Scalp-ear-nipple syndrome

Summary

Scalp-ear-nipple syndrome (MONDO:0008404) is a disease caused by KCTD1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KCTD1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 44
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000385	Small earlobe	Very frequent (80-99%)
HP:0000951	Abnormality of the skin	Very frequent (80-99%)
HP:0001965	Abnormality of the scalp	Very frequent (80-99%)
HP:0006709	Aplasia/Hypoplasia of the nipples	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0008551	Microtia	Very frequent (80-99%)
HP:0009738	Abnormality of the antihelix	Very frequent (80-99%)
HP:0011251	Underdeveloped antitragus	Very frequent (80-99%)
HP:0011272	Underdeveloped tragus	Very frequent (80-99%)
HP:0100783	Breast aplasia	Very frequent (80-99%)
HP:0000010	Recurrent urinary tract infections	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001231	Abnormal fingernail morphology	Frequent (30-79%)
HP:0100540	Palpebral edema	Frequent (30-79%)
HP:0100651	Type I diabetes mellitus	Frequent (30-79%)
HP:0000073	Ureteral duplication	Occasional (5-29%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000625	Eyelid coloboma	Occasional (5-29%)
HP:0000966	Hypohidrosis	Occasional (5-29%)
HP:0005580	Duplication of renal pelvis	Occasional (5-29%)
HP:0012330	Pyelonephritis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	scalp-ear-nipple syndrome
Mondo ID	MONDO:0008404
MeSH	C536623
OMIM	181270
Orphanet	2036
DOID	DOID:0111550
ICD-11	88843032
SNOMED CT	721888002
UMLS	C1867020
MedGen	357183
GARD	0000159
Is cancer (heuristic)	no

Also known as: Finlay-Marks syndrome · hereditary syndrome of lumpy scalp, odd ears and rudimentary nipples · scalp ear nipple syndrome · scalp-ear-nipple syndrome · Sen syndrome · SENS

Data availability: 44 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome without intellectual disability › scalp-ear-nipple syndrome

