Congenital Isolated ACTH Deficiency

Mendelian MONDO:0008720 Pathograph 26 Show in embeddings browser Adrenal Insufficiency Hypopituitarism

Congenital isolated ACTH deficiency is an autosomal recessive form of secondary (central) adrenal insufficiency in which the anterior pituitary fails to produce adrenocorticotropin (ACTH) while every other pituitary hormone axis is preserved and pituitary imaging is normal. This entry is scoped to the neonatal-onset form caused by biallelic loss-of-function variants in TBX19 (TPIT), a T-box transcription factor expressed only in the pituitary pro-opiomelanocortin (POMC) lineages. Without TBX19, corticotroph precursors form but cannot complete terminal differentiation or express POMC, so ACTH is absent, the adrenal cortex is understimulated and becomes hypoplastic, and cortisol is deficient from birth. Affected neonates present with severe hypoglycemia, often with seizures, prolonged cholestatic jaundice, and a high risk of sudden neonatal death; an earlier sibling's unexplained neonatal death is a common feature of the family history. Mineralocorticoid secretion is preserved, so hyperkalemia is not a feature. Lifelong glucocorticoid replacement with hydrocortisone, with stress dosing, reverses the metabolic and hepatic features, and early treatment allows normal growth and development.

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1
Inheritance
6
Pathophys.
15
Phenotypes
26
Pathograph
1
Genes
3
Variants
2
Medical Actions
1
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Affected individuals are homozygous or compound heterozygous for TBX19 loss-of-function variants, and their parents are unaffected heterozygous carriers. Consanguinity is frequent in reported families.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:15613420 SUPPORT Human Clinical
"All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission."
Biallelic variants in patients with heterozygous unaffected parents establish autosomal recessive transmission.
PMID:22170728 SUPPORT Human Clinical
"These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers."
The largest reported series confirms recessive inheritance with healthy heterozygous carriers.
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Pathophysiology

6
TBX19 Biallelic Loss of Function
Biallelic germline TBX19 variants abolish the function of the T-box transcription factor TPIT. Reported alleles include nonsense and frameshift variants that trigger nonsense-mediated mRNA decay, splice-site and exonic synonymous variants that cause missplicing, multi-exon deletions, and missense variants within the T-box that abolish DNA binding or disrupt protein-protein interactions with PITX1 and coactivators.
TBX19 hgnc:11596 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TBX19 (hgnc:11596). hgnc:11596 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Homozygous or compound heterozygous loss-of-function TBX19 alleles.
DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). GO:0000981 is a molecular function from the Gene Ontology.
Downstream
Loss of TPIT-PITX1 Activation of POMC Transcription
Show evidence (4 references)
PMID:22170728 SUPPORT Human Clinical
"TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects."
Summarizes the loss-of-function mechanisms of the patient alleles.
PMID:12651888 SUPPORT In Vitro
"The S128F and I171T mutations were found to be completely devoid of activity in transfected cells (Fig. 3C,E) and to have no in vitro DNA-binding activity (Fig. 3D,F)."
Transfection and gel-shift assays show patient missense alleles lose transcriptional and DNA-binding activity.
PMID:17652218 SUPPORT In Vitro
"Although the M86 residue is located within the T-box DNA-binding domain, it did not affect monomer DNA-binding activity per se, but it impaired DNA binding with other DNA-bound proteins, including itself (homodimers) and pituitary homeobox 1 (Pitx1)."
A missense allele can cause loss of function by disrupting cooperative binding with PITX1 rather than monomer DNA binding.
+ 1 more reference
Loss of TPIT-PITX1 Activation of POMC Transcription
In pituitary POMC-lineage cells TPIT binds a POMC regulatory element next to the homeoprotein PITX1, and the two factors cooperate to activate POMC transcription. TPIT is not expressed in hypothalamic POMC neurons or in other tissues, so its loss removes POMC expression specifically from the pituitary while sparing extra-pituitary POMC.
corticotroph CL:0002309 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves corticotroph (CL:0002309). CL:0002309 is a cell type from the Cell Ontology.
positive regulation of transcription by RNA polymerase II GO:0045944 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology.
