Congenital isolated adrenocorticotropic hormone deficiency

Summary

Congenital isolated adrenocorticotropic hormone deficiency (MONDO:0008720) is a disease caused by TBX19 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: TBX19 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 91
• Phenotypes (HPO): 11
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001998	Neonatal hypoglycemia	Obligate (100%)
HP:0008163	Decreased circulating cortisol level	Obligate (100%)
HP:0011735	Adrenocorticotropin deficient adrenal insufficiency	Obligate (100%)
HP:0000835	Adrenal hypoplasia	Very frequent (80-99%)
HP:0002615	Hypotension	Very frequent (80-99%)
HP:0002902	Hyponatremia	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0002173	Hypoglycemic seizures	Frequent (30-79%)
HP:0006579	Prolonged neonatal jaundice	Frequent (30-79%)
HP:0012115	Hepatitis	Occasional (5-29%)
HP:0002153	Hyperkalemia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital isolated adrenocorticotropic hormone deficiency
Mondo ID	MONDO:0008720
EFO	EFO:1001979
MeSH	C535668
OMIM	201400
Orphanet	199296
DOID	DOID:0080150
SNOMED CT	237692001
UMLS	C0342388
MedGen	137968
GARD	0005727
Is cancer (heuristic)	no

Also known as: ACTH deficiency, isolated · adrenocorticotropic hormone deficiency · congenital isolated adrenocorticotropic hormone deficiency (disease) · IAD · isolated ACTH deficiency · isolated adrenocorticotropic hormone deficiency

Data availability: 91 ClinVar variants · 4 GenCC gene-disease records · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › combined pituitary hormone deficiencies, genetic form › congenital isolated adrenocorticotropic hormone deficiency

Related subtypes (8): isolated congenital growth hormone deficiency, septooptic dysplasia, non-acquired combined pituitary hormone deficiency with spine abnormalities, short stature-pituitary and cerebellar defects-small sella turcica syndrome, pituitary hormone deficiency, combined, 6, panhypopituitarism, pituitary hormone deficiency, combined, 1, pituitary hormone deficiency, combined or isolated, 8

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

91 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 16 benign, 14 pathogenic, 9 likely pathogenic, 7 conflicting classifications of pathogenicity, 2 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
587393	NM_000329.3(RPE65):c.825C>G (p.Tyr275Ter)	RPE65	Pathogenic	criteria provided, multiple submitters, no conflicts
1676659	NM_005149.3(TBX19):c.688G>T (p.Glu230Ter)	TBX19	Pathogenic	criteria provided, multiple submitters, no conflicts
1687306	NM_005149.3(TBX19):c.665+1G>T	TBX19	Pathogenic	criteria provided, single submitter
293458	NM_005149.3(TBX19):c.535C>T (p.Arg179Ter)	TBX19	Pathogenic	criteria provided, multiple submitters, no conflicts
3340178	NM_005149.3(TBX19):c.727+1G>A	TBX19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488619	NM_005149.3(TBX19):c.568C>T (p.Gln190Ter)	TBX19	Pathogenic	criteria provided, single submitter
495297	K146R	TBX19	Pathogenic	no assertion criteria provided
5440	NM_005149.3(TBX19):c.856C>T (p.Arg286Ter)	TBX19	Pathogenic	criteria provided, multiple submitters, no conflicts
5441	NM_005149.3(TBX19):c.383C>T (p.Ser128Phe)	TBX19	Pathogenic	no assertion criteria provided
5442	NM_005149.3(TBX19):c.257T>G (p.Met86Arg)	TBX19	Pathogenic	no assertion criteria provided
5443	NM_005149.3(TBX19):c.782del (p.Asn261fs)	TBX19	Pathogenic	criteria provided, multiple submitters, no conflicts
560672	NM_005149.3(TBX19):c.158_159del (p.Arg53fs)	TBX19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560673	NM_005149.3(TBX19):c.265del (p.Leu89fs)	TBX19	Pathogenic	no assertion criteria provided
560675	NM_005149.3(TBX19):c.665+1del	TBX19	Pathogenic	no assertion criteria provided
561125	NM_005149.3(TBX19):c.627C>G (p.Tyr209Ter)	TBX19	Pathogenic	criteria provided, multiple submitters, no conflicts
828147	NM_005149.3(TBX19):c.377C>T (p.Pro126Leu)	TBX19	Pathogenic	criteria provided, single submitter
1283918	NM_005149.3(TBX19):c.206G>A (p.Arg69Gln)	TBX19	Likely pathogenic	criteria provided, single submitter
2500768	NM_005149.3(TBX19):c.666-2A>T	TBX19	Likely pathogenic	criteria provided, single submitter
3065395	NM_005149.3(TBX19):c.617A>G (p.Lys206Arg)	TBX19	Likely pathogenic	criteria provided, single submitter
3233371	NM_005149.3(TBX19):c.604-1G>C	TBX19	Likely pathogenic	criteria provided, single submitter
4277977	NM_005149.3(TBX19):c.566C>T (p.Thr189Ile)	TBX19	Likely pathogenic	criteria provided, single submitter
4294492	NM_005149.3(TBX19):c.469-1G>A	TBX19	Likely pathogenic	criteria provided, single submitter
4848595	NM_005149.3(TBX19):c.288G>A (p.Thr96=)	TBX19	Likely pathogenic	criteria provided, single submitter
4848823	NM_005149.3(TBX19):c.299G>A (p.Arg100His)	TBX19	Likely pathogenic	criteria provided, single submitter
828166	NM_005149.3(TBX19):c.608C>T (p.Thr203Met)	TBX19	Likely pathogenic	criteria provided, single submitter
1645569	NM_005149.3(TBX19):c.603+7GT[17]	TBX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293456	NM_005149.3(TBX19):c.204-3T>C	TBX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293457	NM_005149.3(TBX19):c.315C>T (p.Asn105=)	TBX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293460	NM_005149.3(TBX19):c.597T>C (p.Asn199=)	TBX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293473	NM_005149.3(TBX19):c.603+13G>T	TBX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TBX19	Definitive	Autosomal recessive	congenital isolated adrenocorticotropic hormone deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX19	Orphanet:199296	Congenital isolated ACTH deficiency
RPE65	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
RPE65	Orphanet:65	Leber congenital amaurosis
RPE65	Orphanet:791	Retinitis pigmentosa