Related subtypes (167): Treacher-Collins syndrome, branchio-oto-renal syndrome, acrorenal syndrome, Townes-Brocks syndrome, Ascher syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, branchiooculofacial syndrome, Gordon syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, Alagille syndrome, cleft palate-lateral synechia syndrome, blepharocheilodontic syndrome, craniofacial-deafness-hand syndrome, cryptomicrotia-brachydactyly-excess fingertip arch syndrome, Beare-Stevenson cutis gyrata syndrome, Cyprus facial-neuromusculoskeletal syndrome, deafness-craniofacial syndrome, short stature-valvular heart disease-characteristic facies syndrome, 3-M syndrome, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, multinodular goiter-cystic kidney-polydactyly syndrome, hand-foot-genital syndrome, Bencze syndrome, oculoauriculovertebral spectrum with radial defects, Holt-Oram syndrome, mullerian duct anomalies-limb anomalies syndrome, Aase-Smith syndrome, LADD syndrome, Noonan syndrome with multiple lentigines, median nodule of the upper lip, Nager acrofacial dysostosis, Marshall syndrome, Binder syndrome, Schilbach-Rott syndrome, nasopalpebral lipoma-coloboma syndrome, autosomal dominant prognathism, short stature-craniofacial anomalies-genital hypoplasia syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, flat face-microstomia-ear anomaly syndrome, Czeizel-Losonci syndrome, otospondylomegaepiphyseal dysplasia, autosomal dominant, ventricular extrasystoles with syncopal episodes-perodactyly-robin sequence syndrome, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, acrofacial dysostosis, Weyers type, Freeman-Sheldon syndrome, Ackerman syndrome, acro-renal-mandibular syndrome, acrocraniofacial dysostosis, PAGOD syndrome, alar cartilages hypoplasia-coloboma-telecanthus syndrome, microcephaly-albinism-digital anomalies syndrome, fetal akinesia deformation sequence, Cooper-Jabs syndrome, Barber-Say syndrome, Beemer-Ertbruggen syndrome, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, camptodactyly syndrome, Guadalajara type 1, camptodactyly syndrome, Guadalajara type 2, heart defects-limb shortening syndrome, Verloove Vanhorick-Brubakk syndrome, Juberg-Hayward syndrome, heart defect - tongue hamartoma - polysyndactyly syndrome, Fraser syndrome, split hand-foot malformation 1 with sensorineural hearing loss, von Voss-Cherstvoy syndrome, autosomal recessive faciodigitogenital syndrome, gingival fibromatosis-facial dysmorphism syndrome, Fibulo-ulnar hypoplasia-renal anomalies syndrome, frontofacionasal dysplasia, genito-palato-cardiac syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Holzgreve-Wagner-Rehder syndrome, hydrocephaly-tall stature-joint laxity syndrome, McKusick-Kaufman syndrome, acrofrontofacionasal dysostosis 2, Vici syndrome, Donohue syndrome, Dahlberg-Borer-Newcomer syndrome, macrosomia-microphthalmia-cleft palate syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, Nijmegen breakage syndrome, lethal congenital contracture syndrome 1, Richieri Costa-da Silva syndrome, Keipert syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, ichthyosis-oral and digital anomalies syndrome, otoonychoperoneal syndrome, PHAVER syndrome, polysyndactyly-cardiac malformation syndrome, postaxial acrofacial dysostosis, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, renal-genital-middle ear anomalies, Richieri Costa-Pereira syndrome, SHORT syndrome, tetraamelia-multiple malformations syndrome, thymic-renal-anal-lung dysplasia, trigonocephaly-bifid nose-acral anomalies syndrome, white forelock with malformations, syndactyly-telecanthus-anogenital and renal malformations syndrome, Abruzzo-Erickson syndrome, CHILD syndrome, pentalogy of Cantrell, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, short tarsus-absence of lower eyelashes syndrome, PARC syndrome, CODAS syndrome, pectus excavatum-macrocephaly-dysplastic nails syndrome, velo-facial-skeletal syndrome, anophthalmia plus syndrome, van den Ende-Gupta syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, diaphragmatic defect-limb deficiency-skull defect syndrome, cleft lip/palate-intestinal malrotation-cardiopathy syndrome, Matthew-Wood syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, dislocation of the hip-dysmorphism syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, grange syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, arhinia, choanal atresia, and microphthalmia, anonychia-microcephaly syndrome, developmental malformations-deafness-dystonia syndrome, lethal congenital contracture syndrome 2, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, lethal congenital contracture syndrome 3, Fontaine progeroid syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, Nijmegen breakage syndrome-like disorder, Warsaw breakage syndrome, even-plus syndrome, split-foot malformation-mesoaxial polydactyly syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, digitotalar dysmorphism, heart-hand syndrome type 2, night blindness-skeletal anomalies-dysmorphism syndrome, Charlie M syndrome, facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome, cleft lip-retinopathy syndrome, Cole-Carpenter syndrome, progressive non-infectious anterior vertebral fusion, dysmorphism-pectus carinatum-joint laxity syndrome, Hirschsprung disease-type D brachydactyly syndrome, mandibuloacral dysplasia, contractures - webbed neck - micrognathia - hypoplastic nipples syndrome, Thomas syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, branchiootic syndrome, auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome, Axenfeld-Rieger syndrome, macrostomia-preauricular tags-external ophthalmoplegia syndrome, pelvis syndrome, Fanconi anemia, van der Woude syndrome, hypertrichosis-acromegaloid facial appearance syndrome, 49,XYYYY syndrome, congenital vertebral-cardiac-renal anomalies syndrome, structural heart defects and renal anomalies syndrome, Greig cephalopolysyndactyly-contiguous gene 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

