 9 dpf) while human patients survive with a chronic multisystem phenotype — strong evidence that all reported human alleles are hypomorphic. The zebrafish also reveals a tissue-specific requirement (pre-hypertrophic chondrocytes) not obvious from the human phenotype, and predicts the human delayed skeletal maturation.
Transmission / zoonotic potential / cross-species susceptibility: not applicable (non-communicable genetic disease).

15. Model Organisms

15.1 Zebrafish (Danio rerio) — the best-characterized model

Anderson RA et al., "Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency," Disease Models & Mechanisms 2020 (PMID:32430393; PMC7328163; DOI 10.1242/dmm.042549). Evidence source: MODEL_ORGANISM.

"Human disorders of the post-squalene cholesterol biosynthesis pathway frequently result in skeletal abnormalities, yet our understanding of the mechanisms involved is limited. In a forward-genetic approach, we have found that a late-onset skeletal mutant, named kolibernu7, is the result of a cis-acting regulatory mutation leading to loss of methylsterol monooxygenase 1 (msmo1) expression within pre-hypertrophic chondrocytes."

Alleles: - kolibernu7 — a cis-regulatory mutation causing tissue-restricted loss of msmo1 expression in pre-hypertrophic chondrocytes; produces a viable, late-onset skeletal phenotype. (Notable: this allele class — regulatory, tissue-specific — has no human counterpart yet described, and is a concrete hypothesis for undiagnosed WES-negative skeletal patients.) - msmo1^nu81^ — a 37-bp insertion causing frameshift and premature truncation (functional null). Homozygotes "die by 9 dpf."

Key findings: - Rescued mutants develop "dramatic skeletal abnormalities, with a loss of Msmo1 activity resulting in a more-severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1a expression." - Dual pathogenic mechanism disentangled genetically: double lss^nu60^;msmo1^nu81^ mutants (blocking the pathway further upstream at lanosterol synthase) survive longer than msmo1^nu81^ alone, indicating "toxic sterol intermediates may contribute to the death" — i.e., lethality reflects both cholesterol deprivation and methylsterol toxicity. This is the cleanest in vivo demonstration anywhere of the substrate-toxicity arm and is the direct biological justification for statin (substrate-reduction) therapy in patients. - Tissue-specific rescue: liver-restricted Tg(fabp10a:msmo1:pA)^nu100^ suppresses early lethality, yielding juvenile mutants phenotypically indistinguishable from kol^nu7^ — establishing hepatic msmo1 as sufficient for survival while local chondrocyte expression governs the skeletal phenotype.

Phenotype recapitulation: excellent for the skeletal dimension (maps onto human delayed skeletal maturation) and for the dual-mechanism biochemistry. Limitations: does not model psoriasiform dermatitis (no mammalian epidermal barrier equivalent), cataract, or the human immune phenotype; the null is lethal, so it does not model the human hypomorphic steady state without engineered rescue.

Resources: ZFIN.

15.2 Mouse (Mus musculus)

MGI:1913484 (Msmo1, Chr 8). MGI records 14 mutations/alleles: 8 gene-trapped, 3 targeted, 2 endonuclease-mediated, 1 chemically induced; 20 IMSR strains/lines available; 15 phenotype references.

IMPC (mousephenotype.org, MGI:1913484): the pipeline reports 0 significant phenotypes, with 20 of 24 physiological systems tested. Viability data were collected but the homozygous viability call was not resolvable from the accessible page.

Important caveat for curation: the "0 significant phenotypes" result must be interpreted with care. Given that zebrafish msmo1 nulls are larval-lethal, a null-allele mouse would most plausibly be embryonic/perinatal lethal — in which case IMPC adult pipelines would return no significant adult phenotypes because homozygotes are absent, not because they are normal. Do not curate "0 significant phenotypes" as evidence that Msmo1 loss is benign in mouse. I could not verify the IMPC viability call; this should be checked directly at IMPC before any assertion.

