X-linked adrenal hypoplasia congenita

Summary

X-linked adrenal hypoplasia congenita (MONDO:0010264) is a disease caused by NR0B1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: NR0B1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 369
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	8	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	8	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0003154	Increased circulating ACTH level	Obligate (100%)
HP:0000953	Hyperpigmentation of the skin	Very frequent (80-99%)
HP:0008163	Decreased circulating cortisol level	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Frequent (30-79%)
HP:0046504	Decreased libido	Frequent (30-79%)
HP:0100639	Erectile dysfunction	Frequent (30-79%)
HP:0000044	Hypogonadotropic hypogonadism	Frequent (30-79%)
HP:0000798	Oligozoospermia	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002153	Hyperkalemia	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0002902	Hyponatremia	Frequent (30-79%)
HP:0008186	Adrenocortical cytomegaly	Frequent (30-79%)
HP:0008207	Primary adrenal insufficiency	Frequent (30-79%)
HP:0008734	Decreased testicular size	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0030344	Decreased circulating luteinizing hormone level	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002225	Sparse pubic hair	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked adrenal hypoplasia congenita
Mondo ID	MONDO:0010264
OMIM	300200
Orphanet	95702
DOID	DOID:0080156
NCIT	C123725
SNOMED CT	93235007
UMLS	C0342482
MedGen	87442
GARD	0000555
Is cancer (heuristic)	no

Also known as: adrenal hypoplasia congenita · adrenal hypoplasia, congenital · adrenal hypoplasia, congenital, X-linked recessive · AHC · X-linked adrenal hypoplasia congenita · X-linked AHC · X-linked congenital adrenal hypoplasia

Data availability: 369 ClinVar variants · 6 GenCC gene-disease records · 17 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked adrenal hypoplasia congenita

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

Subtypes (1): adrenal hypoplasia, cytomegalic type

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

369 retrieved; paginated sample, class counts are floors:

139 likely benign, 98 pathogenic, 71 uncertain significance, 26 benign, 14 conflicting classifications of pathogenicity, 11 likely pathogenic, 6 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2423143	NC_000023.10:g.(?28807461)(33229429_?)dup	DMD	Pathogenic	criteria provided, single submitter
444071	NC_000023.10:g.(29976475_30082636)_(31196736_31462831)del	GK-AS1	Pathogenic	criteria provided, single submitter
444076	NC_000023.11:g.30307936_30311263del	LOC108410393	Pathogenic	criteria provided, single submitter
444069	NC_000023.10:g.(28450110_28771544)_(31838019_32614088)del	LOC126863236	Pathogenic	criteria provided, single submitter
444070	NC_000023.10:g.(29155333_29973170)_(30327505_30577779)del	MAGEB2	Pathogenic	criteria provided, single submitter
1075657	NM_000475.5(NR0B1):c.226C>T (p.Gln76Ter)	NR0B1	Pathogenic	criteria provided, single submitter
10949	NM_000475.5(NR0B1):c.847C>T (p.Gln283Ter)	NR0B1	Pathogenic	no assertion criteria provided
10950	NM_000475.5(NR0B1):c.1107G>A (p.Trp369Ter)	NR0B1	Pathogenic	no assertion criteria provided
10951	NM_000475.5(NR0B1):c.788T>A (p.Leu263Ter)	NR0B1	Pathogenic	no assertion criteria provided
10952	NM_000475.5(NR0B1):c.800G>C (p.Arg267Pro)	NR0B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10953	NM_000475.5(NR0B1):c.704G>A (p.Trp235Ter)	NR0B1	Pathogenic	no assertion criteria provided
10954	NM_000475.5(NR0B1):c.513G>A (p.Trp171Ter)	NR0B1	Pathogenic	no assertion criteria provided
10955	NM_000475.5(NR0B1):c.839del (p.Leu280fs)	NR0B1	Pathogenic	no assertion criteria provided
10956	NM_000475.5(NR0B1):c.273C>A (p.Tyr91Ter)	NR0B1	Pathogenic	criteria provided, single submitter
10957	NM_000475.5(NR0B1):c.1319A>T (p.Asn440Ile)	NR0B1	Pathogenic	no assertion criteria provided
10958	NM_000475.5(NR0B1):c.1183C>T (p.Gln395Ter)	NR0B1	Pathogenic	criteria provided, single submitter
10959	NM_000475.5(NR0B1):c.813C>G (p.Tyr271Ter)	NR0B1	Pathogenic	no assertion criteria provided
10960	NM_000475.5(NR0B1):c.1376_1377delinsG (p.Asp459fs)	NR0B1	Pathogenic	no assertion criteria provided
10961	NM_000475.5(NR0B1):c.765del (p.Cys255fs)	NR0B1	Pathogenic	no assertion criteria provided
10964	NM_000475.5(NR0B1):c.1146G>T (p.Lys382Asn)	NR0B1	Pathogenic	no assertion criteria provided
10965	NM_000475.5(NR0B1):c.873G>C (p.Trp291Cys)	NR0B1	Pathogenic	no assertion criteria provided
10966	NG_009814.1:g.(?4989)(10173_?)del	NR0B1	Pathogenic	no assertion criteria provided
10967	NM_000475.5(NR0B1):c.1231_1234del (p.Leu411fs)	NR0B1	Pathogenic	criteria provided, single submitter
10968	NM_000475.5(NR0B1):c.591C>A (p.Tyr197Ter)	NR0B1	Pathogenic	no assertion criteria provided
10969	NM_000475.5(NR0B1):c.1316T>G (p.Ile439Ser)	NR0B1	Pathogenic	no assertion criteria provided
10970	NM_000475.5(NR0B1):c.501del (p.Gly169fs)	NR0B1	Pathogenic	criteria provided, multiple submitters, no conflicts
10971	NM_000475.5(NR0B1):c.1142T>A (p.Leu381His)	NR0B1	Pathogenic	no assertion criteria provided
10972	NR0B1, 1-BP INS, 430G	NR0B1	Pathogenic	no assertion criteria provided
10973	NM_000475.5(NR0B1):c.1138T>G (p.Tyr380Asp)	NR0B1	Pathogenic	no assertion criteria provided
10974	NC_000023.11:g.30304157_30306387delinsTGGAAATTATATATATTTCCAAATAAA	NR0B1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 9 · 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
NR0B1	Definitive	X-linked	X-linked adrenal hypoplasia congenita	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR0B1	Orphanet:242	46,XY complete gonadal dysgenesis
NR0B1	Orphanet:251510	46,XY partial gonadal dysgenesis
NR0B1	Orphanet:393	46,XX testicular difference of sex development
NR0B1	Orphanet:95702	X-linked adrenal hypoplasia congenita
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR0B1	HGNC:7960	ENSG00000169297	P51843	Nuclear receptor subfamily 0 group B member 1	gencc,clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
GK-AS1	HGNC:40255	ENSG00000243055		GK antisense RNA 1	clinvar
MAGEB2	HGNC:6809	ENSG00000099399	O15479	Melanoma-associated antigen B2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR0B1	Nuclear receptor subfamily 0 group B member 1	Nuclear receptor that lacks a DNA-binding domain and acts as a corepressor that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
MAGEB2	Melanoma-associated antigen B2	May enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases.

