Ichthyosis prematurity syndrome

Summary

Ichthyosis prematurity syndrome (MONDO:0012089) is a disease caused by SLC27A4 (GenCC Definitive), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include etanercept.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC27A4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 38
• Phenotypes (HPO): 5
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0001622	Premature birth	Very frequent (80-99%)
HP:0001880	Eosinophilia	Very frequent (80-99%)
HP:0002643	Neonatal respiratory distress	Very frequent (80-99%)
HP:0007549	Desquamation of skin soon after birth	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ichthyosis prematurity syndrome
Mondo ID	MONDO:0012089
MeSH	C536271
OMIM	608649
Orphanet	88621
NCIT	C62590
SNOMED CT	12381000132107
UMLS	C1837610
MedGen	324839
GARD	0009886
Is cancer (heuristic)	no

Also known as: congenital ichthyosis type 4 · ichthyosis congenita IV · ichthyosis prematurity syndrome · idiopathic pneumonia syndrome · IPS

Data availability: 38 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › ichthyosis prematurity syndrome

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, autosomal dominant deafness - onychodystrophy syndrome, keratoderma hereditarium mutilans, Rombo syndrome, Sjogren-Larsson syndrome, mucosulfatidosis, ANE syndrome, frontonasal dysplasia with alopecia and genital anomaly, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

38 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 10 likely pathogenic, 9 pathogenic, 6 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1171020	NM_005094.4(SLC27A4):c.1208G>A (p.Cys403Tyr)	SLC27A4	Pathogenic	no assertion criteria provided
1171021	NM_005094.4(SLC27A4):c.1529G>A (p.Arg510His)	SLC27A4	Pathogenic	no assertion criteria provided
1171022	NM_005094.4(SLC27A4):c.1322dup (p.Gly442fs)	SLC27A4	Pathogenic	criteria provided, single submitter
1171023	NM_005094.4(SLC27A4):c.988-19A>G	SLC27A4	Pathogenic	no assertion criteria provided
156253	NM_005094.4(SLC27A4):c.1504C>T (p.Arg502Ter)	SLC27A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686197	NM_005094.4(SLC27A4):c.1065del (p.Arg356fs)	SLC27A4	Pathogenic	criteria provided, multiple submitters, no conflicts
2052115	NM_005094.4(SLC27A4):c.1430T>A (p.Val477Asp)	SLC27A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735354	NM_005094.4(SLC27A4):c.1A>G (p.Met1Val)	SLC27A4	Pathogenic	criteria provided, multiple submitters, no conflicts
3254621	NM_005094.4(SLC27A4):c.871_877+19del	SLC27A4	Pathogenic	criteria provided, single submitter
5742	NM_005094.4(SLC27A4):c.504C>A (p.Cys168Ter)	SLC27A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5744	NM_005094.4(SLC27A4):c.274G>A (p.Ala92Thr)	SLC27A4	Pathogenic	no assertion criteria provided
5746	NM_005094.4(SLC27A4):c.899A>G (p.Gln300Arg)	SLC27A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5747	NM_005094.4(SLC27A4):c.988-2A>G	SLC27A4	Pathogenic	no assertion criteria provided
802517	NM_005094.4(SLC27A4):c.1799_1800del (p.Glu600fs)	SLC27A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810428	NM_005094.4(SLC27A4):c.1447C>T (p.Gln483Ter)	SLC27A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2750485	NM_005094.4(SLC27A4):c.1628-1G>A	SLC27A4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062255	NM_005094.4(SLC27A4):c.839A>T (p.Asp280Val)	SLC27A4	Likely pathogenic	criteria provided, single submitter
3596461	NM_005094.4(SLC27A4):c.28dup (p.Val10fs)	SLC27A4	Likely pathogenic	criteria provided, single submitter
3596462	NM_005094.4(SLC27A4):c.199C>T (p.Arg67Ter)	SLC27A4	Likely pathogenic	criteria provided, single submitter
3596463	NM_005094.4(SLC27A4):c.786-2A>G	SLC27A4	Likely pathogenic	criteria provided, single submitter
3596464	NM_005094.4(SLC27A4):c.898C>T (p.Gln300Ter)	SLC27A4	Likely pathogenic	criteria provided, single submitter
3596465	NM_005094.4(SLC27A4):c.1579dup (p.Arg527fs)	SLC27A4	Likely pathogenic	criteria provided, single submitter
5743	NM_005094.4(SLC27A4):c.716-1G>A	SLC27A4	Likely pathogenic	criteria provided, single submitter
802516	NM_005094.4(SLC27A4):c.1523C>T (p.Thr508Met)	SLC27A4	Likely pathogenic	criteria provided, single submitter
978727	NM_005094.4(SLC27A4):c.1511G>T (p.Arg504Leu)	SLC27A4	Likely pathogenic	criteria provided, single submitter
1368194	NM_005094.4(SLC27A4):c.986C>T (p.Thr329Met)	SLC27A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2436009	NM_005094.4(SLC27A4):c.1510C>T (p.Arg504Cys)	SLC27A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2385751	NM_005094.4(SLC27A4):c.1413G>C (p.Lys471Asn)	SLC27A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2436008	NM_005094.4(SLC27A4):c.868C>T (p.His290Tyr)	SLC27A4	Uncertain significance	criteria provided, single submitter
2585313	NM_005094.4(SLC27A4):c.166G>A (p.Gly56Ser)	SLC27A4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC27A4	Definitive	Autosomal recessive	ichthyosis prematurity syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC27A4	Orphanet:88621	Ichthyosis-prematurity syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC27A4	HGNC:10998	ENSG00000167114	Q6P1M0	Long-chain fatty acid transport protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC27A4	Long-chain fatty acid transport protein 4	Mediates the levels of long-chain fatty acids (LCFA) in the cell by facilitating their transport across cell membranes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC27A4	Enzyme (other)	yes	6.2.1.3	AMP-dep_synth/lig_dom, AMP-binding_CS, Lipocalin_CS