No published Msmo1 mouse model of MSMO1 deficiency exists — i.e., no paper reporting a mouse that recapitulates the human MCCPD phenotype. This is a major, explicitly curatable knowledge gap and an obvious target for a HUMAN_MODEL_MISMATCH discussion entry: the human disease is a hypomorphic missense disorder, and the available mouse alleles are nulls/gene-traps that likely do not model it.

The informative mammalian in vivo data come from the paralogous gene Nsdhl (same C4-demethylation complex): "Analysis of Nsdhl-deficient mice confirmed dramatic loss of internalized growth factor receptors in fibroblasts and reduced activation of EGFR signaling in NSDHL-lacking skin regions" (PMID:23125191), and "we ablated Nsdhl in adult keratinocytes expressing KRAS(G12D)... Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α" (PMID:26344763). The classic Nsdhl mouse alleles are bare patches (Bpa) and striated (Str) — X-linked dominant, male-lethal, modeling CHILD syndrome. These are paralog models and must be curated as such, not as MSMO1 models.

Resources: MGI, IMPC, IMSR, KOMP/EuMMCR, MMRRC.

15.3 Cellular and in vitro models

Patient-derived dermal fibroblasts — the workhorse human model. Demonstrate elevated methylsterols, 3-fold increased S-G2-M/G0-G1 ratio in cholesterol-restricted medium, constitutive IL-6 production suppressible by simvastatin, diminished EGFR/ERK signaling, and disrupted vesicular trafficking (PMID:21285510, PMID:24144731). Evidence source: IN_VITRO.
Pharmacologic phenocopy model — SMO inhibition with ATZ in normal human lymphoblasts and leukocytes reproduces both the cell-cycle activation (3-fold S-G2-M/G0-G1 increase) and the immune phenotype (>6-fold TLR-2^+^TLR-4^−^ granulocyte increase; 2-fold CD8 decrease). This chemical-genetic approach is elegant because it establishes causality in normal human cells and is directly reusable.
siRNA/shRNA knockdown in cancer cell lines — used to define the EGFR-trafficking role (RAB11 vs RAB7) and the EGFR-inhibitor-sensitization phenotype, including A431 xenografts sensitized to cetuximab (PMID:23125191).
Yeast (S. cerevisiae erg25 mutants) — the original genetic system defining the enzymatic step; available via SGD.
iPSC, organoid, and 3D skin-equivalent models: none published. Given that the disease's most treatable manifestation is cutaneous, a patient-iPSC-derived keratinocyte or 3D epidermal-equivalent model is a conspicuous missing tool.

15.4 Model summary and gaps

Model	Recapitulates	Does not recapitulate	Status
Zebrafish msmo1^nu81^ (null)	Lethality; dual sterol-toxicity/deficiency mechanism	Skin, lens, immune, hypomorphic steady state	Published, robust
Zebrafish kol^nu7^ (cis-regulatory)	Skeletal dysplasia; chondrocyte patterning	Everything non-skeletal	Published, robust
Mouse Msmo1 alleles	— (no disease model published)	Entire human phenotype	Gap
Mouse Nsdhl (Bpa/Str)	EGFR trafficking, LXR/ABCA1, skin sterol biology	Is a paralog, X-linked, models CHILD not MCCPD	Published; use with care
Patient fibroblasts	Sterol accumulation, hyperproliferation, IL-6, EGFR signaling	Tissue architecture, in vivo immunity	Published, well characterized
ATZ chemical phenocopy	Cell cycle, granulocyte TLR phenotype	Chronic/developmental effects	Published
iPSC / organoid / 3D skin	—	—	Gap — none exist

Appendix A — Consolidated evidence table (verified PMIDs and DOIs)

