congenital lipoid adrenal hyperplasia due to STAR deficency

Summary

congenital lipoid adrenal hyperplasia due to STAR deficency (MONDO:0008725) is a disease caused by STAR (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: STAR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 213
• Phenotypes (HPO): 25

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000953	Hyperpigmentation of the skin	Very frequent (80-99%)
HP:0003154	Increased circulating ACTH level	Very frequent (80-99%)
HP:0008730	Female external genitalia in individual with 46,XY karyotype	Very frequent (80-99%)
HP:0000055	Abnormality of female external genitalia	Frequent (30-79%)
HP:0000841	Hyperactive renin-angiotensin system	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002153	Hyperkalemia	Frequent (30-79%)
HP:0002902	Hyponatremia	Frequent (30-79%)
HP:0008163	Decreased circulating cortisol level	Frequent (30-79%)
HP:0008221	Adrenal hyperplasia	Frequent (30-79%)
HP:0030347	Abnormal circulating androgen level	Frequent (30-79%)
HP:0000037	Male pseudohermaphroditism	Occasional (5-29%)
HP:0000053	Macroorchidism	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0010885	Avascular necrosis	Occasional (5-29%)
HP:0003002	Breast carcinoma	Very rare (<1-4%)
HP:0012114	Endometrial carcinoma	Very rare (<1-4%)
HP:0040187	Neonatal sepsis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital lipoid adrenal hyperplasia due to STAR deficency
Mondo ID	MONDO:0008725
OMIM	201710
Orphanet	90790
SNOMED CT	44231009
UMLS	C0342474
MedGen	83341
GARD	0001465
Is cancer (heuristic)	no

Also known as: CLAH · congenital adrenal hyperplasia lipoid · LCAH · lipoid adrenal hyperplasia · lipoid congenital adrenal hyperplasia

Data availability: 213 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › steroid inherited metabolic disorder › congenital adrenal hyperplasia › congenital lipoid adrenal hyperplasia due to STAR deficency

Related subtypes (7): congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency, congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency, non-classic congenital adrenal hyperplasia, classic congenital adrenal hyperplasia

Subtypes (2): classic congenital lipoid adrenal hyperplasia due to STAR deficency, non-classic congenital lipoid adrenal hyperplasia due to STAR deficency

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

213 retrieved; paginated sample, class counts are floors:

