Occipital horn syndrome

Summary

Occipital horn syndrome (MONDO:0010572) is a disease caused by ATP7A (GenCC Definitive), with 1 cohort gene and 4 clinical trials. Top therapeutic interventions include droxidopa and copper histidine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP7A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,744
• Phenotypes (HPO): 70
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

70 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000270	Delayed cranial suture closure	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000929	Abnormal skull morphology	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0002514	Cerebral calcification	Very frequent (80-99%)
HP:0100777	Exostoses	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0000926	Platyspondyly	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0000952	Jaundice	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0000987	Atypical scarring of skin	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001396	Cholestasis	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002036	Hiatus hernia	Frequent (30-79%)
HP:0002045	Hypothermia	Frequent (30-79%)
HP:0002578	Gastroparesis	Frequent (30-79%)
HP:0002617	Dilatation	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0002748	Rickets	Frequent (30-79%)
HP:0002749	Osteomalacia	Frequent (30-79%)
HP:0003019	Abnormality of the wrist	Frequent (30-79%)
HP:0004279	Short palm	Frequent (30-79%)
HP:0004408	Abnormality of the sense of smell	Frequent (30-79%)
HP:0005293	Venous insufficiency	Frequent (30-79%)
HP:0010562	Keloids	Frequent (30-79%)
HP:0012115	Hepatitis	Frequent (30-79%)
HP:0025270	Abnormal esophagus physiology	Frequent (30-79%)
HP:0100240	Synostosis of joints	Frequent (30-79%)
HP:0100633	Esophagitis	Frequent (30-79%)
HP:0100699	Scarring	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000015	Bladder diverticulum	Occasional (5-29%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000774	Narrow chest	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	occipital horn syndrome
Mondo ID	MONDO:0010572
MeSH	C537860
OMIM	304150
Orphanet	198
DOID	DOID:0111272
SNOMED CT	59399004
UMLS	C0268353
MedGen	82793
GARD	0004017
Is cancer (heuristic)	no

Also known as: cutis laxa X-linked · cutis laxa, X-linked · EDS IX (formerly) · EDS9 · Ehlers-Danlos syndrome, occipital horn type · Ehlers-Danlos syndrome, occipital horn type (formerly) · occipital horn syndrome · occipital horn syndrome, X-linked recessive · OHS

Data availability: 1,744 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-variable intellectual disability syndrome › occipital horn syndrome

Related subtypes (68): acromegaloid facial appearance syndrome, Hypoglossia-hypodactyly syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, campomelic dysplasia, cerebrocostomandibular syndrome, autosomal dominant popliteal pterygium syndrome, Pallister-Hall syndrome, autosomal dominant primary microcephaly, microgastria-limb reduction defect syndrome, Mobius syndrome, oculodentodigital dysplasia, Char syndrome, Prader-Willi syndrome, Silver-Russell syndrome, ulnar-mammary syndrome, short stature-wormian bones-dextrocardia syndrome, ablepharon macrostomia syndrome, Goodman syndrome, anophthalmia/microphthalmia-esophageal atresia syndrome, microphthalmia with limb anomalies, Antley-Bixler syndrome, campomelia, Cumming type, CHARGE syndrome, Toriello-Carey syndrome, Donnai-Barrow syndrome, lethal faciocardiomelic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, hypomandibular faciocranial dysostosis, isotretinoin-like syndrome, split hand-foot malformation 3, oculotrichoanal syndrome, Hennekam-Beemer syndrome, Mietens syndrome, Schinzel-Giedion syndrome, SHORT syndrome, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, hydrocephalus-costovertebral dysplasia-Sprengel anomaly syndrome, Potocki-Shaffer syndrome, Marshall-Smith syndrome, PHACE syndrome, Noonan syndrome-like disorder with loose anagen hair, branchiogenic deafness syndrome, combined immunodeficiency with faciooculoskeletal anomalies, chromosome 1p32-p31 deletion syndrome, Malan overgrowth syndrome, dysmorphism-conductive hearing loss-heart defect syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, short stature-heart defect-craniofacial anomalies syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, polyvalvular heart disease syndrome, Kallmann syndrome-heart disease syndrome, Meier-Gorlin syndrome, symptomatic form of Coffin-Lowry syndrome in female carriers, Prader-Willi-like syndrome, contractures-developmental delay-Pierre Robin syndrome, 22q11.2 deletion syndrome, Noonan syndrome, Carpenter syndrome, Bosley-Salih-Alorainy syndrome, Sotos syndrome, Robinow syndrome, King-Denborough syndrome, Weiss-Kruszka syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, 4q25 proximal deletion syndrome, restrictive dermopathy 1, mosaic SMO 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