PMID	Citation	Year	Evidence source	Role in this entry
21285510	He M, Kratz LE, Michel JJ, Vallejo AN, Ferris L, Kelley RI, et al. Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. J Clin Invest. DOI 10.1172/JCI42650. PMC3049385	2011	HUMAN_CLINICAL (+ IN_VITRO)	Landmark / disease-defining. Index patient, first mutations, sterol values, immunophenotype, LXR/MAS hypothesis, failed therapies
24144731	He M, Smith LD, Chang R, Li X, Vockley J. The role of sterol-C4-methyl oxidase in epidermal biology. Biochim Biophys Acta 1841(3):331-5. DOI 10.1016/j.bbalip.2013.10.009. PMC3943829	2014	HUMAN_CLINICAL (review)	Patients 2–4; treatment algorithm with doses; EGFR trafficking; PSORS9
23125191	Sukhanova A, Gorin A, Serebriiskii IG, et al. Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation. Cancer Discov. DOI 10.1158/2159-8290.CD-12-0031	2013	IN_VITRO + MODEL_ORGANISM	EGFR trafficking/degradation mechanism; ketoconazole upstream-block rescue
26344763	Gabitova L, Restifo D, Gorin A, et al. Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR. Cell Rep. DOI 10.1016/j.celrep.2015.08.023	2015	MODEL_ORGANISM + IN_VITRO	MAS→LXRα→ABCA1/ABCG1/LDLR axis (via Nsdhl paralog)
26038696	Yasuda K, et al. Human hepatic metabolism of the anti-osteoporosis drug eldecalcitol involves sterol C4-methyl oxidase. Pharmacol Res Perspect.	2015	IN_VITRO	Non-sterol substrate; drug-metabolism relevance
28673550	Frisso G, Gelzo M, Procopio E, Sica C, Lenza MP, Dello Russo A, Donati MA, Salvatore F, Corso G. A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization. Mol Genet Metab. DOI 10.1016/j.ymgme.2017.06.013	2017	HUMAN_CLINICAL	Patient 5; microcephaly-negative phenotype; p.Gly202Glu; diagnostic recommendation
32430393	Anderson RA, et al. Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency. Dis Model Mech. DOI 10.1242/dmm.042549. PMC7328163	2020	MODEL_ORGANISM	msmo1 null lethality; chondrocyte patterning; dual-mechanism genetics
33161406	Kalay Yildizhan I, Gökpınar İli E, Onoufriadis A, Kocyigit P, Kesidou E, Simpson MA, McGrath JA, Yürür Kutlay N, Kundakci N. New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis. Cytogenet Genome Res 160(9):523-530. DOI 10.1159/000511126	2020	HUMAN_CLINICAL	Turkish siblings; p.Asn27Thr; ocular spectrum; oral+topical therapy
37195326	Tkemaladze T, Bratland E, Bregvadze K, Shatirishvili T, Tatishvili N, Abzianidze E, Houge G, Douzgou S. MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly. Clin Dysmorphol. DOI 10.1097/MCD.0000000000000461	2023	HUMAN_CLINICAL	Georgian siblings; polydactyly, alopecia, spasticity; p.Glu183Ala; treatment response
41718295	Hassas N, Drackley A, Ivanisevic J, Ralay Ranaivo H, Kurup SP. Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant—Case Report and Literature Review. Reports 9(1):45. DOI 10.3390/reports9010045. PMC12922104	2026	HUMAN_CLINICAL	Most recent case; ACMG reclassification of p.Gly115Arg; gnomAD v4.1 data; lens mechanism; MRI findings
(no PMID)	Morales JA, Curry CJ, Enns GM. Clinical characterization of a new individual with mild SC4MOL deficiency: diagnostic and therapeutic implications. J Transl Genet Genom. DOI 10.20517/jtgg.2022.01	2022	HUMAN_CLINICAL	Mildest reported case; normal OFC and cholesterol; detailed statin dosing; language response
(PMID unconfirmed)	MSMO1 promotes chemotherapy resistance through modulation of T-MAS metabolism via PERK/eIF2α/ATF4/CHOP pathway. iScience. PII S2589004226001653	2026	IN_VITRO	T-MAS/ER-stress mechanism; verify PMID before citing

Structured-source references available for this entry: - ORPHA:488168 — Orphanet record (I was blocked by Orphanet's bot protection during this session; fetch the cache with just structured-rebuild-orphanet --id 488168 and quote actual rows rather than relying on my summary). - CGGV: / CGDS: — not available; ClinGen has published no MSMO1 curation. - NCIT: P302 treatment indications — none expected for this indication (all therapy is off-label). - ICEES: — not applicable (ultra-rare; will not appear in EHR comorbidity data).

