Hypotrichosis simplex

Summary

Hypotrichosis simplex (MONDO:0018914) is a disease (an umbrella term covering 8 Mondo subtypes) with 9 cohort genes and 1 clinical trial. Top therapeutic interventions include gentamicin sulfate.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 9
• ClinVar variants: 3
• Phenotypes (HPO): 6
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		38	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000653	Sparse eyelashes	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0002209	Sparse scalp hair	Very frequent (80-99%)
HP:0002231	Sparse body hair	Very frequent (80-99%)
HP:0045075	Sparse eyebrow	Very frequent (80-99%)
HP:0008070	Sparse hair	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypotrichosis simplex
Mondo ID	MONDO:0018914
MeSH	C537160
Orphanet	55654
SNOMED CT	723362004
UMLS	C1854310
MedGen	344257
GARD	0009170
Is cancer (heuristic)	no

Also known as: hereditary hypotrichosis simplex

Data availability: 3 ClinVar variants · 7 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › disorder of pilosebaceous unit › hair anomaly › alopecia › hypotrichosis simplex

Related subtypes (25): alopecia, isolated, telogen effluvium, alopecia areata, chemotherapy-induced alopecia, alopecia mucinosa, atrichia with papular lesions, loose anagen syndrome, Satoyoshi syndrome, alopecia-intellectual disability-hypergonadotropic hypogonadism syndrome, hereditary hypotrichosis with recurrent skin vesicles, alopecia antibody deficiency, pseudopelade of Brocq, frontal fibrosing alopecia, Quinquaud’s folliculitis decalvans, Graham Little-Piccardi-Lassueur syndrome, lichen planopilaris, alopecia totalis, hypotrichosis simplex of the scalp, endocrine alopecia, alopecia universalis onychodystrophy vitiligo, central centrifugal cicatricial alopecia, ectodermal dysplasia alopecia preaxial polydactyly, Slti-Salem syndrome, microcephaly sparse hair intellectual disability seizures, alopecia universalis

Subtypes (8): hypotrichosis 8, hypotrichosis 7, hypotrichosis 1, hypotrichosis 6, hypotrichosis 9, hypotrichosis 10, hypotrichosis 11, hypotrichosis 12

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1687039	NM_001793.6(CDH3):c.665_666dup (p.Ser223fs)	CDH3	Pathogenic	no assertion criteria provided
16792	NM_000400.4(ERCC2):c.2164C>T (p.Arg722Trp)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
225403	NM_139248.3(LIPH):c.736T>A (p.Cys246Ser)	LIPH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 19 · 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
DSG4	Definitive	Autosomal recessive	hypotrichosis 6	5
LIPH	Definitive	Autosomal recessive	hypotrichosis 7	5
APCDD1	Strong	Autosomal dominant	hypotrichosis 1	4
LPAR6	Strong	Autosomal recessive	hypotrichosis 8	6
LSS	Strong	Autosomal recessive	hypotrichosis 14	11
RPL21	Strong	Autosomal dominant	hypotrichosis 12	4
SNRPE	Strong	Autosomal dominant	hypotrichosis 11	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LIPH	Orphanet:170	Woolly hair
LIPH	Orphanet:55654	Hypotrichosis simplex
RPL21	Orphanet:55654	Hypotrichosis simplex
SNRPE	Orphanet:55654	Hypotrichosis simplex
LPAR6	Orphanet:170	Woolly hair
LPAR6	Orphanet:55654	Hypotrichosis simplex
APCDD1	Orphanet:55654	Hypotrichosis simplex
DSG4	Orphanet:55654	Hypotrichosis simplex
DSG4	Orphanet:573	Monilethrix
LSS	Orphanet:1366	Autosomal recessive palmoplantar keratoderma and congenital alopecia
LSS	Orphanet:2850	Alopecia-intellectual disability syndrome
LSS	Orphanet:55654	Hypotrichosis simplex
LSS	Orphanet:98994	Total early-onset cataract
CDH3	Orphanet:1573	Hypotrichosis with juvenile macular degeneration
CDH3	Orphanet:1897	EEM syndrome
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LIPH	HGNC:18483	ENSG00000163898	Q8WWY8	Lipase member H	gencc,clinvar
RPL21	HGNC:10313	ENSG00000122026	P46778	Large ribosomal subunit protein eL21	gencc
SNRPE	HGNC:11161	ENSG00000182004	P62304	Small nuclear ribonucleoprotein E	gencc
LPAR6	HGNC:15520	ENSG00000139679	P43657	Lysophosphatidic acid receptor 6	gencc
APCDD1	HGNC:15718	ENSG00000154856	Q8J025	Protein APCDD1	gencc
DSG4	HGNC:21307	ENSG00000175065	Q86SJ6	Desmoglein-4	gencc
LSS	HGNC:6708	ENSG00000160285	P48449	Lanosterol synthase	gencc
CDH3	HGNC:1762	ENSG00000062038	P22223	Cadherin-3	clinvar
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIPH	Lipase member H	Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid.
RPL21	Large ribosomal subunit protein eL21	Component of the large ribosomal subunit.
SNRPE	Small nuclear ribonucleoprotein E	Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome.
LPAR6	Lysophosphatidic acid receptor 6	Binds to oleoyl-L-alpha-lysophosphatidic acid (LPA).
APCDD1	Protein APCDD1	Negative regulator of the Wnt signaling pathway.
DSG4	Desmoglein-4	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
LSS	Lanosterol synthase	Key enzyme in the cholesterol biosynthesis pathway.
CDH3	Cadherin-3	Cadherins are calcium-dependent cell adhesion proteins.
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.44