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
Nuclear receptor	1	96.5×	0.031
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR0B1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Nuclear_hrmn_rcpt, Nuclear_receptor_repeat
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
GK-AS1	Other/Unknown	no
MAGEB2	Other/Unknown	no		MHD_dom, MAGE_N, MAGE

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
primordial germ cell in gonad	2
adrenal tissue	1
left adrenal gland	1
right adrenal gland	1
dorsal root ganglion	1
skeletal muscle tissue of rectus abdominis	1
trigeminal ganglion	1
blood	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR0B1	130	broad	marker	right adrenal gland, left adrenal gland, adrenal tissue
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
GK-AS1	130		marker	primordial germ cell in gonad, blood, colonic epithelium
MAGEB2	36	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DMD	2,479
NR0B1	1,753
MAGEB2	1,159
GK-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DMD	P11532	6
NR0B1	P51843	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAGEB2	O15479	72.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 4 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	1	154.3×	0.013	DMD
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.013	DMD
Nuclear Receptor transcription pathway	1	100.2×	0.013	NR0B1
Non-integrin membrane-ECM interactions	1	77.2×	0.013	DMD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of muscle system process	1	5617.3×	0.004	DMD
regulation of cellular response to growth factor stimulus	1	5617.3×	0.004	DMD
cardiac muscle cell action potential	1	2808.7×	0.004	DMD
intracellular protein localization	2	69.8×	0.004	NR0B1, DMD
regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion	1	1404.3×	0.004	DMD
negative regulation of intracellular steroid hormone receptor signaling pathway	1	1404.3×	0.004	NR0B1
peptide biosynthetic process	1	1404.3×	0.004	DMD
negative regulation of steroid biosynthetic process	1	1123.5×	0.005	NR0B1
regulation of skeletal muscle contraction	1	936.2×	0.005	DMD
regulation of calcium ion transmembrane transport	1	702.2×	0.006	DMD
sex determination	1	561.7×	0.006	NR0B1
Sertoli cell differentiation	1	510.7×	0.006	NR0B1
synaptic signaling	1	510.7×	0.006	DMD
male sex determination	1	468.1×	0.006	NR0B1
Leydig cell differentiation	1	401.2×	0.007	NR0B1
gonad development	1	374.5×	0.007	NR0B1
hypothalamus development	1	351.1×	0.007	NR0B1
regulation of sodium ion transmembrane transport	1	351.1×	0.007	DMD
muscle cell development	1	312.1×	0.007	DMD
negative regulation of gluconeogenesis	1	267.5×	0.007	NR0B1
response to muscle stretch	1	255.3×	0.007	DMD
response to immobilization stress	1	244.2×	0.007	NR0B1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	224.7×	0.007	DMD
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	224.7×	0.007	DMD
adrenal gland development	1	224.7×	0.007	NR0B1
pituitary gland development	1	216.1×	0.007	NR0B1
muscle cell cellular homeostasis	1	216.1×	0.007	DMD
motile cilium assembly	1	193.7×	0.008	DMD
endodermal cell differentiation	1	165.2×	0.009	NR0B1
maintenance of blood-brain barrier	1	160.5×	0.009	DMD

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
NR0B1	PODOFILOX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR0B1	3	4
DMD	0	0
GK-AS1	0	0
MAGEB2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PODOFILOX	4	NR0B1
VORINOSTAT	4	NR0B1
COLFORSIN	2	NR0B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR0B1	3	Functional:2, Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
PODOFILOX	4	NR0B1
VORINOSTAT	4	NR0B1
COLFORSIN	2	NR0B1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NR0B1
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	3	DMD, GK-AS1, MAGEB2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DMD	0	—
GK-AS1	0	—
MAGEB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.