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
TBX19	HGNC:11596	ENSG00000143178	O60806	T-box transcription factor TBX19	gencc,clinvar
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX19	T-box transcription factor TBX19	Transcriptional regulator involved in developmental processes.
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX19	Transcription factor	no		TF_T-box, TF_Brachyury, p53-like_TF_DNA-bd_sf
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
lower esophagus mucosa	1
pituitary gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1
retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX19	167	tissue_specific	yes	adenohypophysis, pituitary gland, lower esophagus mucosa
RPE65	92	tissue_specific	marker	pigmented layer of retina, retina, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPE65	1,414
TBX19	869

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPE65	Q16518	95.34
TBX19	O60806	64.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
The canonical retinoid cycle in rods (twilight vision)	1	519.1×	0.006	RPE65
Visual phototransduction	1	259.6×	0.006	RPE65
Sensory Perception	1	95.2×	0.011	RPE65

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
zeaxanthin biosynthetic process	1	8426.0×	0.002	RPE65
vitamin A metabolic process	1	1203.7×	0.007	RPE65
retina homeostasis	1	561.7×	0.007	RPE65
neural retina development	1	468.1×	0.007	RPE65
retinal metabolic process	1	468.1×	0.007	RPE65
pituitary gland development	1	324.1×	0.007	TBX19
detection of light stimulus involved in visual perception	1	324.1×	0.007	RPE65
cell fate specification	1	263.3×	0.007	TBX19
retinoid metabolic process	1	247.8×	0.007	RPE65
mesoderm formation	1	247.8×	0.007	TBX19
regulation of cell differentiation	1	216.1×	0.007	TBX19
heart morphogenesis	1	187.2×	0.008	TBX19
circadian rhythm	1	122.1×	0.011	RPE65
anatomical structure morphogenesis	1	69.6×	0.017	TBX19
regulation of cell population proliferation	1	57.7×	0.020	TBX19
visual perception	1	39.8×	0.027	RPE65
regulation of transcription by RNA polymerase II	1	5.8×	0.164	TBX19

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBX19	0	0
RPE65	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase

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

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	1	RPE65
E	Difficult family or no structure, no drug	1	TBX19

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBX19	0	—
RPE65	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns