IFAP syndrome 2 is the autosomal dominant form of ichthyosis follicularis, atrichia and photophobia syndrome, caused by heterozygous SREBF1 variants that destroy the site-1 protease cleavage site of SREBP1. It is the mirror image of the X-linked form. IFAP syndrome 1 disables the protease, MBTPS2, that makes the second of two cuts releasing SREBP from the Golgi membrane; IFAP syndrome 2 leaves both proteases intact and instead mutates the substrate at the residues the first protease has to recognise. Either way the transcription factor never reaches the nucleus, which is why one gene on the X chromosome and another on chromosome 17 produce a clinically near-identical triad. Curating them as separate entries records two lesions in one cascade rather than two diseases that merely look alike. The consequences follow the tissues that depend most on locally made lipid. Scalp skin from affected individuals shows collapsed transcription of LDLR and of the keratins expressed in the outer root sheath, alongside raised keratinocyte apoptosis - the follicle fails structurally and the hair is lost. The eye is affected through the meibomian gland rather than the cornea directly: the gland secretes a wax-ester-shifted, higher-melting meibum that will not spread, and the photophobia, punctate keratopathy and vascularising keratitis follow from an unstable tear-film lipid layer. That reframes the ocular disease from an irritation problem to a lipid-secretion one, and it is the part of this entry with the most direct biochemical evidence. One nosological question sits at the centre of the entry rather than at its edge. Hereditary mucoepithelial dysplasia was described as a separate disorder for decades, and is caused by the same recurrent SREBF1 variant; a 2026 series applying ClinGen lumping-and-splitting criteria concluded the two are one condition with variable expressivity, and proposed a unifying name. MONDO still carries them as separate terms, so this entry curates IFAP syndrome 2 as MONDO names it, maps to the HMD term as a close match rather than an exact one, and records the argument in a discussion instead of silently picking a side.
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Conditions with similar clinical presentations that must be differentiated from IFAP Syndrome 2:
name: IFAP Syndrome 2
creation_date: "2026-09-02T18:30:00Z"
category: Mendelian
disease_term:
preferred_term: IFAP syndrome 2 (SREBF1-related)
term:
id: MONDO:0100221
label: IFAP syndrome 2
description: >-
IFAP syndrome 2 is the autosomal dominant form of ichthyosis follicularis,
atrichia and photophobia syndrome, caused by heterozygous SREBF1 variants that
destroy the site-1 protease cleavage site of SREBP1.
It is the mirror image of the X-linked form. IFAP syndrome 1 disables the
protease, MBTPS2, that makes the second of two cuts releasing SREBP from the
Golgi membrane; IFAP syndrome 2 leaves both proteases intact and instead
mutates the substrate at the residues the first protease has to recognise.
Either way the transcription factor never reaches the nucleus, which is why one
gene on the X chromosome and another on chromosome 17 produce a clinically
near-identical triad. Curating them as separate entries records two lesions in
one cascade rather than two diseases that merely look alike.
The consequences follow the tissues that depend most on locally made lipid.
Scalp skin from affected individuals shows collapsed transcription of LDLR and
of the keratins expressed in the outer root sheath, alongside raised
keratinocyte apoptosis - the follicle fails structurally and the hair is lost.
The eye is affected through the meibomian gland rather than the cornea
directly: the gland secretes a wax-ester-shifted, higher-melting meibum that
will not spread, and the photophobia, punctate keratopathy and vascularising
keratitis follow from an unstable tear-film lipid layer. That reframes the
ocular disease from an irritation problem to a lipid-secretion one, and it is
the part of this entry with the most direct biochemical evidence.
One nosological question sits at the centre of the entry rather than at its
edge. Hereditary mucoepithelial dysplasia was described as a separate disorder
for decades, and is caused by the same recurrent SREBF1 variant; a 2026 series
applying ClinGen lumping-and-splitting criteria concluded the two are one
condition with variable expressivity, and proposed a unifying name. MONDO
still carries them as separate terms, so this entry curates IFAP syndrome 2 as
MONDO names it, maps to the HMD term as a close match rather than an exact
one, and records the argument in a discussion instead of silently picking a
side.
parents:
- hereditary disease
- Genodermatosis
synonyms:
- IFAP2
- autosomal dominant IFAP syndrome
- SREBF1-related IFAP syndrome
- ichthyosis follicularis, atrichia and photophobia syndrome 2
- ichthyosis follicularis, alopecia and photophobia syndrome, autosomal dominant
mappings:
mondo_mappings:
- term:
id: MONDO:0008017
label: hereditary mucoepithelial dysplasia
mapping_predicate: skos:closeMatch
mapping_source: dismech
mapping_justification: >-
Hereditary mucoepithelial dysplasia and SREBF1-related IFAP syndrome are
caused by the same recurrent SREBF1 variant, and a 2026 case series
applying the ClinGen lumping-and-splitting criteria favours treating them
as one condition with variable expressivity. Deliberately recorded as a
close match rather than an exact one: MONDO still maintains two terms, and
asserting exactMatch here would retire a concept on the strength of one
series. See the discussion on lumping in this entry.
classifications:
harrisons_chapter:
- classification_value: DERMATOLOGY
notes: >-
Presents as a congenital genodermatosis and is usually first seen by
dermatology on the cutaneous triad.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
An autosomal dominant Mendelian disorder identified by exome sequencing,
with variants clustering in a four-residue functional hotspot.
references:
- reference: PMID:32497488
title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
- reference: PMID:41130335
title: "Abnormal meibum is associated with SREBF1 mutation and IFAP Syndrome-2."
- reference: PMID:41492963
title: "Phenotypic Expansion of Autosomal Dominant SREBF1-Related Ichthyosis Follicularis, Atrichia, Photophobia: It Is in Fact the Same Condition as Hereditary Mucoepithelial Dysplasia."
- reference: PMID:39912473
title: "The variant c.1670G>A in the SREBF1 gene is associated with unusual clinical manifestations of IFAP syndrome."
- reference: PMID:32902915
title: "Exome sequencing identifies a SREBF1 recurrent ARG557CYS mutation as the cause of hereditary mucoepithelial dysplasia in a family with high clinical variability."
- reference: PMID:37699567
title: "Recurrent Vascularizing Keratitis in Infants With Hereditary Mucoepithelial Dysplasia Related to SREBF1 Mutation."
- reference: PMID:39603447
title: "Ocular manifestations of SREBF1-associated hereditary mucoepithelial dysplasia."
- reference: PMID:39278528
title: "Long-term follow-up of ocular involvement in hereditary mucoepithelial dysplasia."
- reference: PMID:33742461
title: "Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum."
- reference: PMID:39005171
title: "A gain-of-function variant in SREBF1 causes generalized skin hyperpigmentation with congenital cataracts."
- reference: PMID:16268889
title: "Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin."
inheritance:
- name: Autosomal dominant inheritance
description: >-
Autosomal dominant. Most probands carry a de novo variant, but transmission
is documented - the founding cohort included affected mothers in their late
forties, and a father-daughter pair has been reported - so this is a
dominant disorder that is reproductively compatible rather than one
maintained solely by new mutation.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
expressivity: VARIABLE
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The present report describes the identification via whole-exome sequencing
of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically
diverse individuals with autosomal-dominant IFAP syndrome.
explanation: >-
Establishes heterozygous SREBF1 variants and dominant inheritance in the
founding cohort.
- reference: PMID:32902915
reference_title: "Exome sequencing identifies a SREBF1 recurrent ARG557CYS mutation as the cause of hereditary mucoepithelial dysplasia in a family with high clinical variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, a novel HMD pedigree, including an affected father and his
daughter, is reported.
explanation: >-
Documented vertical transmission of the same SREBF1 lesion, which is what
makes the dominant inheritance clinically actionable rather than a
description of de novo events.
pathophysiology:
- name: SREBF1 Cleavage-Site Variant
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: ESTABLISHED
description: >-
A heterozygous missense substitution or small in-frame deletion in SREBF1
affecting residues 527, 528 or 530 - the motif site-1 protease must
recognise before it can cut SREBP1.