Appendix B — Curation notes and flagged uncertainties

Verified during this research (safe to use): - MONDO:0014793, OMIM:616834, OMIM gene 607545, ORPHA:488168, MedGen C5567510/UID 1798933, GARD 0017886, UMLS C5567510, HGNC:10545, NCBI Gene 6307, UniProt Q15800, EC 1.14.18.9, ENSG00000052802, NM_006745.5 - All 20 HPO terms in §3.1 (retrieved live from the HPO/JAX annotation API) - HP:0001596 Alopecia, HP:0010442 Polydactyly, HP:0100259 Postaxial polydactyly (OLS4) - GO:0000254, GO:0006695 (OLS4) - CL:0011004, CL:0002224 (OLS4) - CHEBI:16113 cholesterol, CHEBI:17813 FF-MAS, CHEBI:18364 14-demethyllanosterol (T-MAS) (OLS4) - gnomAD v4.0 constraint via ClinGen: pLI 0, LOEUF 0.9, %HI 44.79 - All verbatim quotes in this report were taken from PubMed abstract pages or PMC full text and should validate as exact substrings — but still run just fetch-reference + just validate-references on each before committing.

Explicitly NOT verified — verify with OAK before entry: - All ontology IDs marked (unverified) in §3.2, §6.8, §7, and §12.9 — in particular every NCIT and CHEBI drug ID in the treatment table. - ICD-10 E78.7 mapping (inferred, not confirmed as the official Orphanet mapping). - The iScience 2026 PMID. - Per-variant ClinVar classifications. - IMPC Msmo1 homozygous viability call.

NEC (Named Entity Confusion) preflight — passed. The gene named throughout every retrieved source is MSMO1/SC4MOL at 4q32.3; the OMIM number 616834 is consistent across OMIM, MedGen, Orphanet, GARD, and MONDO; and the MONDO cross-references resolve to the same UMLS concept. There is no eponym, numbered-series, or synonym collision risk here. The one adjacent-entity risk to watch is NSDHL/CHILD syndrome — the same enzyme complex, frequently co-cited, and the source of much of the mammalian in vivo data. Do not attribute Nsdhl mouse findings (Bpa/Str, keratinocyte KRAS ablation) to MSMO1.

Highest-value knowledge gaps to curate as discussions: 1. KNOWLEDGE_GAP — No natural history study, registry, survival data, or QoL measurement exists for any patient. 2. HUMAN_MODEL_MISMATCH — No mouse model of MSMO1 deficiency exists; available Msmo1 alleles are nulls/gene-traps while every human allele is hypomorphic missense, and zebrafish nulls are lethal. IMPC's "0 significant phenotypes" is likely an artifact of homozygote absence, not evidence of a benign knockout. 3. KNOWLEDGE_GAP — Whether treatment initiated presymptomatically (via cascade testing) alters neurodevelopmental outcome; the critical-period hypothesis is untested. 4. KNOWLEDGE_GAP — MAS are physiologically concentrated in testis and ovary, yet no fertility, gonadal, or meiotic data have ever been reported in patients. 5. KNOWLEDGE_GAP (emerging hypothesis) — Whether heterozygous MSMO1 carriers (who show elevated methylsterols and abnormal granulocyte activation) are at increased risk of common inflammatory skin disease; PSORS9 candidacy remains untested. Curate as mechanistic_hypotheses with status: EMERGING, not as an asserted mechanism. 6. KNOWLEDGE_GAP — No human cis-regulatory MSMO1 allele has been described, despite the zebrafish kol^nu7^ precedent; WES-negative patients with compatible phenotypes should have WGS.