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)	3	4.0×	0.133
GPCR	1	2.7×	0.553
Scaffold/PPI	1	1.9×	0.553
Other/Unknown	4	0.8×	0.847

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LIPH	Enzyme (other)	yes	3.1.1.32	TAG_lipase, Lipase, Lipase_LIPH
RPL21	Scaffold/PPI	no		Ribosomal_eL21, Translation_prot_SH3-like_sf, Ribosomal_eL21_CS
SNRPE	Other/Unknown	no		Sm_dom_euk/arc, LSM_dom_sf, snRNP-E
LPAR6	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM
APCDD1	Other/Unknown	no		APCDD1_dom, APCDD1
DSG4	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin
LSS	Enzyme (other)	yes	5.4.99.7	Terpene_synthase_CS, Terpenoid_cyclase/PrenylTrfase, Squalene_cyclase
CDH3	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2

Expression context

Cohort genes with no expression data: 0.

9 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
buccal mucosa cell	1
pancreatic ductal cell	1
rectum	1
calcaneal tendon	1
embryo	1
cortical plate	1
ventricular zone	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
decidua	1
nipple	1
upper arm skin	1
esophagus mucosa	1
lower lobe of lung	1
male germ line stem cell (sensu Vertebrata) in testis	1
C1 segment of cervical spinal cord	1
mucosa of stomach	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LIPH	187	broad	marker	buccal mucosa cell, rectum, pancreatic ductal cell
RPL21	154	ubiquitous	marker	calcaneal tendon, embryo, ganglionic eminence
SNRPE	175	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate
LPAR6	269	ubiquitous	marker	gingival epithelium, gingiva, lower esophagus mucosa
APCDD1	249	broad	marker	upper arm skin, nipple, decidua
DSG4	24		marker	male germ line stem cell (sensu Vertebrata) in testis, esophagus mucosa, lower lobe of lung
LSS	134	ubiquitous	marker	mucosa of stomach, C1 segment of cervical spinal cord, skin of leg
CDH3	213	tissue_specific	marker	secondary oocyte, oocyte, mammary duct
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPL21	4,162
ERCC2	2,746
CDH3	1,749
DSG4	1,636
LSS	1,562
APCDD1	884
LPAR6	822
SNRPE	719
LIPH	635