Downstream
Arrested Corticotroph Terminal Differentiation
Show evidence (3 references)
PMID:11290323 SUPPORT In Vitro
"In pituitary cells, Tpit activation of POMC gene transcription requires cooperation with Pitx1, the two factors binding to contiguous sites within the same regulatory element."
Establishes that TPIT activates POMC transcription together with PITX1.
PMID:11290323 SUPPORT Model Organism
"We identified Tpit, a novel T box factor only present in the two pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, and apparently in no other tissue, including hypothalamic POMC neurons."
The restricted expression of TPIT explains why the deficiency is confined to pituitary POMC.
PMID:39776042 SUPPORT In Vitro
"TBX19 and PITX1 cooperated, resulting in a strong synergistic activation effect on POMC transcriptional expression."
Confirms the TBX19-PITX1 synergy on the POMC promoter with the human protein.
Arrested Corticotroph Terminal Differentiation
TPIT is required for late differentiation of the POMC lineage but not for lineage commitment. In its absence, presumptive corticotrophs are present at about normal abundance and express early markers such as NeuroD1, but they do not reach terminal differentiation, so the anterior pituitary is left with very few ACTH-producing cells. In the mouse intermediate lobe, cells destined to be melanotrophs instead become gonadotrophs; the human intermediate lobe regresses during fetal life, so this fate switch has no clear human counterpart.
corticotroph CL:0002309 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves corticotroph (CL:0002309). CL:0002309 is a cell type from the Cell Ontology.
corticotropin hormone secreting cell differentiation GO:0060128 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased corticotropin hormone secreting cell differentiation (GO:0060128). GO:0060128 is a biological process from the Gene Ontology.
adenohypophysis UBERON:0002196 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in adenohypophysis (UBERON:0002196). UBERON:0002196 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pituitary ACTH Deficiency
Show evidence (3 references)
PMID:12651892 SUPPORT Model Organism
"Tpit is a positive regulator for late POMC cell differentiation and POMC expression, but it is not essential for lineage commitment."
Tpit knockout mice show that TPIT acts at the terminal step of POMC-lineage differentiation.
PMID:12651892 SUPPORT Model Organism
"showing that the presumptive corticotroph cells are present (at about normal abundance) but are not able to reach terminal differentiation (POMC expression)."
Corticotroph precursors persist but cannot complete differentiation without TPIT.
PMID:12651892 SUPPORT Model Organism
"Inactivation of the Tpit gene results in almost complete loss of POMC-expressing cells in this tissue, which now has a large number of gonadotrophs and a few clusters of Pit-1-independent thyrotrophs."
In the mouse intermediate lobe, loss of TPIT also redirects precursors to the gonadotroph fate.
Pituitary ACTH Deficiency
Plasma ACTH is low or undetectable and CRH does not raise it. Other anterior pituitary hormones (GH, TSH, gonadotropins, prolactin) are produced normally and the pituitary is structurally normal, which separates this disorder from combined pituitary hormone deficiencies. Autopsy of an affected neonate showed a pituitary of normal morphology lacking ACTH immunoreactivity.
adenohypophysis UBERON:0002196 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in adenohypophysis (UBERON:0002196). UBERON:0002196 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Glucocorticoid Deficiency
Adrenal Cortex Hypoplasia
Decreased circulating ACTH concentration
Show evidence (3 references)
PMID:12651888 SUPPORT Model Organism
"Homozygous (−/−) mutant mice have very low, albeit detectable, plasma ACTH levels, whereas wild-type (+/+) and heterozygous (+/−) mice have similar normal levels (Fig. 1A)."
Tpit-null mice reproduce the ACTH deficiency.
PMID:12651888 SUPPORT Human Clinical
"In contrast, acute or repeated treatment with CRH never elicited a response (Table 1, patients 2, 3, 5 and 6)."
Absent response to CRH in patients localizes the defect to the pituitary corticotroph.
PMID:22170728 SUPPORT Human Clinical
"Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones."
Defines the isolated character of the pituitary deficiency.
Adrenal Cortex Hypoplasia
Chronic lack of ACTH trophic drive leaves the adrenal cortex hypoplastic, with the greatest loss in the glucocorticoid-producing zona fasciculata. The adrenals can still respond partially to repeated ACTH injections, showing that the gland is understimulated rather than intrinsically defective.
zona fasciculata of adrenal gland UBERON:0002054 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in zona fasciculata of adrenal gland (UBERON:0002054). UBERON:0002054 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Glucocorticoid Deficiency
Adrenal hypoplasia
Show evidence (2 references)
PMID:12651888 SUPPORT Model Organism
"In addition, adrenal glands were found to be hypoplastic, with the most significant loss at the level of the glucocorticoid-producing fasciculata layer (Fig. 1C)."
Tpit-null mice show adrenal hypoplasia centered on the zona fasciculata.
PMID:12651888 SUPPORT Human Clinical
"These patients did not show a cortisol response to acute injection of ACTH (Table 1), but in two cases (patients 2 and 3), repeated ACTH injection was found to significantly increase cortisol, indicating that adrenal function may be restored upon multiple challenges with ACTH."
The adrenal defect in patients is secondary and partly reversible with repeated ACTH.
Glucocorticoid Deficiency
Cortisol is low or undetectable from birth. Glucocorticoid deficiency removes cortisol support of fasting glucose production and of hepatic and vascular function; this is the proximal cause of the neonatal hypoglycemia, the prolonged cholestatic jaundice and the risk of fatal adrenal crisis. Deficient fetal adrenal steroidogenesis can also lower maternal serum estriol during pregnancy.
cortisol biosynthetic process GO:0034651 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cortisol biosynthetic process (GO:0034651). GO:0034651 is a biological process from the Gene Ontology.
Downstream
Neonatal hypoglycemia
Prolonged cholestatic jaundice
Sudden neonatal death
Decreased circulating cortisol level
Adrenocorticotropin deficient adrenal insufficiency
Hyponatremia
Hypotension
Fatigue
Feeding difficulties
Show evidence (2 references)
PMID:12651888 SUPPORT Model Organism
"The impact of low plasma ACTH on adrenal function was next assessed, and we observed undetectable plasma corticosterone in homozygous mutant, but not in wild-type or heterozygous mice (Fig. 1B)."
Tpit-null mice have absent glucocorticoid production.
PMID:12651888 SUPPORT Human Clinical
"Investigation of pituitary/adrenal function in IAD patients with TPIT mutations (Table 1) showed decreased/undetectable baseline plasma levels of ACTH and cortisol."
Patients with TPIT mutations have low or undetectable cortisol together with low ACTH.
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Pathograph

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Pathograph: causal mechanism network for Congenital Isolated ACTH Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Cardiovascular 1
Hypotension VERY_FREQUENT HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotension (HP:0002615). HP:0002615 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199296 SUPPORT Other
"HP:0002615 | Hypotension | Very frequent (99-80%)"
Orphanet annotates hypotension as very frequent.
Digestive 3
Prolonged cholestatic jaundice FREQUENT Prolonged neonatal jaundice HP:0006579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged neonatal cholestatic jaundice, annotated with Prolonged neonatal jaundice (HP:0006579). HP:0006579 is a phenotype from the Human Phenotype Ontology.
Sequelae: Giant cell hepatitis
Show evidence (4 references)
ORPHA:199296 SUPPORT Other
"HP:0006579 | Prolonged neonatal jaundice | Frequent (79-30%)"
Orphanet annotates prolonged neonatal jaundice as frequent.
PMID:12651888 SUPPORT Human Clinical
"Three patients suffered from prolonged neonatal cholestatic jaundice."
Cholestatic jaundice in three of eight patients with TPIT mutations.
PMID:15301051 SUPPORT Human Clinical
"A 5 day-old male infant was admitted for hypoglycemia, limpness and conjugated hyperbilirubinemia."