600 retrieved; paginated sample, class counts are floors:

306 likely benign, 133 uncertain significance, 63 likely pathogenic, 55 conflicting classifications of pathogenicity, 25 benign, 15 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073823	NC_000023.10:g.(?77270139)(77271398_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1073824	NC_000023.10:g.(?77227108)(77258743_?)del	ATP7A	Pathogenic	criteria provided, single submitter
11782	NM_000052.7(ATP7A):c.1910C>T (p.Ser637Leu)	ATP7A	Pathogenic	criteria provided, single submitter
11783	ATP7A, 8-BP DEL, NT1552	ATP7A	Pathogenic	no assertion criteria provided
11784	NM_000052.7(ATP7A):c.2938C>T (p.Arg980Ter)	ATP7A	Pathogenic	criteria provided, multiple submitters, no conflicts
11792	NM_000052.7(ATP7A):c.3911A>G (p.Asn1304Ser)	ATP7A	Pathogenic	criteria provided, multiple submitters, no conflicts
11793	NM_000052.7(ATP7A):c.601C>T (p.Arg201Ter)	ATP7A	Pathogenic	criteria provided, multiple submitters, no conflicts
11795	NM_000052.7(ATP7A):c.4156C>T (p.Pro1386Ser)	ATP7A	Pathogenic	criteria provided, single submitter
1351221	NM_000052.7(ATP7A):c.2186G>A (p.Trp729Ter)	ATP7A	Pathogenic	criteria provided, single submitter
1356350	NC_000023.10:g.(?77264993)(77268389_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1365570	NC_000023.10:g.(?77243718)(77245474_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1403273	NM_000052.7(ATP7A):c.802C>T (p.Gln268Ter)	ATP7A	Pathogenic	criteria provided, single submitter
1458814	NC_000023.10:g.(?77275721)(77279056_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1459436	NC_000023.10:g.(?77227108)(77227268_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1460210	NM_000052.7(ATP7A):c.3560G>A (p.Trp1187Ter)	ATP7A	Pathogenic	criteria provided, single submitter
1726836	NM_000052.7(ATP7A):c.412C>T (p.Gln138Ter)	ATP7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320240	NM_000052.7(ATP7A):c.2557G>T (p.Gly853Ter)	ATP7A	Likely pathogenic	criteria provided, single submitter
1345204	NM_000052.7(ATP7A):c.2172+5G>A	ATP7A	Likely pathogenic	criteria provided, single submitter
1496499	NM_000052.7(ATP7A):c.2498+2T>G	ATP7A	Likely pathogenic	criteria provided, single submitter
1723931	NM_000052.7(ATP7A):c.3667_3669delinsA (p.Cys1223fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1723955	NM_000052.7(ATP7A):c.753_755delinsA (p.Asp251fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1723972	NM_000052.7(ATP7A):c.3793_3794del (p.Ala1265fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724000	NM_000052.7(ATP7A):c.338_339del (p.Val113fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724030	NM_000052.7(ATP7A):c.526A>T (p.Lys176Ter)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724063	NM_000052.7(ATP7A):c.1296_1297del (p.Gly433fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724086	NM_000052.7(ATP7A):c.2110C>T (p.Gln704Ter)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724174	NM_000052.7(ATP7A):c.420_423delinsCTGTCTCTTATACACAT (p.Lys140fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724179	NM_000052.7(ATP7A):c.1875_1876del (p.Gly626fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724300	NM_000052.7(ATP7A):c.360_363delinsAA (p.Gln121fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724321	NM_000052.7(ATP7A):c.1439_1443del (p.Asp480fs)	ATP7A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · 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
ATP7A	Definitive	X-linked	occipital horn syndrome	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP7A	Orphanet:139557	X-linked distal spinal muscular atrophy type 3
ATP7A	Orphanet:198	Occipital horn syndrome
ATP7A	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:565	Menkes disease