The allelic spectrum is narrow and mechanistically legible: these are not
scattered loss-of-function variants but a functional hotspot, and their
common property is that they leave the protein intact while making it
uncleavable. That has two consequences a curator should keep separate. The
protein is still made, so this is not haploinsufficiency; and the uncleavable
product is suspected of suppressing output from the normal allele, which is
why the disease is dominant with a single hit rather than requiring both.
genes:
- preferred_term: SREBF1
term:
id: hgnc:11289
label: SREBF1
genetic_context:
gene:
preferred_term: SREBF1
term:
id: hgnc:11289
label: SREBF1
allele_type: missense substitution or small in-frame deletion at the S1P recognition motif
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Variants at residues 527-530 abolish site-1 protease cleavage. Curated as
loss of function because that is what the assays measure - reduced
cleavage, blocked nuclear entry, reduced reporter activity. A
dominant-negative component is plausible from the dominance of the trait
and from residual activity well above zero in the reporter assay, but no
experiment has separated a dominant-negative effect from simple
haploinsufficiency of the pathway, so the stronger category is not
asserted.
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The three detected SREBF1 mutations caused substitution or deletion of
residues 527, 528, and 530, which are crucial for S1P cleavage.
explanation: >-
Names the hotspot residues and the function they serve, which is the whole
content of this node.
downstream:
- target: Blocked Site-1 Proteolytic Activation of SREBP1
causal_link_type: DIRECT
description: >-
The variant residues are the protease recognition site, so disrupting them
prevents the first cut.
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vitro investigation of SREBP1 variants demonstrated impaired S1P
cleavage, which prohibited nuclear translocation of the transcriptionally
active form of SREBP1.
explanation: >-
Measures the cleavage step directly in the variant proteins, which is
this edge rather than either node alone.
- name: Blocked Site-1 Proteolytic Activation of SREBP1
biological_scale: MOLECULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
SREBP1 is a membrane-tethered precursor that becomes a transcription factor
only after two sequential cuts - site-1 protease in the Golgi lumen, then
site-2 protease within the membrane - which release the active
amino-terminal domain into the cytosol for import into the nucleus. With the
site-1 recognition motif destroyed, the cascade stops at the first step and
the active fragment is never generated.
This is the node that makes IFAP syndrome 1 and 2 one disease mechanism
approached from two directions: IFAP syndrome 1 removes the second protease,
this removes the first cut's substrate site, and both leave SREBP stranded on
the membrane.
biological_processes:
- preferred_term: SREBP signaling pathway
modifier: DECREASED
term:
id: GO:0032933
label: SREBP signaling pathway
- preferred_term: proteolytic processing of SREBP1
modifier: DECREASED
term:
id: GO:0016485
label: protein processing
cellular_components:
- preferred_term: Golgi membrane
term:
id: GO:0000139
label: Golgi membrane
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P
and subsequent translocation into the nucleus where it binds to sterol
regulatory elements (SRE).
explanation: >-
The two-cut activation cascade this node interrupts. Graded OTHER: the
paper states it as established background biochemistry rather than
reporting it.
downstream:
- target: Reduced Nuclear SREBP1 Transcriptional Output
causal_link_type: DIRECT
description: >-
No cleaved fragment reaches the nucleus, so target-gene transcription
falls.
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
As a result, SREBP1 variants exhibited significantly lower
transcriptional activity compared to the wild-type, as demonstrated via
luciferase reporter assay.
explanation: >-
Connects blocked cleavage to lost transcriptional output in the same
experiment, which is what this edge asserts.
- name: Reduced Nuclear SREBP1 Transcriptional Output
biological_scale: CELLULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
SREBP-driven lipogenic transcription falls. Two things are worth noting for
anyone reading the assays. The reduction is partial, not absolute - reporter
activity in the mutants runs well below wild type but is not abolished -
which fits a disease compatible with normal lifespan and adult reproduction.
And the effect is confirmed in patient tissue rather than only in transfected
cells: LDLR, the canonical SREBP target, is down in scalp skin from affected
individuals.
biological_processes:
- preferred_term: lipid biosynthetic process
modifier: DECREASED
term:
id: GO:0008610
label: lipid biosynthetic process
- preferred_term: cholesterol biosynthetic process
modifier: DECREASED
term:
id: GO:0006695
label: cholesterol biosynthetic process
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
RNA sequencing of the scalp skin from IFAP-affected individuals revealed a
dramatic reduction in transcript levels of low-density lipoprotein receptor
(LDLR) and of keratin genes known to be expressed in the outer root sheath
of hair follicles.
explanation: >-
Confirms the transcriptional deficit in patient tissue, and names the two
target classes - a lipid gene and follicular keratins - that split the
pathograph below.
- reference: PMID:39912473
reference_title: "The variant c.1670G>A in the SREBF1 gene is associated with unusual clinical manifestations of IFAP syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunohistochemistry of samples from the psoriatic-like plaques on the
lower limb from one of the patients showed enhanced staining for IL-17A and
S100A8, with reduced nuclear translocation of SREBP1.
explanation: >-
Independent demonstration of reduced nuclear SREBP1 in patient skin, from a
different variant than the founding hotspot.
downstream:
- target: Failure of Follicular Keratinization
causal_link_type: DIRECT
description: >-
Outer-root-sheath keratin transcription falls with SREBP1 output.
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
RNA sequencing of the scalp skin from IFAP-affected individuals revealed
a dramatic reduction in transcript levels of low-density lipoprotein
receptor (LDLR) and of keratin genes known to be expressed in the outer
root sheath of hair follicles.
explanation: >-
The follicular keratins are measured in the same patient tissue as the
transcriptional deficit, which is the step this edge makes.
- target: Keratinocyte Apoptosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Raised apoptosis accompanies the lipid-synthetic deficit in patient scalp;
the authors themselves put this forward as a contributing mechanism rather
than a demonstrated one.
- target: Meibomian Gland Lipid Synthesis Failure
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
The meibomian gland is a specialized sebaceous gland whose secretion is
SREBP-dependent lipid; reduced lipogenic transcription alters what it can
make.
- name: Failure of Follicular Keratinization
biological_scale: TISSUE
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The hair follicle and interfollicular epidermis cannot execute their
keratinization programme. Two visible things follow: the infundibulum plugs
with keratotic material, which is the spiny follicular papule seen
clinically, and the shaft itself is structurally defective, with cuticle
warping and detachment on scanning electron microscopy.
The specificity is what makes this node informative rather than generic. It
is the outer root sheath keratins that collapse, which is exactly the
compartment whose failure would give a hair that forms and then breaks rather
than a follicle that never forms.
biological_processes:
- preferred_term: keratinization
modifier: DECREASED
term:
id: GO:0031424
label: keratinization
- preferred_term: hair follicle development
modifier: ABNORMAL
term:
id: GO:0001942
label: hair follicle development
cell_types:
- preferred_term: outer root sheath cell
term:
id: CL:0002561
label: outer root sheath cell
locations:
- preferred_term: hair follicle
term:
id: UBERON:0002073
label: hair follicle
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Together with previous research, the present findings suggest that SREBP
signaling plays an essential role in epidermal differentiation, skin
barrier formation, hair growth, and eye function.
explanation: >-
The authors' summary of which tissue programmes depend on this pathway,
which is the set of consequences this node and its siblings represent.
downstream:
- target: Follicular hyperkeratosis
causal_link_type: DIRECT
- target: Atrichia and hypotrichosis
causal_link_type: DIRECT
- name: Keratinocyte Apoptosis
biological_scale: CELLULAR
role: effector
mechanism_confidence: PROVISIONAL
description: >-
Keratinocyte death is increased in scalp skin from affected individuals.
Curated as provisional deliberately. The observation is real and made in
patient tissue, but the paper reporting it frames the link to hyperkeratosis
and hypotrichosis as something that might contribute, not something shown -
and it is a correlation in a biopsy rather than a manipulation. Curating it
at higher confidence would state more than the source does.
biological_processes:
- preferred_term: apoptotic process
modifier: INCREASED
term:
id: GO:0006915
label: apoptotic process
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An increased rate of in situ keratinocyte apoptosis, which might contribute
to skin hyperkeratosis and hypotrichosis, was also detected in scalp
samples from affected individuals.
explanation: >-
The measurement and the authors' own hedged reading of its causal role,
which is why this node carries PROVISIONAL confidence.
downstream:
- target: Atrichia and hypotrichosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed by the reporting authors as a contributor to hair loss alongside
the keratinization defect, not demonstrated as a separate cause.
- name: Meibomian Gland Lipid Synthesis Failure
biological_scale: TISSUE
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The meibomian gland secretes lipid of the wrong composition. Lipidomic
analysis of meibum from an affected individual found it enriched in saturated
wax esters, raising the saturated-to-unsaturated ratio to grossly abnormal
levels.