Conjugated hyperbilirubinemia with hypoglycemia at presentation in a TPIT-mutant neonate.
+ 1 more reference
Giant cell hepatitis HP:0200084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Giant cell cholestatic hepatitis, annotated with Giant cell hepatitis (HP:0200084). HP:0200084 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12651888 SUPPORT Human Clinical
"Hepatic needle biopsy in two cases revealed accumulation of biliary pigments in the liver cells and in the bile canaliculi, and also giant cells cholestatic hepatitis."
Liver biopsy in two TPIT-mutant patients showed giant cell cholestatic hepatitis.
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor feeding, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39664280 SUPPORT Human Clinical
"The main clinical manifestations were hypoglycemia, jaundice, convulsions, feeding difficulties, poor mental response, hypotonia, and growth retardation."
Feeding difficulties are among the main manifestations in a pooled review of 35 cases.
Endocrine 4
Adrenocorticotropin deficient adrenal insufficiency OBLIGATE HP:0011735 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary adrenal insufficiency due to isolated ACTH deficiency, annotated with Adrenocorticotropin deficient adrenal insufficiency (HP:0011735). HP:0011735 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199296 SUPPORT Other
"HP:0011735 | Adrenocorticotropin deficient adrenal insufficiency | Obligate (100%)"
Orphanet annotates ACTH-deficient adrenal insufficiency as obligate.
PMID:34564059 SUPPORT Human Clinical
"Congenital isolated ACTH deficiency (IAD) is a rare cause of secondary adrenal insufficiency characterised by low plasma ACTH and serum cortisol in the setting of otherwise preserved anterior pituitary function."
Describes the secondary adrenal insufficiency with preserved other pituitary function.
Decreased circulating ACTH concentration HP:0002920 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low plasma ACTH, annotated with Decreased circulating ACTH concentration (HP:0002920). HP:0002920 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12651888 SUPPORT Human Clinical
"Investigation of pituitary/adrenal function in IAD patients with TPIT mutations (Table 1) showed decreased/undetectable baseline plasma levels of ACTH and cortisol."
Low or undetectable plasma ACTH in patients with TPIT mutations.
PMID:30747411 SUPPORT Human Clinical
"The child was hypocortisolemic (0.1 μg/dl), and ACTH levels were extremely low (< 5.0 pg/ml)."
Case report documenting extremely low ACTH with hypocortisolemia.
Decreased circulating cortisol level OBLIGATE HP:0008163 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low plasma cortisol, annotated with Decreased circulating cortisol level (HP:0008163). HP:0008163 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199296 SUPPORT Other
"HP:0008163 | Decreased circulating cortisol level | Obligate (100%)"
Orphanet annotates low cortisol as obligate.
PMID:39664280 SUPPORT Human Clinical
"Further endocrine examination showed low levels of cortisol (<0.1 µg/dl) and adrenocorticotropic hormone (ACTH, 2.l pg/ml), but the levels of growth hormone (GH), luteinizing hormone, and thyroid stimulating hormone were within normal limits (Table 1)."
Undetectable cortisol with low ACTH and normal other pituitary hormones in a TBX19 case.
Adrenal hypoplasia VERY_FREQUENT HP:0000835 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adrenal hypoplasia (HP:0000835). HP:0000835 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199296 SUPPORT Other
"HP:0000835 | Adrenal hypoplasia | Very frequent (99-80%)"
Orphanet annotates adrenal hypoplasia as very frequent.
PMID:12651888 SUPPORT Human Clinical
"Investigation at autopsy of the dead sibling of family V revealed bilateral adrenal hypoplasia and normal pituitary morphology with the absence of ACTH immunoreactivity (Dechelotte et al. 1994), which is very similar to the phenotype of Tpit−/− mice."
Autopsy of an affected sibling showed bilateral adrenal hypoplasia.
Metabolism 3
Neonatal hypoglycemia OBLIGATE HP:0001998 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal hypoglycemia (HP:0001998). HP:0001998 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hypoglycemic seizures Apnea
Show evidence (2 references)
ORPHA:199296 SUPPORT Other
"HP:0001998 | Neonatal hypoglycemia | Obligate (100%)"
Orphanet annotates neonatal hypoglycemia as obligate.
