Aplasia cutis congenita

Summary

Aplasia cutis congenita (MONDO:0007145) is a disease caused by BMS1 (GenCC Strong), with 4 cohort genes and 7 clinical trials. Top therapeutic interventions include pembrolizumab, dovitinib, and nevanimibe.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Causal gene: BMS1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 4
• Phenotypes (HPO): 13
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Worldwide	Validated
Prevalence at birth	1-5 / 10 000	10	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	7.69	Denmark	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0001057	Aplasia cutis congenita	Very frequent (80-99%)
HP:0001362	Skull defect	Very frequent (80-99%)
HP:0004471	Aplasia cutis congenita over the scalp vertex	Very frequent (80-99%)
HP:0007383	Congenital localized absence of skin	Very frequent (80-99%)
HP:0010301	Spinal dysraphism	Very frequent (80-99%)
HP:0200042	Skin ulcer	Frequent (30-79%)
HP:0001770	Toe syndactyly	Occasional (5-29%)
HP:0003010	Prolonged bleeding time	Occasional (5-29%)
HP:0004348	Abnormality of bone mineral density	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)
HP:0010783	Erythema	Occasional (5-29%)
HP:5200061	Tactile hypersensitivity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aplasia cutis congenita
Mondo ID	MONDO:0007145
OMIM	107600
Orphanet	1114
DOID	DOID:0080661
ICD-11	350175828
NCIT	C98822
SNOMED CT	35484002
UMLS	C0282160
MedGen	79390
GARD	0005835
NORD	794
Is cancer (heuristic)	no

Also known as: ACC · aplasia cutis congenita · aplasia cutis congenita (disease) · aplasia cutis congenita nonsyndromic · aplasia cutis congenita recessive · aplasia cutis congenita, nonsyndromic · scalp defect congenital

Data availability: 4 ClinVar variants · 6 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › dermis disorder › mixed dermis disorder › aplasia cutis congenita

Related subtypes (5): scalp defects-postaxial polydactyly syndrome, scalp-ear-nipple syndrome, aplasia cutis congenita-intestinal lymphangiectasia syndrome, linear skin defects with multiple congenital anomalies, recessive aplasia cutis congenita of limbs

Subtypes (3): aplasia cutis-myopia syndrome, aplasia cutis autosomal recessive, aplasia cutis congenita dominant

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

4 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
155924	NM_014753.4(BMS1):c.2789G>A (p.Arg930His)	BMS1	Pathogenic	no assertion criteria provided
1275745	NM_014753.4(BMS1):c.2225C>T (p.Pro742Leu)	BMS1	Uncertain significance	criteria provided, single submitter
3778906	NM_014753.4(BMS1):c.2194T>G (p.Leu732Val)	BMS1	Uncertain significance	criteria provided, single submitter
3893003	NM_014753.4(BMS1):c.883del (p.Ser295fs)	BMS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 13 · 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
BMS1	Strong	Autosomal dominant	aplasia cutis congenita	3
DLL4	Supportive	Autosomal dominant	aplasia cutis congenita	5
ITGB4	Supportive	Autosomal dominant	aplasia cutis congenita	14
PLEC	Supportive	Autosomal dominant	aplasia cutis congenita	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMS1	Orphanet:1114	Aplasia cutis congenita
DLL4	Orphanet:1114	Aplasia cutis congenita
DLL4	Orphanet:974	Adams-Oliver syndrome
ITGB4	Orphanet:1114	Aplasia cutis congenita
ITGB4	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
ITGB4	Orphanet:251393	Localized junctional epidermolysis bullosa
ITGB4	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
ITGB4	Orphanet:79403	Junctional epidermolysis bullosa with pyloric atresia
PLEC	Orphanet:1114	Aplasia cutis congenita
PLEC	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
PLEC	Orphanet:254361	Plectin-related limb-girdle muscular dystrophy R17
PLEC	Orphanet:257	Epidermolysis bullosa simplex with muscular dystrophy
PLEC	Orphanet:79401	PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMS1	HGNC:23505	ENSG00000165733	Q14692	Ribosome biogenesis protein BMS1 homolog	gencc,clinvar
DLL4	HGNC:2910	ENSG00000128917	Q9NR61	Delta-like protein 4	gencc
ITGB4	HGNC:6158	ENSG00000132470	P16144	Integrin beta-4	gencc
PLEC	HGNC:9069	ENSG00000178209	Q15149	Plectin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMS1	Ribosome biogenesis protein BMS1 homolog	GTPase required for the synthesis of 40S ribosomal subunits and for processing of pre-ribosomal RNA (pre-rRNA) at sites A0, A1, and A2.
DLL4	Delta-like protein 4	Involved in the Notch signaling pathway as Notch ligand.
ITGB4	Integrin beta-4	Integrin alpha-6/beta-4 is a receptor for laminin.
PLEC	Plectin	Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Antibody/Immunoglobulin	1	7.3×	0.318
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMS1	Other/Unknown	no		BMS1_TSR1_C, AARP2CN, P-loop_NTPase
DLL4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, DSL
ITGB4	Antibody/Immunoglobulin	yes		EGF, Integrin_bsu_VWA, Calx_beta
PLEC	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of tongue	2
tibial nerve	2
pharyngeal mucosa	1
tendon of biceps brachii	1
apex of heart	1
vena cava	1
minor salivary gland	1
skin of leg	1
hindlimb stylopod muscle	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMS1	287	ubiquitous	marker	tendon of biceps brachii, body of tongue, pharyngeal mucosa
DLL4	188	broad	marker	vena cava, apex of heart, body of tongue
ITGB4	267	broad	marker	tibial nerve, minor salivary gland, skin of leg
PLEC	283	ubiquitous	marker	sural nerve, hindlimb stylopod muscle, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMS1	3,587
PLEC	3,529
DLL4	2,749
ITGB4	2,536