44 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 12 pathogenic, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
235827	NM_001142730.3(KCTD1):c.2031C>A (p.Asp677Glu)	KCTD1	Pathogenic	no assertion criteria provided
235828	NM_001142730.3(KCTD1):c.1882C>T (p.Pro628Ser)	KCTD1	Pathogenic	no assertion criteria provided
4533333	I66F	KCTD1	Pathogenic	no assertion criteria provided
4533334	KCTD1, 3-BP INS, 186GTT	KCTD1	Pathogenic	no assertion criteria provided
4533335	G62V	KCTD1	Pathogenic	no assertion criteria provided
55881	NM_001142730.3(KCTD1):c.1913C>A (p.Ala638Glu)	KCTD1	Pathogenic	no assertion criteria provided
55882	NM_001142730.3(KCTD1):c.1916C>G (p.Pro639Arg)	KCTD1	Pathogenic	no assertion criteria provided
55883	NM_001142730.3(KCTD1):c.1916C>T (p.Pro639Leu)	KCTD1	Pathogenic	no assertion criteria provided
55884	NM_001142730.3(KCTD1):c.1916C>A (p.Pro639His)	KCTD1	Pathogenic	no assertion criteria provided
55885	NM_001142730.3(KCTD1):c.1923C>A (p.His641Gln)	KCTD1	Pathogenic	no assertion criteria provided
55886	NM_001142730.3(KCTD1):c.1922A>C (p.His641Pro)	KCTD1	Pathogenic	no assertion criteria provided
55887	NM_001142730.3(KCTD1):c.2045A>C (p.His682Pro)	KCTD1	Pathogenic	no assertion criteria provided
3254677	NM_001142730.3(KCTD1):c.2056G>C (p.Asp686His)	KCTD1	Likely pathogenic	criteria provided, single submitter
55888	NM_001142730.3(KCTD1):c.2009G>A (p.Gly670Asp)	KCTD1	Likely pathogenic	criteria provided, single submitter
2358043	NM_001142730.3(KCTD1):c.220G>T (p.Asp74Tyr)	KCTD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2973468	NM_001142730.3(KCTD1):c.2545C>T (p.Arg849Trp)	KCTD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1307491	NM_001142730.3(KCTD1):c.2384C>T (p.Ser795Leu)	KCTD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2175670	NM_001142730.3(KCTD1):c.2133+4A>G	KCTD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2238493	NM_001142730.3(KCTD1):c.1106G>A (p.Ser369Asn)	KCTD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433049	NM_001142730.3(KCTD1):c.1882C>A (p.Pro628Thr)	KCTD1	Uncertain significance	criteria provided, single submitter
2474719	NM_001142730.3(KCTD1):c.2561C>T (p.Pro854Leu)	KCTD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2515330	NM_001142730.3(KCTD1):c.2387C>T (p.Thr796Met)	KCTD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3583209	NM_001142730.3(KCTD1):c.2551C>A (p.Pro851Thr)	KCTD1	Uncertain significance	criteria provided, single submitter
3583210	NM_001142730.3(KCTD1):c.2495G>A (p.Gly832Glu)	KCTD1	Uncertain significance	criteria provided, single submitter
3583212	NM_001142730.3(KCTD1):c.2440-10_2440-9insA	KCTD1	Uncertain significance	criteria provided, single submitter
3583213	NM_001142730.3(KCTD1):c.2392G>A (p.Val798Ile)	KCTD1	Uncertain significance	criteria provided, single submitter
3583214	NM_001142730.3(KCTD1):c.2384C>A (p.Ser795Ter)	KCTD1	Uncertain significance	criteria provided, single submitter
3583215	NM_001142730.3(KCTD1):c.2379C>A (p.His793Gln)	KCTD1	Uncertain significance	criteria provided, single submitter
3583216	NM_001142730.3(KCTD1):c.2355_2363del (p.Ser786_Asn788del)	KCTD1	Uncertain significance	criteria provided, single submitter
3583217	NM_001142730.3(KCTD1):c.2344G>A (p.Val782Met)	KCTD1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
KCTD1	Strong	Autosomal dominant	scalp-ear-nipple syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCTD1	Orphanet:2036	Scalp-ear-nipple 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
KCTD1	HGNC:18249	ENSG00000134504	Q719H9	BTB/POZ domain-containing protein KCTD1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCTD1	BTB/POZ domain-containing protein KCTD1	May repress the transcriptional activity of AP-2 family members, including TFAP2A, TFAP2B and TFAP2C to various extent.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCTD1	Other/Unknown	no		BTB/POZ_dom, T1-type_BTB, SKP1/BTB/POZ_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oviduct epithelium	1
penis	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCTD1	243	ubiquitous	marker	oviduct epithelium, upper arm skin, penis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCTD1	567

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCTD1	Q719H9	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	1142.0×	0.004	KCTD1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	634.4×	0.004	KCTD1
RNA Polymerase II Transcription	1	22.5×	0.066	KCTD1
Gene expression (Transcription)	1	17.8×	0.066	KCTD1
Generic Transcription Pathway	1	15.1×	0.066	KCTD1

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
protein homooligomerization	1	122.1×	0.016	KCTD1
negative regulation of DNA-templated transcription	1	31.6×	0.032	KCTD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCTD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	KCTD1

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)
KCTD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.