PMID:12651888 SUPPORT Human Clinical
"Neonatal hypoglycemia was the major reason leading to diagnosis of ACTH deficiency."
Hypoglycemia was the presenting feature in the first TPIT-mutant series.
Hypoglycemic seizures FREQUENT HP:0002173 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemic seizures (HP:0002173). HP:0002173 is a phenotype from the Human Phenotype Ontology.
Sequelae: Global developmental delay
Show evidence (2 references)
ORPHA:199296 SUPPORT Other
"HP:0002173 | Hypoglycemic seizures | Frequent (79-30%)"
Orphanet annotates hypoglycemic seizures as frequent.
PMID:32344415 SUPPORT Human Clinical
"After hydrocortisone treatment, there was resolution of the hypoglycemia and the convulsions were controlled."
Convulsions accompanied hypoglycemia and resolved with glucocorticoid replacement.
Hyponatremia VERY_FREQUENT HP:0002902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyponatremia (HP:0002902). HP:0002902 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:199296 SUPPORT Other
"HP:0002902 | Hyponatremia | Very frequent (99-80%)"
Orphanet annotates hyponatremia as very frequent.
ORPHA:199296 SUPPORT Other
"HP:0002153 | Hyperkalemia | Excluded (0%)"
Orphanet records hyperkalemia as excluded, which distinguishes this disorder from primary adrenal insufficiency.
Nervous System 1
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay after delayed treatment, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:39664280 SUPPORT Human Clinical
"Among the 15 patients with different degrees of nervous system developmental delays, 13 initiated treatment when more than 1-year-old."
Developmental delay clusters in patients whose treatment started late.
PMID:36890856 SUPPORT BACKGROUND Human Clinical
"Indeed, one of the main consequences of undiagnosed adrenal crises and inadequately adjusted hydrocortisone treatment in IAD due to TBX19 mutations is cognitive impairment (2, 4, 5, 20)."
Cognitive impairment follows undiagnosed crises or inadequate treatment.
PMID:31998673 SUPPORT Human Clinical
"The older brother developed subdural hematoma, intractable epilepsy, and developmental delays. In contrast, the younger sister received timely glucocorticoid replacement therapy and had no long-term complications while maintaining a good quality of life."
Sibling comparison in which only the late-treated child developed delays.
Respiratory 1
Apnea HP:0002104 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Apnea (HP:0002104). HP:0002104 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27535729 SUPPORT Human Clinical
"He was referred to our hospital for further evaluation and management because of signs of jaundice, hypoglycaemia, one episode of apnoea lasting about 20 s and poor feeding at day 11 of life."
Apnea at presentation in a TBX19-confirmed neonate.
PMID:34564059 SUPPORT Human Clinical
"We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks."
Respiratory arrest with hypoglycemia at presentation in a TBX19 neonate.
Constitutional 2
Sudden neonatal death Sudden death HP:0001699 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden neonatal death, annotated with Sudden death (HP:0001699). HP:0001699 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:15613420 SUPPORT Human Clinical
"This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death."
The disease is identified as an underestimated cause of neonatal death.
PMID:12651888 SUPPORT Human Clinical
"Two patients were the second children of the sibship, the eldest sibling having died suddenly at birth (families IV and V)."
Prior sudden neonatal sibling deaths in families with TPIT mutations.
PMID:27535729 SUPPORT Human Clinical
"This diagnosis has a 20% mortality potential if unrecognised."
Estimated mortality of unrecognized neonatal IAD.
+ 1 more reference
Fatigue VERY_FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:199296 SUPPORT Other
"HP:0012378 | Fatigue | Very frequent (99-80%)"
Orphanet annotates fatigue as very frequent.
🧬

Genetic Associations

1
TBX19 (Causative)
Gene: TBX19 hgnc:11596 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TBX19 (hgnc:11596). hgnc:11596 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:12651888 SUPPORT Human Clinical
"This work defines congenital early onset IAD as a relatively homogeneous clinical entity caused by recessive transmission of loss-of-function mutations in the TPIT gene."