The consequence is physical rather than inflammatory, and that is the point:
saturated wax esters melt at a higher temperature than unsaturated ones, so
the secretion is thicker and expresses poorly at lid temperature. This is the
step that turns a transcription-factor defect into an ocular surface disease,
and it explains why photophobia in this disorder is not simply corneal
irritation.
cell_types:
- preferred_term: meibocyte
term:
id: CL:0000317
label: sebocyte
locations:
- preferred_term: meibomian gland
term:
id: UBERON:0001818
label: tarsal gland
biological_processes:
- preferred_term: lipid biosynthetic process
modifier: ABNORMAL
term:
id: GO:0008610
label: lipid biosynthetic process
evidence:
- reference: PMID:41130335
reference_title: "Abnormal meibum is associated with SREBF1 mutation and IFAP Syndrome-2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our data showed that IFAP-2 meibum was enriched with SWE which increased
the SWE/UWE ratio to highly abnormal levels.
explanation: >-
The compositional abnormality itself, measured by mass spectrometry in
patient meibum.
- reference: PMID:41130335
reference_title: "Abnormal meibum is associated with SREBF1 mutation and IFAP Syndrome-2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thus, our study demonstrated possible links between the p.Arg527Cys
mutation in SREBP1 protein, upregulation of SWE in the IFAP-2 meibum, and
MG dysfunction.
explanation: >-
Links the genotype to the lipid change to gland dysfunction, which is the
chain this node sits in. The authors say possible links, and the entry does
not upgrade that.
downstream:
- target: Ocular Surface Lipid Layer Instability
causal_link_type: DIRECT
description: >-
A higher-melting, poorly expressible secretion cannot form a competent
tear-film lipid layer.
evidence:
- reference: PMID:41130335
reference_title: "Abnormal meibum is associated with SREBF1 mutation and IFAP Syndrome-2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The higher melting temperature of SWE compared to that of UWE correlated
well with poor expressibility and abnormal thickness of IFAP-2 meibum.
explanation: >-
The physical property that carries the causal step, correlated with the
gland's measured behaviour.
- name: Ocular Surface Lipid Layer Instability
biological_scale: TISSUE
role: effector
mechanism_confidence: PROVISIONAL
description: >-
Without a competent lipid layer the tear film is unstable, the corneal
epithelium is exposed and repeatedly breaks down, and the surface becomes
photophobic and prone to vascularizing keratitis.
Provisional because the chain from meibum composition to keratopathy is
assembled from two literatures - one lipidomic study and a set of ocular case
series - rather than measured end to end in one cohort. The individual
findings are solid; their linkage is inference.
locations:
- preferred_term: cornea
term:
id: UBERON:0000964
label: cornea
cell_types:
- preferred_term: corneal epithelial cell
term:
id: CL:0000575
label: corneal epithelial cell
evidence:
- reference: PMID:39603447
reference_title: "Ocular manifestations of SREBF1-associated hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient has severe MGD, with resulting keratitis and photosensitivity,
and bilateral glaucoma, which has not previously been reported in
association with HMD.
explanation: >-
A clinical account in which the keratitis and photophobia are attributed to
the meibomian gland dysfunction, which is the causal ordering this node
encodes.
- reference: PMID:39278528
reference_title: "Long-term follow-up of ocular involvement in hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ocular examination revealed meibomian gland dysfunction and superficial
corneal vascularization and opacity.
explanation: >-
The two findings co-occurring in one patient, documented over seven years
of follow-up.
downstream:
- target: Photophobia
causal_link_type: DIRECT
- target: Vascularizing keratitis
causal_link_type: DIRECT
phenotypes:
- category: Integument
name: Follicular hyperkeratosis
description: >-
Generalized spiny follicular keratotic papules, present from soon after
birth. Some affected individuals instead show lamellar-type scaling or
psoriasiform plaques, so the cutaneous presentation is less stereotyped than
the syndrome's name implies.
phenotype_term:
preferred_term: Follicular hyperkeratosis
term:
id: HP:0007502
label: Follicular hyperkeratosis
onset:
onset_category: CONGENITAL
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IFAP syndrome is a rare genetic disorder characterized by ichthyosis
follicularis, atrichia, and photophobia.
explanation: >-
Ichthyosis follicularis is the first element of the defining triad.
- category: Integument
name: Atrichia and hypotrichosis
description: >-
Hair loss ranging from complete congenital atrichia to sparse, fragile hair,
affecting scalp, eyebrows, eyelashes and body hair. It is non-scarring, which
separates it at the bedside from the scarring alopecias, and in some
individuals it is cyclical - hair regrows and is lost again - rather than a
single congenital absence.
phenotype_term:
preferred_term: Atrichia
term:
id: HP:0500262
label: Atrichia
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IFAP syndrome is a rare genetic disorder characterized by ichthyosis
follicularis, atrichia, and photophobia.
explanation: >-
Atrichia is the second element of the defining triad.
- reference: PMID:37699567
reference_title: "Recurrent Vascularizing Keratitis in Infants With Hereditary Mucoepithelial Dysplasia Related to SREBF1 Mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, the loss of scalp hair developed in a cyclical pattern,
causing diffuse scalp alopecia in the patients.
explanation: >-
Documents the cyclical rather than fixed course of the hair loss, which
matters for counselling and for interpreting apparent regrowth.
- category: Eye
name: Photophobia
description: >-
Near-universal, typically from the first months of life, and generally the
most disabling feature. It is a consequence of ocular surface disease rather
than a primary neurological light sensitivity. Notably it can be absent - two
individuals with a variant outside the founding hotspot had no apparent
photophobia at all - so its absence does not exclude the diagnosis.
phenotype_term:
preferred_term: Photophobia
term:
id: HP:0000613
label: Photophobia
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IFAP syndrome is a rare genetic disorder characterized by ichthyosis
follicularis, atrichia, and photophobia.
explanation: >-
Photophobia is the third element of the defining triad.
- reference: PMID:39912473
reference_title: "The variant c.1670G>A in the SREBF1 gene is associated with unusual clinical manifestations of IFAP syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe two cases of IFAP syndrome without apparent photophobia, one of
which exhibited severe psoriasis-like plaques limited to the extensor sides
of both lower limbs.
explanation: >-
The documented exception, curated so the entry does not present photophobia
as obligate.
- category: Eye
name: Meibomian gland dysfunction
description: >-
Present in almost every reported individual and the mechanistic hinge of the
ocular phenotype: the gland makes lipid of the wrong composition, so the tear
film has no stable outer layer. HPO has no term for meibomian gland
dysfunction itself, so this is bound to posterior blepharitis, the closest
available concept for disease of the meibomian-gland-bearing posterior lid
margin, with the precise entity carried in the preferred term.
phenotype_term:
preferred_term: Meibomian gland dysfunction
term:
id: HP:0025610
label: Posterior blepharitis
frequency: VERY_FREQUENT
evidence:
- reference: PMID:39603447
reference_title: "Ocular manifestations of SREBF1-associated hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This syndrome is associated with a variety of ocular conditions, including
cataracts, nystagmus, keratitis, meibomian gland dysfunction (MGD), and
decreased visual acuity.
explanation: >-
Lists meibomian gland dysfunction among the syndrome's characteristic
ocular findings.
- category: Eye
name: Vascularizing keratitis
description: >-
Corneal new vessels growing centripetally from the whole limbal
circumference, with stromal opacity forming at the advancing edge. It waxes
and wanes over years rather than progressing steadily, and partially responds
to topical corticosteroid - so an apparently deteriorating cornea in this
disorder is not necessarily on a one-way course.
phenotype_term:
preferred_term: Corneal neovascularization
term:
id: HP:0011496
label: Corneal neovascularization
frequency: FREQUENT
evidence:
- reference: PMID:37699567
reference_title: "Recurrent Vascularizing Keratitis in Infants With Hereditary Mucoepithelial Dysplasia Related to SREBF1 Mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients had vascularizing keratitis in both eyes, characterized by
the growth of corneal new vessels from the 360 degrees periphery to the
center and the formation of stromal leucomatous opacity at the leading
edge.
explanation: >-
The morphology of the keratitis, described precisely enough to distinguish
it from ordinary infectious or exposure keratitis.
sequelae:
- target: Corneal opacity
causal_link_type: DIRECT
description: >-
Stromal leucomatous opacity forms at the leading edge of the vessels.