Intra-cohort edges

A	B	Sources
ITGB4	PLEC	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLEC	Q15149	14
ITGB4	P16144	13
BMS1	Q14692	3
DLL4	Q9NR61	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Type I hemidesmosome assembly	2	519.1×	1e-04	ITGB4, PLEC
Assembly of collagen fibrils and other multimeric structures	2	100.2×	0.002	ITGB4, PLEC
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	407.9×	0.021	DLL4
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	259.6×	0.022	DLL4
Caspase-mediated cleavage of cytoskeletal proteins	1	237.9×	0.022	PLEC
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	190.3×	0.023	DLL4
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	119.0×	0.024	DLL4
Collagen formation	1	114.2×	0.024	ITGB4
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	109.8×	0.024	DLL4
Syndecan interactions	1	105.7×	0.024	ITGB4
Laminin interactions	1	95.2×	0.024	ITGB4
Activated NOTCH1 Transmits Signal to the Nucleus	1	89.2×	0.024	DLL4
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	69.6×	0.029	ITGB4
Developmental Cell Lineages	1	56.0×	0.031	ITGB4
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	49.2×	0.031	DLL4
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	49.2×	0.031	DLL4
Cell junction organization	1	46.8×	0.031	ITGB4
rRNA modification in the nucleus and cytosol	1	46.8×	0.031	BMS1
rRNA processing in the nucleus and cytosol	1	40.2×	0.033	BMS1
Non-integrin membrane-ECM interactions	1	38.6×	0.033	ITGB4
rRNA processing	1	36.6×	0.033	BMS1
Cell-Cell communication	1	34.4×	0.034	ITGB4
Extracellular matrix organization	1	15.8×	0.069	ITGB4
Major pathway of rRNA processing in the nucleolus and cytosol	1	15.4×	0.069	BMS1
Metabolism of RNA	1	10.4×	0.096	BMS1
Developmental Biology	1	3.6×	0.249	ITGB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hemidesmosome assembly	2	1203.7×	7e-05	ITGB4, PLEC
protein-containing complex organization	1	4213.0×	0.006	PLEC
actomyosin contractile ring assembly actin filament organization	1	4213.0×	0.006	PLEC
skeletal myofibril assembly	1	2106.5×	0.006	PLEC
blood vessel lumenization	1	2106.5×	0.006	DLL4
leukocyte migration involved in immune response	1	1404.3×	0.006	PLEC
peripheral nervous system myelin formation	1	1404.3×	0.006	ITGB4
ventral spinal cord interneuron fate commitment	1	1404.3×	0.006	DLL4
regulation of neural retina development	1	1404.3×	0.006	DLL4
cellular response to hydrostatic pressure	1	1404.3×	0.006	PLEC
endonucleolytic cleavage of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	1053.2×	0.007	BMS1
tight junction organization	1	842.6×	0.008	PLEC
cardiac atrium morphogenesis	1	702.2×	0.008	DLL4
nail development	1	601.9×	0.008	ITGB4
trophoblast cell migration	1	601.9×	0.008	ITGB4
pericardium morphogenesis	1	526.6×	0.008	DLL4
dorsal aorta morphogenesis	1	526.6×	0.008	DLL4
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	526.6×	0.008	DLL4
cardiac ventricle morphogenesis	1	468.1×	0.009	DLL4
keratinocyte development	1	383.0×	0.009	PLEC
peripheral nervous system myelin maintenance	1	383.0×	0.009	PLEC
mesodermal cell differentiation	1	383.0×	0.009	ITGB4
skin morphogenesis	1	351.1×	0.010	ITGB4
cellular response to fluid shear stress	1	324.1×	0.010	PLEC
T cell chemotaxis	1	280.9×	0.011	PLEC
regulation of vascular permeability	1	280.9×	0.011	PLEC
ventricular trabecula myocardium morphogenesis	1	263.3×	0.011	DLL4
negative regulation of cell migration involved in sprouting angiogenesis	1	247.8×	0.011	DLL4
intermediate filament cytoskeleton organization	1	234.1×	0.012	PLEC
fibroblast migration	1	210.7×	0.012	PLEC

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BMS1	0	0
DLL4	0	0
ITGB4	0	0
PLEC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PLEC	12	Binding:12
ITGB4	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	ITGB4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	BMS1, DLL4, PLEC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BMS1	0	—
DLL4	0	—
ITGB4	2	—
PLEC	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	2
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06066333	PHASE2	RECRUITING	Study of Radiotherapy and Pembrolizumab in People With Adrenocortical Carcinoma
NCT01262235	PHASE1/PHASE2	COMPLETED	A Dose Finding Study of TKM-080301 Infusion in Neuroendocrine Tumors (NET) and Adrenocortical Carcinoma (ACC) Patients
NCT01678105	PHASE2	COMPLETED	A Phase II Study of Dovitinib in Recurrent and/or Metastatic Adenoid Cystic Carcinoma of the Salivary Glands
NCT01898715	PHASE1	COMPLETED	Phase 1 Study of ATR-101 in Subjects With Advanced Adrenocortical Carcinoma
NCT01630421	Not specified	RECRUITING	Genetic and Functional Analysis of Aplasia Cutis Congenital (ACC)
NCT00170326	Not specified	COMPLETED	Progressive Ventricular Dysfunction Prevention in Pacemaker Patients
NCT01117792	Not specified	COMPLETED	Subcutaneous Implantable Defibrillator (S-ICD) System - CE Clinical Investigation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PEMBROLIZUMAB	4	1
DOVITINIB	3	1
NEVANIMIBE	2	2
CHEMBL4578973	0	1