90 uncertain significance, 45 likely pathogenic, 24 pathogenic, 20 conflicting classifications of pathogenicity, 17 pathogenic/likely pathogenic, 11 likely benign, 4 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12159	NM_000500.9(CYP21A2):c.1360C>T (p.Pro454Ser)	CYP21A2	Pathogenic	criteria provided, multiple submitters, no conflicts
3595582	NM_000349.3(STAR):c.5_11del (p.Leu2fs)	LOC108863620	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070762	NM_000349.3(STAR):c.64+1G>A	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074325	NM_000349.3(STAR):c.144G>A (p.Trp48Ter)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076650	NM_000349.3(STAR):c.719del (p.Thr240fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
1428946	NM_000349.3(STAR):c.465+2T>C	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457197	NM_000349.3(STAR):c.422_423insTT (p.Met141fs)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2039092	NM_000349.3(STAR):c.661_713dup (p.Leu239fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
2101047	NM_000349.3(STAR):c.707_708delinsCTT (p.Lys236fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
2136659	NM_000349.3(STAR):c.407del (p.Glu136fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
35553	NM_000349.3(STAR):c.577C>T (p.Arg193Ter)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
36782	NM_000349.3(STAR):c.135del (p.Ser46fs)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370502	NM_000349.3(STAR):c.629_630del (p.Pro210fs)	STAR	Pathogenic	criteria provided, single submitter
4062011	NM_000349.3(STAR):c.37T>C (p.Ser13Pro)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
448533	NM_000349.3(STAR):c.505G>A (p.Glu169Lys)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4818220	NM_000349.3(STAR):c.465+2T>A	STAR	Pathogenic	criteria provided, single submitter
4819786	NM_000349.3(STAR):c.490dup (p.Thr164fs)	STAR	Pathogenic	criteria provided, single submitter
550550	NM_000349.3(STAR):c.544C>T (p.Arg182Cys)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
550766	NM_000349.3(STAR):c.814C>T (p.Arg272Cys)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550998	NM_000349.3(STAR):c.64+1G>T	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
551230	NM_000349.3(STAR):c.574C>T (p.Arg192Cys)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551640	NM_000349.3(STAR):c.298_299del (p.Gln101fs)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553482	NM_000349.3(STAR):c.779T>C (p.Leu260Pro)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553713	NM_000349.3(STAR):c.229C>T (p.Gln77Ter)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
554752	NM_000349.3(STAR):c.677del (p.Val226fs)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
556387	NM_000349.3(STAR):c.811del (p.Leu271fs)	STAR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
558171	NM_000349.3(STAR):c.714del (p.Lys238fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
558205	NM_000349.3(STAR):c.695del (p.Gly232fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
586680	NM_000349.3(STAR):c.201_202del (p.Tyr68fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts
632520	NM_000349.3(STAR):c.125dup (p.Thr44fs)	STAR	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 5 · 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
STAR	Definitive	Autosomal recessive	congenital lipoid adrenal hyperplasia due to STAR deficency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAR	Orphanet:325524	Classic congenital lipoid adrenal hyperplasia due to STAR deficency
STAR	Orphanet:325529	Non-classic congenital lipoid adrenal hyperplasia due to STAR deficency
STAR	Orphanet:361	Familial glucocorticoid deficiency
CYP21A2	Orphanet:315306	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
CYP21A2	Orphanet:315311	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STAR	HGNC:11359	ENSG00000147465	P49675	Steroidogenic acute regulatory protein, mitochondrial	gencc,clinvar
CYP21A2	HGNC:2600	ENSG00000231852	P08686	Steroid 21-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAR	Steroidogenic acute regulatory protein, mitochondrial	Plays a key role in steroid hormone synthesis by enhancing the metabolism of cholesterol into pregnenolone.
CYP21A2	Steroid 21-hydroxylase	A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAR	Other/Unknown	no		StAR-like, START_lipid-bd_dom, START-like_dom_sf
CYP21A2	Enzyme (other)	yes	1.14.14.16	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	2
right adrenal gland	2
right adrenal gland cortex	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAR	184	broad	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
CYP21A2	130	tissue_specific	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAR	1,246
CYP21A2	28

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAR	P49675	4
CYP21A2	P08686	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
Defective CYP21A2 causes AH3	1	2855.0×	0.004	CYP21A2
Mineralocorticoid biosynthesis	1	713.8×	0.007	CYP21A2
Glucocorticoid biosynthesis	1	439.2×	0.007	CYP21A2
Pregnenolone biosynthesis	1	407.9×	0.007	STAR
Metabolism of steroid hormones	1	259.6×	0.008	STAR
Endogenous sterols	1	196.9×	0.009	CYP21A2
Metabolism of steroids	1	68.8×	0.023	STAR
Mitochondrial protein degradation	1	57.1×	0.024	STAR
Metabolism of lipids	1	15.8×	0.076	STAR
Metabolism of proteins	1	6.2×	0.165	STAR
Metabolism	1	5.8×	0.165	STAR

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucocorticoid biosynthetic process	2	1532.0×	4e-06	STAR, CYP21A2
steroid biosynthetic process	2	601.9×	1e-05	STAR, CYP21A2
positive regulation of bile acid biosynthetic process	1	2808.7×	0.001	STAR
mineralocorticoid biosynthetic process	1	2106.5×	0.001	CYP21A2
cortisol biosynthetic process	1	1053.2×	0.002	CYP21A2
regulation of steroid biosynthetic process	1	766.0×	0.002	STAR
intracellular cholesterol transport	1	648.1×	0.002	STAR
sterol metabolic process	1	421.3×	0.003	CYP21A2
steroid metabolic process	1	168.5×	0.007	CYP21A2
cholesterol metabolic process	1	98.0×	0.010	STAR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
CYP21A2	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP21A2	4	4
STAR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP21A2	15	Binding:10, ADMET:5
STAR	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP21A2	1.14.14.16	steroid 21-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP21A2
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	STAR

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)
STAR	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.