Establishes TBX19 loss of function as the cause of congenital early-onset IAD.
PMID:11290323 SUPPORT Human Clinical
"TPIT gene mutations were found in patients with isolated deficiency of pituitary POMC-derived ACTH, in support of an essential role of Tpit for differentiation of the pituitary POMC lineage."
First report of TPIT mutations in patients with isolated ACTH deficiency.
Variants (3)
TBX19 c.856C>T (p.Arg286Ter) Pathogenic
Gene: TBX19 hgnc:11596 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TBX19 (hgnc:11596). hgnc:11596 is a gene from the HUGO Gene Nomenclature Committee.
Recurrent nonsense variant (R286X) reported homozygous in multiple families of different origins; predicted to cause nonsense-mediated mRNA decay.
Show evidence (2 references)
PMID:39776042 SUPPORT Human Clinical
"The TBX19 variant, c.856C>T (p.R286*) was classified as pathogenic according to ACMG"
ACMG classification of the recurrent R286* variant.
PMID:29858850 SUPPORT Human Clinical
"Both cases were homozygous for c.856 C>T (p.R286*), and hydrocortisone treatment was initiated."
Homozygous R286* in affected siblings.
TBX19 p.Met86Arg
Gene: TBX19 hgnc:11596 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TBX19 (hgnc:11596). hgnc:11596 is a gene from the HUGO Gene Nomenclature Committee.
Missense variant in the T-box that preserves monomer DNA binding but disrupts cooperative binding with PITX1 and recruitment of the SRC2 coactivator; reported in compound heterozygosity with c.782delA.
Show evidence (2 references)
PMID:17652218 SUPPORT In Vitro
"Furthermore, TPIT M86R is deficient in the recruitment of the coactivator SRC2 that partly mediates the CRH stimulation of proopiomelanocortin transcription."
Functional characterization of the M86R allele.
PMID:15476446 SUPPORT Human Clinical
"The missense mutation (Met86Arg) in exon 2 within the T-box (or DNA binding domain) is predicted to disrupt DNA binding."
Identification of M86R in early-onset IAD siblings, who were compound heterozygous with a frameshift allele.
TBX19 c.840del (p.Glu280AspfsTer27) Pathogenic
Gene: TBX19 hgnc:11596 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TBX19 (hgnc:11596). hgnc:11596 is a gene from the HUGO Gene Nomenclature Committee.
Frameshift variant found in four patients from three families with roots in the same region of northern Morocco, suggesting a founder effect.
Show evidence (1 reference)
PMID:36890856 SUPPORT Human Clinical
"Two of these families were consanguineous, and after investigations all of three were discovered to have roots in the same mountainous region of northern Morocco, suggesting a founder effect."
Founder variant in northern Moroccan families.
💊

Medical Actions

2
Hydrocortisone Replacement Therapy
Action: Glucocorticoid replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Glucocorticoid replacement therapy, annotated with Hormone Replacement Therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Agent: hydrocortisone CHEBI:17650 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydrocortisone, annotated with cortisol (CHEBI:17650). CHEBI:17650 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Lifelong oral hydrocortisone replacement, around 15 mg/m2/day in reported TBX19 cases, with increased doses during illness or other stress. Treatment reverses hypoglycemia, seizures and cholestasis, and early treatment allows normal growth and development.
Mechanism Target:
BYPASSES Glucocorticoid Deficiency — Exogenous hydrocortisone replaces the cortisol the ACTH-deprived adrenal cortex cannot make, bypassing the pituitary defect.
Show evidence (1 reference)
PMID:12651888 SUPPORT Human Clinical
"Symptoms of adrenal insufficiency disappeared after cortisol replacement therapy in all cases."
Cortisol replacement resolved adrenal insufficiency in all TPIT-mutant patients.