- category: Eye
name: Corneal opacity
description: >-
Stromal opacification following the keratitis, and the main threat to vision.
It is not irreversible: with sustained ocular surface management one child's
opacity improved greatly over seven years, which is an argument for treating
aggressively rather than accepting the cornea as lost.
phenotype_term:
preferred_term: Corneal opacity
term:
id: HP:0007957
label: Corneal opacity
evidence:
- reference: PMID:39278528
reference_title: "Long-term follow-up of ocular involvement in hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
With appropriate management and close follow-up over 7 years, corneal
opacity improved greatly.
explanation: >-
Documents both the finding and its reversibility under management.
- category: Eye
name: Cataract
description: >-
Childhood-onset lens opacity, reported among the syndrome's characteristic
ocular conditions. Whether it is a direct consequence of disrupted lens lipid
metabolism or secondary to chronic ocular surface disease and its treatment
is not established - a relevant question given that a gain-of-function SREBF1
variant causes congenital cataract as part of a different disorder.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:39603447
reference_title: "Ocular manifestations of SREBF1-associated hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This syndrome is associated with a variety of ocular conditions, including
cataracts, nystagmus, keratitis, meibomian gland dysfunction (MGD), and
decreased visual acuity.
explanation: >-
Lists cataract among the characteristic ocular findings.
- category: Eye
name: Nystagmus
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:39603447
reference_title: "Ocular manifestations of SREBF1-associated hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This syndrome is associated with a variety of ocular conditions, including
cataracts, nystagmus, keratitis, meibomian gland dysfunction (MGD), and
decreased visual acuity.
explanation: >-
Lists nystagmus among the characteristic ocular findings.
- category: Eye
name: Reduced visual acuity
description: >-
The functional endpoint of the ocular disease, driven by corneal
opacification and cataract rather than by retinal or optic nerve pathology.
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:39603447
reference_title: "Ocular manifestations of SREBF1-associated hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This syndrome is associated with a variety of ocular conditions, including
cataracts, nystagmus, keratitis, meibomian gland dysfunction (MGD), and
decreased visual acuity.
explanation: >-
Lists decreased visual acuity among the characteristic ocular findings.
- category: Eye
name: Glaucoma
description: >-
Reported in one child and explicitly flagged by the authors as not previously
associated with this disorder. Curated because it is sight-threatening and
silent, so a single credible report is enough to justify measuring pressure;
the frequency is unknown and no frequency is asserted.
phenotype_term:
preferred_term: Glaucoma
term:
id: HP:0000501
label: Glaucoma
evidence:
- reference: PMID:39603447
reference_title: "Ocular manifestations of SREBF1-associated hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient has severe MGD, with resulting keratitis and photosensitivity,
and bilateral glaucoma, which has not previously been reported in
association with HMD.
explanation: >-
The single reported case, quoted including the authors' statement of its
novelty so the entry does not imply an established association.
- category: Head and Neck
name: Erythematous oral mucosa
description: >-
Mucosal erythema, described in the hereditary mucoepithelial dysplasia
literature alongside perineal erythematous intertrigo and conjunctival
involvement. Mucosal disease has historically been the feature used to call a
case HMD rather than IFAP, which is precisely why the two were split, and is
now part of the evidence that they should not have been.
phenotype_term:
preferred_term: Erythematous oral mucosa
term:
id: HP:0034418
label: Erythematous oral mucosa
evidence:
- reference: PMID:32902915
reference_title: "Exome sequencing identifies a SREBF1 recurrent ARG557CYS mutation as the cause of hereditary mucoepithelial dysplasia in a family with high clinical variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Prominent clinical features include non-scarring alopecia, mucosal
erythema, perineal erythematous intertrigo, and involvement of the
conjunctival mucosa.
explanation: >-
Names the mucosal features in individuals carrying the same SREBF1 lesion
as IFAP syndrome 2.
- category: Digestive
name: Gastroesophageal reflux
description: >-
Newly recognized in this disorder. Three of four patients in a 2026 series
had significant gastrointestinal disease, and the authors note explicitly
that gastrointestinal manifestations had not been described in
SREBF1-related IFAP before - which is itself part of the argument that IFAP
and hereditary mucoepithelial dysplasia are one condition, since the HMD
literature does report them.
phenotype_term:
preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
evidence:
- reference: PMID:41492963
reference_title: "Phenotypic Expansion of Autosomal Dominant SREBF1-Related Ichthyosis Follicularis, Atrichia, Photophobia: It Is in Fact the Same Condition as Hereditary Mucoepithelial Dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three of our four patients had significant gastrointestinal manifestations
including gastroesophageal reflux disease and esophageal strictures/webs.
explanation: >-
The reported gastrointestinal involvement, in molecularly confirmed
SREBF1-related IFAP patients.
- category: Digestive
name: Esophageal stricture
description: >-
Reported with reflux in the same 2026 series. Clinically consequential and
easy to miss: a child with a congenital skin and eye syndrome who feeds
poorly is likely to have it attributed to the syndrome in general rather than
investigated.
phenotype_term:
preferred_term: Esophageal stricture
term:
id: HP:0002043
label: Esophageal stricture
evidence:
- reference: PMID:41492963
reference_title: "Phenotypic Expansion of Autosomal Dominant SREBF1-Related Ichthyosis Follicularis, Atrichia, Photophobia: It Is in Fact the Same Condition as Hereditary Mucoepithelial Dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three of our four patients had significant gastrointestinal manifestations
including gastroesophageal reflux disease and esophageal strictures/webs.
explanation: >-
Names oesophageal strictures and webs in the same molecularly confirmed
patients.
- category: Integument
name: Psoriasiform dermatitis
description: >-
An atypical presentation associated with a variant outside the founding
527-530 hotspot: severe psoriasis-like plaques confined to the extensor lower
limbs, with IL-17A and S100A8 staining resembling psoriasis. Worth curating
because it is the one report suggesting an inflammatory branch to this
disease rather than a purely structural one.
phenotype_term:
preferred_term: Psoriasiform dermatitis
term:
id: HP:0003765
label: Psoriasiform dermatitis
frequency: VERY_RARE
evidence:
- reference: PMID:39912473
reference_title: "The variant c.1670G>A in the SREBF1 gene is associated with unusual clinical manifestations of IFAP syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe two cases of IFAP syndrome without apparent photophobia, one of
which exhibited severe psoriasis-like plaques limited to the extensor sides
of both lower limbs.
explanation: >-
The clinical description of the psoriasiform presentation and its
distribution.
genetic:
- name: SREBF1
association: >-
Heterozygous missense and small in-frame deletion variants at the site-1
protease cleavage motif.
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: SREBF1
term:
id: hgnc:11289
label: SREBF1
notes: >-
Two numbering conventions are in circulation for the recurrent variant and
they are easy to mistake for different alleles. The hereditary mucoepithelial
dysplasia literature reports c.1669C>T p.Arg557Cys; the IFAP literature and
the 2026 lumping series report NM_004176.5 c.1579C>T, and the lipidomic study
calls the same change p.Arg527Cys. These are the same substitution described
against different transcripts. Anyone reconciling case reports or searching
for the variant should expect both, and should not conclude that a family
carries a novel allele on the strength of the coordinate alone.
SREBF1 also carries a distinct gain-of-function allele class causing a
different disease entirely - generalized skin hyperpigmentation with
congenital cataracts - so this gene is one where the direction of effect, not
merely the presence of a variant, determines the phenotype.
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The present report describes the identification via whole-exome sequencing
of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically
diverse individuals with autosomal-dominant IFAP syndrome.
explanation: >-
The gene-disease assertion, in 11 unrelated individuals.
- reference: PMID:41130335
reference_title: "Abnormal meibum is associated with SREBF1 mutation and IFAP Syndrome-2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic analysis of the abnormal subject revealed the same c.1579C>T
(p.Arg527Cys) mutation in the SREBF1 gene that was previously associated
with IFAP-2.
explanation: >-
The recurrent variant in one of the two numbering conventions described in
the notes above.
- reference: PMID:32902915
reference_title: "Exome sequencing identifies a SREBF1 recurrent ARG557CYS mutation as the cause of hereditary mucoepithelial dysplasia in a family with high clinical variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Exome sequencing demonstrated that both affected subjects carried a
heterozygous c.1669C>T (p.Arg557Cys) pathogenic variant in the SREBF1 gene.
explanation: >-
The same substitution in the other numbering convention, which is the
concrete basis for the reconciliation warning in the notes.
- reference: PMID:39005171
reference_title: "A gain-of-function variant in SREBF1 causes generalized skin hyperpigmentation with congenital cataracts."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Loss-of-function variants in SREBF1 are responsible for autosomal-dominant
ichthyosis follicularis, alopecia and photophobia syndrome, emphasizing the
significance of lipid homeostasis in skin keratinization.
explanation: >-
Confirms the direction of effect for this disease from a paper describing
the opposite allele class, which is why the notes warn that SREBF1 genotype
alone does not predict phenotype. Graded OTHER: a background statement in a
paper about a different disorder.
diagnosis:
- name: Recognition of the clinical triad
description: >-
Follicular ichthyosis, atrichia and photophobia together, from birth or the
first months. The triad prompts testing but cannot make the diagnosis: it is
shared with the X-linked MBTPS2 form, and neither the skin nor the hair
finding distinguishes them.
presence: >-
The congenital triad in an infant should prompt molecular testing covering
both SREBF1 and MBTPS2.
markers: >-
Spiny follicular keratotic papules, non-scarring alopecia of scalp, brows and
lashes, and photophobia with an abnormal ocular surface. Mucosal erythema and
perineal intertrigo, when present, point to the SREBF1 end of the spectrum.
diagnosis_term:
preferred_term: clinical examination
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IFAP syndrome is a rare genetic disorder characterized by ichthyosis
follicularis, atrichia, and photophobia.
explanation: >-
The triad that defines the clinical recognition step.
- name: SREBF1 sequencing
description: >-
The diagnosis is molecular. Exome sequencing is how every reported case was
found, and targeted sequencing of the 527-530 hotspot is adequate for
confirming a known familial variant or testing a classic presentation
quickly.
presence: >-
A heterozygous SREBF1 variant at the site-1 protease cleavage motif
establishes the diagnosis and separates it from X-linked MBTPS2 disease.
diagnosis_term:
preferred_term: molecular genetic testing for SREBF1
term:
id: NCIT:C19770
label: Molecular Analysis
qualifiers:
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: SREBF1
term:
id: hgnc:11289
label: SREBF1
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The present report describes the identification via whole-exome sequencing
of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically
diverse individuals with autosomal-dominant IFAP syndrome.
explanation: >-
Exome sequencing is the modality that established every case in the
founding cohort.
- name: Ophthalmic surface assessment
description: >-
Slit-lamp examination for meibomian gland dysfunction, corneal
vascularization and opacity, plus intraocular pressure given the reported
glaucoma. This is surveillance rather than diagnosis: the ocular disease is
progressive, partly reversible under treatment, and the leading cause of
lasting impairment.
presence: >-
Meibomian gland dysfunction with superficial corneal vascularization and
opacity is the characteristic ocular finding.
diagnosis_term:
preferred_term: slit-lamp examination
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:39278528
reference_title: "Long-term follow-up of ocular involvement in hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ocular examination revealed meibomian gland dysfunction and superficial
corneal vascularization and opacity.
explanation: >-
What the examination finds, in a case followed from infancy.
differential_diagnoses:
- name: IFAP syndrome 1 (MBTPS2-related, X-linked)
description: >-
The differential that only genetics resolves, and the one where getting it
wrong changes the counselling completely: X-linked recessive rather than
autosomal dominant.
Mechanistically the two are one cascade broken at adjacent points. MBTPS2
encodes the site-2 protease that makes the second cut of SREBP; SREBF1
encodes the substrate of the first cut. Losing either stops the same
activation and produces the same triad, which is why the clinical picture
does not separate them. What can point toward MBTPS2 is an X-linked pedigree,
male predominance, or the additional CNS, skeletal and genital anomalies of
the BRESHECK end of that spectrum.
disease_term:
preferred_term: IFAP syndrome 1
term:
id: MONDO:0100213
label: IFAP syndrome 1, with or without BRESHECK syndrome
distinguishing_features:
- X-linked inheritance with male predominance, versus autosomal dominant here.
- Additional brain, skeletal, genital and renal anomalies in the BRESHECK-spectrum cases have no counterpart in SREBF1 disease.
- Mucosal erythema, perineal intertrigo and gastrointestinal strictures point toward SREBF1.
- Definitive separation is by sequencing, not by examination.
evidence:
- reference: PMID:32497488
reference_title: "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Previous research found that mutations in MBTPS2, encoding site-2-protease
(S2P), underlie X-linked IFAP syndrome.
explanation: >-
States the other gene, its inheritance pattern, and the protease it encodes
- the step adjacent to the one broken here.
- name: Hereditary mucoepithelial dysplasia
description: >-
Historically a separate disorder, now understood to be caused by the same
recurrent SREBF1 variant. It is retained as a differential rather than merged
because MONDO still separates the two, and because the name remains in active
clinical use - a curator or clinician searching only for IFAP will miss the
ocular natural-history literature, which was published almost entirely under
the HMD name.
The substantive argument for lumping is recorded in this entry's discussion
section rather than settled here.
disease_term:
preferred_term: hereditary mucoepithelial dysplasia
term:
id: MONDO:0008017
label: hereditary mucoepithelial dysplasia
distinguishing_features:
- Same gene, same recurrent variant; the historical separation was clinical, not molecular.
- Mucosal and perineal involvement was emphasized under the HMD name, the congenital cutaneous triad under the IFAP name.
- A 2026 series applying ClinGen lumping-and-splitting criteria favours treating them as one condition.
evidence:
- reference: PMID:41492963
reference_title: "Phenotypic Expansion of Autosomal Dominant SREBF1-Related Ichthyosis Follicularis, Atrichia, Photophobia: It Is in Fact the Same Condition as Hereditary Mucoepithelial Dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both are now known to be caused by the same NM_004176.5(SREBF1):c.1579C>T
variant, but were previously described as separate disorders.
explanation: >-
The shared causal variant, which is why this differential is a naming
question rather than a diagnostic one.
- reference: PMID:33742461
reference_title: "Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
These two syndromes share a common clinical spectrum.
explanation: >-
The earlier clinical observation of overlap, made before the shared variant
was recognized. Graded OTHER: a review's synthesis rather than a result it
reports.
- name: SREBF1 gain-of-function hyperpigmentation-cataract disorder
description: >-
A distinct disorder caused by a different class of SREBF1 allele: a nonsense
variant producing a truncated protein that localizes to the nucleus and is
transcriptionally hyperactive, giving generalized hyperpigmentation with
congenital cataracts. It is the reason a reported SREBF1 variant should never
be interpreted as IFAP syndrome 2 without establishing its direction of
effect.
distinguishing_features:
- Generalized skin hyperpigmentation and xerosis rather than follicular ichthyosis and alopecia.
- Congenital cataract is a presenting feature rather than a later complication.
- The variant increases rather than decreases SREBP1 transcriptional activity.
evidence:
- reference: PMID:39005171
reference_title: "A gain-of-function variant in SREBF1 causes generalized skin hyperpigmentation with congenital cataracts."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We demonstrated that a gain-of-function variant of SREBF1 causes a
previously undescribed disorder characterized by generalized skin
hyperpigmentation and congenital cataracts.
explanation: >-
Establishes the separate disorder and its opposite direction of effect.
treatments:
- name: Ocular surface lubrication and meibomian gland care
description: >-
The mainstay, and the intervention with the clearest mechanistic rationale in
the entry: if the gland cannot make spreadable lipid, the tear film needs
replacing and the gland needs help expressing what it does make. Warm
compresses and lid hygiene are the standard meibomian-gland measures, added
here on the strength of the lipid mechanism rather than any trial in this
disorder. Sustained management has been followed by substantial improvement
in corneal opacity over years.
action_category: THERAPEUTIC
treatment_term:
preferred_term: ocular surface supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Meibomian gland dysfunction
term:
id: HP:0025610
label: Posterior blepharitis
- preferred_term: Corneal opacity
term:
id: HP:0007957
label: Corneal opacity
target_mechanisms:
- target: Ocular Surface Lipid Layer Instability
description: >-
Replaces the tear-film lipid function the meibomian gland cannot provide,
acting downstream of a lesion that cannot itself be corrected.
evidence:
- reference: PMID:39278528
reference_title: "Long-term follow-up of ocular involvement in hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient received treatment for meibomian gland dysfunction, dry eye,
and ocular surface inflammation.
explanation: >-
The treatment actually given in a case followed for seven years.
- reference: PMID:39278528
reference_title: "Long-term follow-up of ocular involvement in hereditary mucoepithelial dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
With appropriate management and close follow-up over 7 years, corneal
opacity improved greatly.
explanation: >-
The outcome of that management, which is the reason to treat aggressively
rather than observe.
- name: Topical corticosteroid for vascularizing keratitis
description: >-
Partially effective for the keratitis specifically. Worth distinguishing from
the general ocular surface care above, because the keratitis relapses - it
waxed and waned over five years in the reported infants - so this is episodic
treatment of a recurrent inflammatory event, not maintenance therapy.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: topical corticosteroid
term:
id: NCIT:C29505
label: Topical Corticosteroid
target_phenotypes:
- preferred_term: Corneal neovascularization
term:
id: HP:0011496
label: Corneal neovascularization
evidence:
- reference: PMID:37699567
reference_title: "Recurrent Vascularizing Keratitis in Infants With Hereditary Mucoepithelial Dysplasia Related to SREBF1 Mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The keratitis partially regressed in response to topical corticosteroids
and waxed and waned during the 5 years of follow-up.
explanation: >-
Reports both the partial response and the relapsing course, which together
define how this treatment is used.
- name: Systemic acitretin
description: >-
An oral retinoid for the cutaneous hyperkeratosis. The evidence is a single
case treated before molecular subtyping existed, so it speaks to IFAP
syndrome as a clinical entity rather than to the SREBF1 form specifically -
and its result is as useful for what it did not do as for what it did:
cutaneous features and corneal erosions improved, alopecia and photophobia
did not. A family should be told that in advance.
action_category: THERAPEUTIC
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: Follicular hyperkeratosis
term:
id: HP:0007502
label: Follicular hyperkeratosis
evidence:
- reference: PMID:16268889
reference_title: "Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
A moderate response to acitretin therapy (1 mg/kg) administered for 6
months was observed, with improvement in cutaneous features and corneal
erosions and no change in alopecia or photophobia.
explanation: >-
The dose, the duration and the partial response, including the features
that did not improve. Indirect: the patient was diagnosed clinically in
2005, before SREBF1 was implicated, so the genetic form is not established.
- name: Genetic counseling
description: >-
Autosomal dominant with documented parent-to-child transmission, so the
offspring risk for an affected person is 50% - a different conversation from
the X-linked form, and the practical reason the two must be separated
molecularly. Expressivity within a family is wide: a reported father and
daughter differed substantially in the distribution and severity of their
skin disease.
action_category: COUNSELING_INFORMATIONAL
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:32902915
reference_title: "Exome sequencing identifies a SREBF1 recurrent ARG557CYS mutation as the cause of hereditary mucoepithelial dysplasia in a family with high clinical variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical expression showed significant differences in affected subjects,
especially in the distribution and severity of skin lesions.
explanation: >-
The intrafamilial variability that counselling has to convey: the same
variant does not predict the same severity.
discussions:
- discussion_id: ifap2_hmd_lumping
kind: CONTROVERSY
status: OPEN
prompt: >-
Are SREBF1-related IFAP syndrome and hereditary mucoepithelial dysplasia one
disease with variable expressivity, and should dismech curate them as one
entry?
attaches_to:
- "disease#IFAP Syndrome 2"
- "differential_diagnoses#Hereditary mucoepithelial dysplasia"
rationale: >-
The case for lumping is strong and was made formally rather than
impressionistically. Both conditions are caused by the same recurrent SREBF1
variant. A 2026 series applied the ClinGen lumping-and-splitting criteria and
concluded the two are favoured to be one condition, proposing a unifying
name. Its four patients carried the IFAP label but had the gastrointestinal
manifestations previously described only under the HMD label, which is the
kind of observation that dissolves a split rather than just noting overlap.
Earlier literature had already recorded that the two share a common clinical
spectrum, before anyone knew they shared a variant.
So why is this entry still IFAP syndrome 2?
Because MONDO maintains two terms, and dismech binds to MONDO. Asserting
exactMatch between MONDO:0100221 and MONDO:0008017 would retire a MONDO
concept from the curation queue on the strength of one four-patient series,
which is a decision for the ontology rather than for a KB entry. The mapping
here is therefore skos:closeMatch, which records the relationship without
claiming the identity is settled.
What would settle it: MONDO merging or explicitly relating the two terms, or
a larger series establishing that the phenotypic range is continuous rather
than bimodal. What would complicate it: evidence that the non-hotspot alleles
- the c.1670G>A cases with psoriasiform disease and no photophobia - form a
third group rather than sitting inside one continuum.
The practical consequence for anyone using this entry is immediate and
independent of how the naming resolves. Roughly half the clinical literature
on this disease, including nearly all of the ocular natural-history work, is
published under the HMD name. Searching one name finds half the evidence.
- discussion_id: ifap2_apoptosis_versus_keratinization
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does increased keratinocyte apoptosis contribute independently to the hair
loss, or is it a consequence of the same keratinization failure?
attaches_to:
- "pathophysiology#Keratinocyte Apoptosis"
- "pathophysiology#Failure of Follicular Keratinization"
rationale: >-
The founding paper reports two findings in the same scalp biopsies -
collapsed outer-root-sheath keratin transcription, and raised in situ
keratinocyte apoptosis - and proposes that the apoptosis might contribute to
the hyperkeratosis and hypotrichosis. Might is the operative word, and this
entry keeps it.
The distinction is not academic. If the follicle fails structurally because
it cannot make its keratins, the target for any future therapy is lipid or
keratin supply. If cells are additionally dying, an anti-apoptotic or
barrier-protective approach is a separate lever. And the two predict
different things about the cyclical hair loss documented in some patients: a
purely structural defect predicts hair that grows and breaks, while cell
death predicts follicles that are progressively lost.
Nothing currently separates them. Both observations come from the same
cross-sectional biopsy set, with no time course, no isogenic comparison and
no manipulation. There is also no published cell or animal model of the
cleavage-site allele - unlike IFAP syndrome 1, where a complementation assay
exists - so the question cannot currently be asked experimentally in a system
that carries the disease variant.
proposed_experiments:
- experiment_id: ifap2_keratinocyte_apoptosis_versus_keratin_failure
name: Time-resolved keratinization and apoptosis in SREBF1-variant keratinocytes
description: >-
Introduce the recurrent cleavage-site variant into human keratinocytes or
hair-follicle organoids by genome editing, and compare against isogenic
controls for outer-root-sheath keratin expression, cornification, and
apoptotic index over a differentiation time course, with and without
exogenous cholesterol or fatty acid supplementation.
would_support:
- "pathophysiology#Keratinocyte Apoptosis"
- "pathophysiology#Failure of Follicular Keratinization"
supporting_outcome:
- >-
Apoptosis rises before or independently of the keratin transcriptional
deficit, indicating a separate arm rather than a downstream consequence.
- >-
Lipid supplementation rescues keratin expression while leaving the
apoptotic index unchanged, which would separate the two arms
pharmacologically.
refuting_outcome:
- >-
Apoptosis appears only after and in proportion to the keratinization
failure, and both are rescued together by lipid supplementation, which
would make the apoptosis a readout of the same lesion rather than an
independent mechanism.
notes: >-
Naming and searching. This disease is in the literature under at least three
names: IFAP syndrome 2 or autosomal dominant IFAP syndrome, SREBF1-related
IFAP, and hereditary mucoepithelial dysplasia. The ocular natural history - the
vascularizing keratitis, the meibomian gland dysfunction, the long-term corneal
outcomes - is published almost entirely under the HMD name, while the molecular
work is under the IFAP name. A 2026 series proposed a unifying name, which has
not yet been adopted by the ontologies.
Variant coordinates. The recurrent allele appears as both c.1669C>T p.Arg557Cys
and c.1579C>T p.Arg527Cys, against different transcripts. They are the same
change; see the genetic section.
Relationship to IFAP syndrome 1. Curated as a separate entry rather than a
subtype because the gene, the inheritance pattern and the counselling differ,
even though the two lesions sit one step apart in a single proteolytic cascade.
The mechanistic parallel is recorded in the pathophysiology description and in
the IFAP syndrome 1 differential.
review_notes: >-
Deliberate omissions. No prevalence record: the disorder has a few dozen
published cases across both names and no epidemiological estimate exists, so no
rarity band is asserted. No experimental or animal models section: unlike IFAP
syndrome 1, no cell or animal model carrying a cleavage-site SREBF1 variant has
been published, and the functional work is transient transfection reported
inside the founding paper, which is curated as evidence on the pathophysiology
nodes rather than as a model entry.
Frequencies are given only where the founding cohort or a review states them
qualitatively. Per-feature counts out of the 11-patient cohort circulate in
secondary sources but are not in any abstract cached here, so they are not
asserted.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: IFAP Syndrome 2 (SREBF1-related, autosomal dominant) · 2026-09-02T11:09:33Z · View source
De novo curation of IFAP syndrome 2 (MONDO:0100221) from primary literature plus a claude_code deep-research report (falcon was requested but returned HTTP 402, so the run fell back and the report is named for claude_code). The report's term-validation section flagged 13 CURIEs as naming a different term than the report claimed - among them HP:0100708 for meibomian gland dysfunction, which HPO calls Abnormal microglia morphology, and UBERON:0006238 for meibomian gland, which UBERON calls future brain - so none of its ontology suggestions were copied across; every binding here was resolved independently via OLS. HPO has no meibomian gland dysfunction term, so that phenotype is bound to HP:0025610 Posterior blepharitis with the precise entity in preferred_term. Pathophysiology runs from the SREBF1 site-1 cleavage-site variant through blocked proteolytic activation and reduced nuclear SREBP1 output, forking into follicular keratinization failure, keratinocyte apoptosis, and meibomian gland lipid synthesis failure leading to ocular surface disease. The hereditary mucoepithelial dysplasia lumping question is recorded as a CONTROVERSY discussion with a skos:closeMatch mapping to MONDO:0008017 rather than an exactMatch, since MONDO still maintains both terms. Half the clinical literature for this disease is published under the HMD name, which is recorded in notes. Validated with just validate (schema, terms, 48/48 snippets verified against cached references) plus the same gate suite as the sibling entry in this run.
Overview. IFAP syndrome 2 (IFAP2) is one of two known genetic forms of Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP) syndrome, a rare ectodermal dysplasia/syndromic ichthyosis characterized by the classic triad of non-inflammatory follicular hyperkeratosis (ichthyosis follicularis), congenital or near-congenital hair loss (atrichia/hypotrichosis), and photophobia with corneal disease. Unlike the originally described X-linked form (IFAP syndrome 1, caused by MBTPS2 mutations), IFAP2 is autosomal dominant, caused by heterozygous, largely de novo missense/small in-frame deletion variants in SREBF1 (Sterol Regulatory Element Binding Transcription Factor 1), reported in 2020 by Wang et al. (PMID: 32497488) — "Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome," American Journal of Human Genetics.
Key identifiers: - OMIM: #619016 — IFAP SYNDROME 2; IFAP2 (gene: SREBF1, 184756, chr 17p11.2) - MONDO: MONDO:0100221 (IFAP syndrome 2); parent term MONDO:0100212 (IFAP syndrome, general) - Orphanet: ORPHA2273 (IFAP syndrome, umbrella entry covering both molecular subtypes) - MedGen: C5436607 - GTR: C5436607 - Distinguish from IFAP syndrome 1 (OMIM #308205, X-linked, MBTPS2) and BRESHECK syndrome (a severe MBTPS2-allelic disorder with additional CNS/skeletal/genital anomalies)
Synonyms: Ichthyosis follicularis–atrichia–photophobia syndrome, type 2; autosomal-dominant IFAP syndrome; SREBF1-related IFAP syndrome.
Evidence basis: This is aggregated disease-level knowledge derived from a founding molecular-genetics cohort study (11 unrelated individuals, 2 families + 9 simplex cases) plus subsequent single-patient/small case-series reports — not large-scale EHR/registry data, reflecting the extreme rarity of the condition (well under 100 reported IFAP2 cases worldwide as of 2025).
Causal factor: Purely monogenic/genetic. Heterozygous missense substitutions or small in-frame deletions in SREBF1 disrupt site-1-protease (S1P) recognition and cleavage of the SREBP1 transcription factor, producing a dominant loss-of-function/dominant-negative effect on SREBP-target lipogenic and keratinization gene programs (PMID: 32497488).
Genetic risk factors: - Virtually all reported pathogenic variants cluster in a 4-residue hotspot (residues 527–530) forming the arginine-X-X-leucine (RXXL) S1P recognition motif of SREBP1: - c.1579C>T, p.Arg527Cys — the dominant recurrent variant, found in 9 of 11 individuals (82%) in the founding cohort, arising independently (mostly de novo, confirmed segregating in two families) - c.1582_1584del, p.Asn528del — 2/11 individuals, segregated in Family 1 - c.1589T>C, p.Leu530Pro — 1/11 individuals, confirmed de novo - Additional variants reported subsequently: p.Arg557Cys (chr17:17720597G>A, Ambarchyan et al. 2024, de novo, confirmed absent in both parents) and c.1670G>A (associated with an atypical phenotype lacking photophobia; Zhu et al., PMID: 39912473) - All founding-cohort variants were absent from gnomAD and ExAC, and the key residues (Arg527, Leu530) are highly conserved across species — consistent with pathogenicity (PMID: 32497488). - Inheritance: Autosomal dominant, predominantly arising as de novo mutations in simplex cases, though vertical transmission was documented within two multigenerational families in the founding study (mother-daughter pairs, both surviving to adulthood, indicating compatibility with reproduction and non-lethality of the heterozygous state).
Environmental/other risk factors: None identified — no epidemiological or toxin/exposure association has been reported; this is a purely Mendelian condition.
Protective factors: None reported in the literature.
Gene-environment interactions: Not established; disease expression appears driven by the germline variant itself rather than by environmental modifiers, though phenotypic severity (e.g., presence/absence of photophobia, degree of skin plaque involvement) varies even among carriers of the same recurrent variant (p.Arg527Cys), suggesting stochastic or unidentified modifying factors.
Phenotype data below are drawn from the founding 11-patient cohort (PMID: 32497488) and subsequent case reports (Ambarchyan et al. 2024; Zhu et al. 2025, PMID: 39912473; Zhu et al. 2025 meibum study, PMID: 40778116).
| Phenotype | HPO suggestion | Frequency/notes |
|---|---|---|
| Ichthyosis follicularis / follicular hyperkeratosis | HP:0007431 (Ichthyosis follicularis, atrichia, photophobia) or HP:0100637 (follicular hyperkeratosis) | Present in essentially all patients; onset soon after birth |
| Lamellar-ichthyosis-like scaling (alternative presentation) | HP:0007431 | Some patients present with lamellar rather than purely follicular scale, with/without psoriasiform plaques |
| Psoriasiform / hyperkeratotic plaques, extremities | HP:0007550 (or HP:0031059 psoriasiform dermatitis) | Onset early childhood; one atypical variant (c.1670G>A) produces severe psoriasis-like plaques limited to extensor lower limbs, with IL-17A/S100A8 upregulation on immunohistochemistry |
| Nail dystrophy | HP:0008404 | Reported in cohort |
| Periorificial erythema, angular cheilitis | HP:0100025 (angular cheilitis) | Reported |
| Phenotype | HPO suggestion | Frequency |
|---|---|---|
| Congenital/near-congenital atrichia (complete) | HP:0002298 (atrichia) | 5/11 patients |
| Moderate–severe hypotrichosis (sparse, thin hair) | HP:0000966 | 4/11 patients |
| Hair depigmentation with caliber variation | HP:0011364 (hair shaft abnormality) | 1/11 patients |
| Trichorrhexis nodosa (hair shaft defect on SEM) | HP:0012207 | Cuticle warping/detachment documented by scanning electron microscopy |
| Eyebrow/eyelash/axillary/pubic hair loss | HP:0009806 (sparse eyebrow), HP:0000653-adjacent | Multi-site involvement |
| Phenotype | HPO suggestion | Frequency |
|---|---|---|
| Photophobia | HP:0000613 | Nearly universal (though notably absent in the atypical c.1670G>A cases) |
| Meibomian gland dysfunction | HP:0100708 (Meibomian gland dysfunction) | 10/11 patients; lipidomic study (PMID: 40778116) links abnormal meibum composition directly to defective SREBP1-driven lipogenesis |
| Punctate corneal epithelial defects | HP:0008058 | Common |
| Corneal pannus / progressive corneal opacification | HP:0007957 (corneal neovascularization) | Severe cases can progress to vision loss |
| Cataract (complicated) | HP:0000518 | 9/11 patients; childhood onset |
LOSS_OF_FUNCTION or DOMINANT_NEGATIVE).Suggested ontology terms: HGNC:11289 (SREBF1); GO:0032933 (SREBP signaling pathway); GO:0016126 (sterol biosynthetic process); GO:0006695 (cholesterol biosynthetic process); GO:0045543 (regulation of fatty acid biosynthetic process).
No environmental, lifestyle, or infectious contributing factors have been identified or reported for IFAP2 — it is a purely germline monogenic disorder. No gene-environment interaction data exist.
Ordered causal chain:
Molecular pathways: SREBP/SCAP/Insig sterol-sensing pathway (KEGG/Reactome: SREBP signaling); under sterol-replete conditions SCAP-SREBP is retained in the ER by Insig; upon sterol depletion, the SCAP-SREBP complex traffics via COPII vesicles to the Golgi where sequential S1P then S2P cleavage releases the active nuclear transcription factor — the step disrupted in IFAP2 is the S1P cleavage step (the analogous S2P step is disrupted in X-linked IFAP1/MBTPS2, making IFAP1 and IFAP2 mechanistically parallel/convergent disorders of the same proteolytic cascade).
Cellular processes: epidermal differentiation, cornification, hair follicle keratinization, sebocyte/meibocyte lipogenesis, keratinocyte apoptosis.
Protein dysfunction: SREBP1 loss-of-function via blocked intramembrane proteolysis (a "regulated intramembrane proteolysis," RIP, defect), analogous mechanistically to MBTPS2-related IFAP1/BRESHECK/keratosis follicularis spinulosa decalvans.
Tissue damage mechanisms: lipid-deficiency-driven barrier dysfunction (skin, meibomian gland), chronic follicular keratin plugging, oxidative/apoptotic keratinocyte stress.
Suggested GO terms: GO:0032933 (SREBP signaling pathway); GO:0006694 (steroid biosynthetic process); GO:0044255 (cellular lipid metabolic process); GO:0031424 (keratinization); GO:0008544 (epidermis development); GO:0006915 (apoptotic process). Suggested CL terms: CL:0000312 (keratinocyte); CL:1000428 (outer root sheath cell of hair follicle, if available) or hair follicle-associated keratinocyte; CL:0002261 (sebaceous gland cell, for meibocyte-analog reasoning).
Suggested UBERON terms: UBERON:0001003 (skin epidermis); UBERON:0002073 (hair follicle); UBERON:0006238 (meibomian gland); UBERON:0000964 (cornea); UBERON:0000965 (lens of camera-type eye).
ULTRA_RARE/NOT_YET_DOCUMENTED.Suggested NCIT/LOINC/diagnostic-workflow terms: NCIT:C15709 (Genetic Testing); a WES-based diagnostic term is most appropriate given no single confirmatory lab biomarker exists.
No disease-modifying or curative therapy exists; management is symptomatic and multidisciplinary (dermatology + ophthalmology), extrapolated largely from broader IFAP-syndrome and ichthyosis management literature (much of it published for IFAP1/MBTPS2 cases, but applied analogously to IFAP2):
therapeutic_agent under a treatment_term of NCIT:C15986 (Pharmacotherapy).HUMAN_MODEL_MISMATCH consideration for future curation: no animal model has yet been shown to recapitulate the specific S1P-cleavage-resistant IFAP2 allele).| Citation | Type | Key contribution |
|---|---|---|
| Wang X et al., Am J Hum Genet 2020 (PMID: 32497488) | Human clinical + in vitro functional + transcriptomic | Founding description of SREBF1-related IFAP2: 11 patients, 3 hotspot variants, functional cleavage/nuclear-translocation/reporter assays, scalp RNA-seq, histopathology, TUNEL apoptosis data |
| Ambarchyan et al., Current Pediatrics 2024 | Human clinical case report | Novel p.Arg557Cys de novo variant in a 2-year-old girl; WES-based diagnosis |
| Zhu et al., 2025 (PMID: 39912473) | Human clinical, IHC | c.1670G>A variant causing atypical, photophobia-negative, psoriasiform-predominant phenotype; IL-17A/S100A8 immunohistochemistry |
| Zhu et al., 2025 medRxiv (PMID: 40778116) | Human clinical, lipidomics | Meibum lipid abnormality directly linked to SREBF1 mutation/IFAP2 ocular phenotype |
| OMIM #619016 | Curated clinical synopsis/database | Canonical disease/gene identifiers and clinical synopsis |
| PMID: 16268889 | Human clinical (IFAP syndrome, not variant-specified) | Acitretin treatment response data |
Notable data gaps for KB curation: no formal prevalence estimate; no IFAP2-specific animal model; no disease-specific quality-of-life instrument data; no completed or ongoing clinical trials (NCT) specific to IFAP2; mechanistic link between the apoptosis finding and hyperkeratosis/hypotrichosis phenotype is explicitly stated by the primary authors as associative rather than causally demonstrated; the c.1670G>A "atypical/psoriasiform" phenotype's relationship to the canonical lipogenic-deficiency mechanism is unresolved and would be a good candidate for a HUMAN_MODEL_MISMATCH/knowledge-gap discussion node if curated into dismech.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 5 |
| Resolved | 5 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 5 |
| On topic | 3 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 45 |
| Resolved | 41 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 2 |
| Unverifiable | 2 |
| Terms whose name was checked | 38 |
| Terms named correctly | 20 |
| Terms named as a different term | 13 |
| Terms whose name is worth a second look | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0007431 (2 mentions) - the report calls it "Lamellar-ichthyosis-like scaling (alternative presentation)"; HP calls it Congenital ichthyosiform erythrodermaHP:0100025 (1 mention) - the report calls it "angular cheilitis"; HP calls it OverfriendlinessHP:0002298 (1 mention) - the report calls it "atrichia"; HP calls it Absent hairHP:0000966 (1 mention) - the report calls it "Moderate–severe hypotrichosis (sparse, thin hair)"; HP calls it HypohidrosisHP:0011364 (1 mention) - the report calls it "hair shaft abnormality"; HP calls it White hairHP:0012207 (1 mention) - the report calls it "Trichorrhexis nodosa (hair shaft defect on SEM)"; HP calls it Reduced sperm motilityHP:0100708 (1 mention) - the report calls it "Meibomian gland dysfunction"; HP calls it Abnormal microglia morphologyHP:0008058 (1 mention) - the report calls it "Punctate corneal epithelial defects"; HP calls it Aplasia/Hypoplasia of the optic nerveGO:0045543 (1 mention) - the report calls it "regulation of fatty acid biosynthetic process"; GO calls it gibberellin 2-beta-dioxygenase activityCL:1000428 (1 mention) - the report calls it "outer root sheath cell of hair follicle, if available"; CL calls it stem cell of epidermisCL:0002261 (1 mention) - the report calls it "sebaceous gland cell, for meibocyte-analog reasoning"; CL calls it endothelial cell of viscerocranial mucosaUBERON:0006238 (1 mention) - the report calls it "meibomian gland"; UBERON calls it future brainNCIT:C61004 (1 mention) - the report calls it "Acitretin"; NCIT calls it Tablet for Solution Dosage FormThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
HP:0100637 (obsolete Neoplasia of the nose) (1 mention) - replaced by HP:0012720GO:0044255 (obsolete cellular lipid metabolic process) (1 mention) - replaced by GO:0006629The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
MONDO:0100212 (1 mention) - the report calls it "IFAP syndrome, general"; MONDO calls it IFAP syndromeHP:0007957 (1 mention) - the report calls it "corneal neovascularization"; HP calls it Corneal opacity, and lists "Corneal opacities" among its other namesHP:0000518 (1 mention) - the report calls it "Cataract (complicated)"; HP calls it CataractGO:0044255 (1 mention) - the report calls it "cellular lipid metabolic process"; GO calls it obsolete cellular lipid metabolic processGO:0005783 (1 mention) - the report calls it "endoplasmic reticulum, site of SCAP-SREBP1 pre-processing"; GO calls it endoplasmic reticulumTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.