Suggested conforms_to / module relationships (for dismech structural curation): - MSMO1 deficiency is a strong candidate conformer for a new sterol_biosynthesis_block module (deficient distal enzyme → precursor accumulation + cholesterol deficiency → multisystem developmental and dermatologic disease), which would also cover SLOS, lathosterolosis, desmosterolosis, CHILD, CDPX2, and HEM. No such module currently exists in kb/modules/. - It should not conform to metabolic_intoxication_decompensation — there is no acute decompensation phenotype. - It should not conform to lysosomal_substrate_accumulation — the accumulation is cytosolic/ER-membrane sterol, not lysosomal. - cataract_lens_opacification is a plausible conformance target for the ocular node, though the proximate mechanism (membrane lipid composition) differs from the module's crystallin-aggregation chain — check the module's node definitions before asserting. - The MSMO1/NSDHL/HSD17B7 sterol C4-demethylation complex is a natural grouping axis: a Grouping over MSMO1 deficiency + CHILD syndrome + CK syndrome with grouping_basis: [SHARED_PATHWAY, SHARED_MECHANISM] would be well-supported by the shared EGFR-trafficking and LXR findings.

Sources

He et al. 2011, J Clin Invest — PMID:21285510 · PMC3049385
He et al. 2014, Biochim Biophys Acta — PMID:24144731 · PMC3943829
Sukhanova et al. 2013, Cancer Discov — PMID:23125191
Gabitova et al. 2015, Cell Rep — PMID:26344763
Frisso et al. 2017, Mol Genet Metab — PMID:28673550
Anderson et al. 2020, Dis Model Mech — PMID:32430393
Kalay Yildizhan et al. 2020, Cytogenet Genome Res — PMID:33161406 · Karger
Morales, Curry & Enns 2022, J Transl Genet Genom
Tkemaladze et al. 2023, Clin Dysmorphol — PMID:37195326
Hassas et al. 2026, Reports — PMC12922104 · DOI 10.3390/reports9010045
OMIM 616834 (403 to automated fetch; content accessed via MedGen/GARD/MalaCards mirrors)
NCBI MedGen C5567510
NCBI Gene 6307 — MSMO1
NIH GTR — MSMO1
UniProt Q15800
HPO/JAX annotation API — OMIM:616834
EBI OLS4 (MONDO, GO, CL, CHEBI, HP term verification)
ClinGen — MSMO1 (HGNC:10545)
MGI:1913484 — mouse Msmo1
IMPC — Msmo1
GARD 17886
Orphanet ORPHA:488168 (bot-protected; not directly retrievable this session)
OMIA search — no MSMO1 phenes
MSMO1/T-MAS/PERK chemoresistance, iScience 2026

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Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Overview

Key identifiers

Synonyms and alternative names

Provenance of the information

2. Etiology

Disease causal factors

Risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

3.1 HPO annotation set for OMIM:616834 (retrieved from the HPO/JAX API, August 2026)

3.2 Phenotypes reported in the literature but not yet in the HPO annotation set

3.3 Phenotype characteristics by domain

4. Genetic / Molecular Information

Causal gene

Reported pathogenic variants (all published cases)

Variant classification (ACMG/AMP) — worked example

Allele frequency / population data

Gene-level constraint (ClinGen/gnomAD v4.0, retrieved August 2026)

ClinVar

Somatic vs germline

Functional consequence

Modifier genes

Epigenetics

Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The enzymatic lesion

6.2 Accumulating metabolites — the meiosis-activating sterols

6.3 Causal chain (upstream → downstream)

6.4 Immune system involvement (detailed)

6.5 Link to common disease — PSORS9

6.6 Oncologic mechanism (adjacent, for completeness)

6.7 Molecular profiling in patients

6.8 Ontology term suggestions for pathophysiology nodes

7. Anatomical Structures Affected

Organ level

Tissue and cell level

Subcellular level

Localization and lateralization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Inheritance

Population demographics

10. Diagnostics

10.1 Laboratory / biochemical testing — the diagnostic cornerstone

10.2 Biomarkers

10.3 Imaging

10.4 Functional tests and electrophysiology

10.5 Biopsy and histopathology

10.6 Genetic testing

10.7 Omics-based diagnostics

10.8 Clinical criteria and differential diagnosis

10.9 Screening

11. Outcome / Prognosis

Survival and mortality

Morbidity and function