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
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd

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
buccal mucosa cell	1
trabecular bone tissue	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP7A	3,901

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP7A	Q04656	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Ion influx/efflux at host-pathogen interface	1	2855.0×	0.004	ATP7A
Detoxification of Reactive Oxygen Species	1	300.5×	0.013	ATP7A
Antimicrobial peptides	1	223.9×	0.013	ATP7A
Ion transport by P-type ATPases	1	207.6×	0.013	ATP7A
Cellular response to chemical stress	1	142.8×	0.015	ATP7A
Ion channel transport	1	96.0×	0.019	ATP7A
Cellular responses to stress	1	36.8×	0.043	ATP7A
Cellular responses to stimuli	1	31.5×	0.044	ATP7A
Innate Immune System	1	25.5×	0.044	ATP7A
Transport of small molecules	1	25.1×	0.044	ATP7A
Immune System	1	13.0×	0.077	ATP7A

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
obsolete negative regulation of catecholamine metabolic process	1	8426.0×	0.002	ATP7A
obsolete L-tryptophan metabolic process	1	5617.3×	0.002	ATP7A
epinephrine metabolic process	1	5617.3×	0.002	ATP7A
copper ion export	1	5617.3×	0.002	ATP7A
obsolete tyrosine metabolic process	1	4213.0×	0.002	ATP7A
catecholamine metabolic process	1	4213.0×	0.002	ATP7A
T-helper cell differentiation	1	3370.4×	0.002	ATP7A
copper ion import	1	2407.4×	0.002	ATP7A
pyramidal neuron development	1	2106.5×	0.002	ATP7A
norepinephrine biosynthetic process	1	2106.5×	0.002	ATP7A
copper ion transport	1	1685.2×	0.002	ATP7A
serotonin metabolic process	1	1685.2×	0.002	ATP7A
norepinephrine metabolic process	1	1532.0×	0.002	ATP7A
elastic fiber assembly	1	1532.0×	0.002	ATP7A
positive regulation of melanin biosynthetic process	1	1404.3×	0.002	ATP7A
regulation of oxidative phosphorylation	1	1203.7×	0.002	ATP7A
detoxification of copper ion	1	1123.5×	0.002	ATP7A
removal of superoxide radicals	1	1053.2×	0.002	ATP7A
cerebellar Purkinje cell differentiation	1	1053.2×	0.002	ATP7A
dopamine metabolic process	1	991.3×	0.002	ATP7A
intracellular copper ion homeostasis	1	936.2×	0.002	ATP7A
central nervous system neuron development	1	802.5×	0.002	ATP7A
release of cytochrome c from mitochondria	1	702.2×	0.003	ATP7A
pigmentation	1	702.2×	0.003	ATP7A
hair follicle morphogenesis	1	495.6×	0.003	ATP7A
ATP metabolic process	1	468.1×	0.003	ATP7A
neuron cellular homeostasis	1	455.5×	0.003	ATP7A
skin development	1	443.5×	0.003	ATP7A
dendrite morphogenesis	1	432.1×	0.003	ATP7A
blood vessel remodeling	1	383.0×	0.004	ATP7A

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
ATP7A	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
ATP7A	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter

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	ATP7A

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)
ATP7A	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00811785	PHASE3	COMPLETED	Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency
NCT04977388	PHASE1/PHASE2	COMPLETED	NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome
NCT02699112	Not specified	COMPLETED	Cardiac and Respiratory Function With Non-invasive Ventilation
NCT02765360	Not specified	COMPLETED	EIT Study With COPD and OHS Patients (EIT Step 2)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DROXIDOPA	4	1
COPPER HISTIDINE	3	1
CHEMBL1593851	0	1