Intra-cohort edges

A	B	Sources
APCDD1	LPAR6	string_interaction
DSG4	LIPH	string_interaction
DSG4	LPAR6	string_interaction
LIPH	LPAR6	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL21	P46778	194
SNRPE	P62304	84
ERCC2	P18074	51
CDH3	P22223	19
LPAR6	P43657	2
LSS	P48449	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LIPH	Q8WWY8	90.89
APCDD1	Q8J025	82.10
DSG4	Q86SJ6	65.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nucleotide-like (purinergic) receptors	1	237.9×	0.087	LPAR6
SLBP independent Processing of Histone Pre-mRNAs	1	142.8×	0.087	SNRPE
Cholesterol biosynthesis	1	142.8×	0.087	LSS
Processing of Capped Intronless Pre-mRNA	1	129.8×	0.087	SNRPE
SLBP Dependent Processing of Replication-Dependent Histone Pre-mRNAs	1	129.8×	0.087	SNRPE
P2Y receptors	1	119.0×	0.087	LPAR6
Cytosolic iron-sulfur cluster assembly	1	95.2×	0.087	ERCC2
Lanosterol biosynthesis	1	95.2×	0.087	LSS
Metabolism of non-coding RNA	1	79.3×	0.087	SNRPE
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	51.0×	0.087	ERCC2
RNA Pol II CTD phosphorylation and interaction with CE	1	51.0×	0.087	ERCC2
mRNA Capping	1	47.6×	0.087	ERCC2
Formation of the Early Elongation Complex	1	42.0×	0.087	ERCC2
Glycerophospholipid biosynthesis	1	42.0×	0.087	LIPH
Formation of the HIV-1 Early Elongation Complex	1	42.0×	0.087	ERCC2
RNA Polymerase I Transcription Termination	1	40.8×	0.087	ERCC2
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	39.6×	0.087	LSS
Synthesis of PA	1	36.6×	0.087	LIPH
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	33.2×	0.087	ERCC2
Formation of HIV-1 elongation complex containing HIV-1 Tat	1	32.4×	0.087	ERCC2
Tat-mediated elongation of the HIV-1 transcript	1	32.4×	0.087	ERCC2
Activation of gene expression by SREBF (SREBP)	1	32.4×	0.087	LSS
Dual Incision in GG-NER	1	32.4×	0.087	ERCC2
Formation of Incision Complex in GG-NER	1	31.7×	0.087	ERCC2
Formation of HIV elongation complex in the absence of HIV Tat	1	31.0×	0.087	ERCC2
Adherens junctions interactions	1	31.0×	0.087	CDH3
Cell-cell junction organization	1	31.0×	0.087	CDH3
HIV Transcription Initiation	1	29.1×	0.087	ERCC2
RNA Polymerase II HIV Promoter Escape	1	29.1×	0.087	ERCC2
RNA Polymerase II Promoter Escape	1	29.1×	0.087	ERCC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hair follicle maturation	2	468.1×	5e-04	CDH3, ERCC2
hair follicle development	2	85.1×	0.009	APCDD1, DSG4
triterpenoid biosynthetic process	1	1872.4×	0.010	LSS
negative regulation of timing of catagen	1	1872.4×	0.010	CDH3
positive regulation of mitotic recombination	1	936.2×	0.013	ERCC2
regulation of transport	1	936.2×	0.013	CDH3
homophilic cell-cell adhesion	2	31.2×	0.018	CDH3, DSG4
hair cycle process	1	312.1×	0.022	CDH3
central nervous system myelin formation	1	267.5×	0.022	ERCC2
regulation of odontogenesis of dentin-containing tooth	1	267.5×	0.022	APCDD1
astrocyte cell migration	1	267.5×	0.022	APCDD1
transcription elongation by RNA polymerase I	1	234.1×	0.022	ERCC2
hair cell differentiation	1	234.1×	0.022	ERCC2
7-methylguanosine cap hypermethylation	1	234.1×	0.022	SNRPE
embryonic cleavage	1	187.2×	0.024	ERCC2
regulation of mitotic cell cycle phase transition	1	187.2×	0.024	ERCC2
positive regulation of melanin biosynthetic process	1	156.0×	0.027	CDH3
transcription-coupled nucleotide-excision repair	1	133.8×	0.027	ERCC2
UV protection	1	133.8×	0.027	ERCC2
positive regulation of insulin-like growth factor receptor signaling pathway	1	133.8×	0.027	CDH3
retina homeostasis	1	124.8×	0.028	CDH3
positive regulation of keratinocyte proliferation	1	110.1×	0.030	CDH3
erythrocyte maturation	1	93.6×	0.034	ERCC2
hematopoietic stem cell differentiation	1	85.1×	0.036	ERCC2
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	74.9×	0.036	ERCC2
hematopoietic stem cell proliferation	1	72.0×	0.036	ERCC2
U2-type prespliceosome assembly	1	69.3×	0.036	SNRPE
spliceosomal complex assembly	1	66.9×	0.036	SNRPE
steroid biosynthetic process	1	66.9×	0.036	LSS
spliceosomal snRNP assembly	1	64.6×	0.036	SNRPE

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 6 of 9 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RPL21	GENTAMICIN SULFATE
ERCC2	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC2	16	4
RPL21	1	4
LIPH	0	0
SNRPE	0	0
LPAR6	0	0
APCDD1	0	0
DSG4	0	0
LSS	0	0
CDH3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPL21
SUNITINIB	4	ERCC2
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
RPL21	90	Binding:90
LSS	46	Binding:45, Functional:1
SNRPE	7	Binding:7
LPAR6	5	Binding:4, Functional:1
ERCC2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LIPH	3.1.1.32	phospholipase A1
LSS	5.4.99.7	Lanosterol synthase
ERCC2	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

16 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.

Compound	Max phase	Cohort target (bioactivity)
SUNITINIB	4	ERCC2
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	RPL21, ERCC2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	LPAR6, LSS
D	Druggable family + AlphaFold only, no drug	1	LIPH
E	Difficult family or no structure, no drug	4	SNRPE, APCDD1, DSG4, CDH3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LIPH	0	—
SNRPE	7	—
LPAR6	5	—
APCDD1	0	—
DSG4	0	—
LSS	46	—
CDH3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03492866	PHASE2	UNKNOWN	Efficacy of Topical Gentamycin for Hereditary Hypotrichosis Simplex Caused by Nonsense Mutations in CDSN

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GENTAMICIN SULFATE	4	1
CHEMBL1087542	0	1