Target Phenotypes: Neonatal hypoglycemia HP:0001998 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neonatal hypoglycemia (HP:0001998). HP:0001998 is a phenotype from the Human Phenotype Ontology. Prolonged neonatal jaundice HP:0006579 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Prolonged neonatal jaundice (HP:0006579). HP:0006579 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:36890856 SUPPORT Human Clinical
"Hydrocortisone therapy was continued at 15 mg/m2/day (increased as appropriate in stress situations)."
Maintenance dose with stress adjustment used in TBX19 patients.
PMID:36890856 SUPPORT Human Clinical
"Early diagnosis, timely treatment (hydrocortisone therapy) and preventive education allowed normal development, growth and quality of life in all patients."
Early hydrocortisone with education gives normal outcomes.
PMID:40727905 SUPPORT Human Clinical
"Early hydrocortisone replacement therapy is significant for survival without sequelae."
Early replacement prevents death and sequelae.
+ 1 more reference
Genetic Counseling and Prenatal Diagnosis
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Identifying the familial TBX19 variants permits counseling of carrier parents and prenatal or immediate postnatal diagnosis, so that glucocorticoid replacement can start at birth.
Show evidence (1 reference)
PMID:15613420 SUPPORT Human Clinical
"Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy."
Molecular diagnosis enables prenatal diagnosis and early treatment in at-risk families.
🔬

Diagnosis

4
Morning ACTH and cortisol measurement
Low or undetectable cortisol together with low plasma ACTH, measured in the morning or during spontaneous hypoglycemia, with normal results for the other anterior pituitary axes.
Show evidence (1 reference)
PMID:27535729 SUPPORT Human Clinical
"The other hormone levels (luteinising hormone, follicle stimulating hormone, growth hormone, insulin-like growth factor 1, testosterone, thyroid-stimulating hormone, T4, T3) were within normal limits."
Other pituitary axes are normal in a TBX19-confirmed case, establishing the isolated deficiency.
ACTH and CRH stimulation testing
Cortisol fails to rise after a single ACTH injection but can rise after repeated ACTH injections, while CRH elicits no response, localizing the defect to the corticotroph.
Show evidence (1 reference)
PMID:12651888 SUPPORT Human Clinical
"These patients did not show a cortisol response to acute injection of ACTH (Table 1), but in two cases (patients 2 and 3), repeated ACTH injection was found to significantly increase cortisol, indicating that adrenal function may be restored upon multiple challenges with ACTH."
Characteristic response pattern to ACTH testing.
Maternal serum estriol on prenatal screening
An isolated low maternal unconjugated estriol on the triple-marker screen, with normal fetal ultrasound and after exclusion of steroid sulfatase deficiency and Smith-Lemli-Opitz syndrome, reflects deficient fetal adrenal steroidogenesis and has been reported as a prenatal clue in a TPIT-mutant pregnancy.
Show evidence (2 references)
PMID:16390921 SUPPORT Human Clinical
"A low estriol level in the context of normal fetal sonography and growth, after exclusion of placental sulfatase deficiency and Smith-Lemli-Opitz syndrome, should raise the suspicion of deficient fetal steroidogenesis, which leads to decreased production of adrenal dehydroepiandrosterone sulfate."
Links low maternal estriol to deficient fetal adrenal steroidogenesis.
PMID:16390921 SUPPORT Human Clinical
"In the third pregnancy, a low level was found again, and the mother was referred to our tertiary center."
Recurrent low maternal estriol in successive pregnancies with an affected fetus.
TBX19 molecular testing
Sequencing of TBX19, including splice regions and copy-number analysis, confirms the diagnosis and allows carrier testing and prenatal diagnosis in at-risk families. Synonymous exonic variants may act through missplicing.
Show evidence (1 reference)
PMID:15613420 SUPPORT Human Clinical
"Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy."
Molecular diagnosis enables prenatal diagnosis and early treatment.