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
lower esophagus mucosa	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC27A4	219	ubiquitous	yes	mucosa of transverse colon, lower esophagus mucosa, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC27A4	2,199

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC27A4	Q6P1M0	90.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC27A4 causes ichthyosis prematurity syndrome (IPS)	1	11420.0×	7e-04	SLC27A4
Transport of fatty acids	1	1427.5×	0.003	SLC27A4
Transport of vitamins, nucleosides, and related molecules	1	271.9×	0.010	SLC27A4
SLC transporter disorders	1	203.9×	0.010	SLC27A4
Disorders of transmembrane transporters	1	139.3×	0.011	SLC27A4
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC27A4
Transport of small molecules	1	25.1×	0.045	SLC27A4
Disease	1	13.1×	0.076	SLC27A4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
medium-chain fatty acid transport	1	8426.0×	0.002	SLC27A4
lipid transport across blood-brain barrier	1	3370.4×	0.002	SLC27A4
glucose import in response to insulin stimulus	1	2808.7×	0.002	SLC27A4
very long-chain fatty acid catabolic process	1	2407.4×	0.002	SLC27A4
long-chain fatty acid import into cell	1	1685.2×	0.002	SLC27A4
long-chain fatty acid transport	1	1123.5×	0.002	SLC27A4
long-chain fatty acid metabolic process	1	624.1×	0.003	SLC27A4
fatty acid transport	1	624.1×	0.003	SLC27A4
skin development	1	443.5×	0.004	SLC27A4
negative regulation of insulin receptor signaling pathway	1	374.5×	0.004	SLC27A4
response to nutrient	1	295.6×	0.005	SLC27A4
fatty acid metabolic process	1	193.7×	0.006	SLC27A4
transport across blood-brain barrier	1	179.3×	0.006	SLC27A4
establishment of localization in cell	1	160.5×	0.007	SLC27A4
positive regulation of apoptotic process	1	56.7×	0.018	SLC27A4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC27A4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC27A4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SLC27A4	6.2.1.3	long-chain-fatty-acid-CoA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SLC27A4
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC27A4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00421174	PHASE3	COMPLETED	Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation (BMT CTN 0403)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ETANERCEPT	4	1