{ }

Source YAML

click to show 
name: Congenital Isolated ACTH Deficiency
creation_date: "2026-10-15T01:35:55Z"
category: Mendelian
disease_term:
  preferred_term: congenital isolated adrenocorticotropic hormone deficiency
  term:
    id: MONDO:0008720
    label: congenital isolated adrenocorticotropic hormone deficiency
parents:
- Adrenal Insufficiency
- Hypopituitarism
synonyms:
- congenital isolated adrenocorticotropic hormone deficiency
- isolated ACTH deficiency
- isolated adrenocorticotropic hormone deficiency
- ACTH deficiency, isolated
- IAD
- TBX19 deficiency
- TPIT deficiency
description: >-
  Congenital isolated ACTH deficiency is an autosomal recessive form of
  secondary (central) adrenal insufficiency in which the anterior pituitary
  fails to produce adrenocorticotropin (ACTH) while every other pituitary
  hormone axis is preserved and pituitary imaging is normal. This entry is
  scoped to the neonatal-onset form caused by biallelic loss-of-function
  variants in TBX19 (TPIT), a T-box transcription factor expressed only in the
  pituitary pro-opiomelanocortin (POMC) lineages. Without TBX19, corticotroph
  precursors form but cannot complete terminal differentiation or express
  POMC, so ACTH is absent, the adrenal cortex is understimulated and becomes
  hypoplastic, and cortisol is deficient from birth. Affected neonates present
  with severe hypoglycemia, often with seizures, prolonged cholestatic jaundice,
  and a high risk of sudden neonatal death; an earlier sibling's unexplained
  neonatal death is a common feature of the family history. Mineralocorticoid
  secretion is preserved, so hyperkalemia is not a feature. Lifelong
  glucocorticoid replacement with hydrocortisone, with stress dosing, reverses
  the metabolic and hepatic features, and early treatment allows normal growth
  and development.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous or compound heterozygous for TBX19
    loss-of-function variants, and their parents are unaffected heterozygous
    carriers. Consanguinity is frequent in reported families.
  evidence:
  - reference: PMID:15613420
    reference_title: "Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission."
    explanation: Biallelic variants in patients with heterozygous unaffected parents establish autosomal recessive transmission.
  - reference: PMID:22170728
    reference_title: Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers."
    explanation: The largest reported series confirms recessive inheritance with healthy heterozygous carriers.
pathophysiology:
- name: TBX19 Biallelic Loss of Function
  description: >-
    Biallelic germline TBX19 variants abolish the function of the T-box
    transcription factor TPIT. Reported alleles include nonsense and frameshift
    variants that trigger nonsense-mediated mRNA decay, splice-site and exonic
    synonymous variants that cause missplicing, multi-exon deletions, and
    missense variants within the T-box that abolish DNA binding or disrupt
    protein-protein interactions with PITX1 and coactivators.
  role: trigger
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous or compound heterozygous loss-of-function TBX19 alleles.
  genes:
  - preferred_term: TBX19
    term:
      id: hgnc:11596
      label: TBX19
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: DECREASED
  evidence:
  - reference: PMID:22170728
    reference_title: Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects."
    explanation: Summarizes the loss-of-function mechanisms of the patient alleles.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The S128F and I171T mutations were found to be completely devoid of activity in transfected cells (Fig. 3C,E) and to have no in vitro DNA-binding activity (Fig. 3D,F)."
    explanation: Transfection and gel-shift assays show patient missense alleles lose transcriptional and DNA-binding activity.
  - reference: PMID:17652218
    reference_title: "The TPIT gene mutation M86R associated with isolated adrenocorticotropin deficiency interferes with protein: protein interactions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although the M86 residue is located within the T-box DNA-binding domain, it did not affect monomer DNA-binding activity per se, but it impaired DNA binding with other DNA-bound proteins, including itself (homodimers) and pituitary homeobox 1 (Pitx1)."
    explanation: A missense allele can cause loss of function by disrupting cooperative binding with PITX1 rather than monomer DNA binding.
  - reference: PMID:34564059
    reference_title: Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally."
    explanation: A synonymous exonic variant causes loss of function through missplicing, widening the allelic spectrum.
  downstream:
  - target: Loss of TPIT-PITX1 Activation of POMC Transcription
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39776042
      reference_title: Functional study of three cases with novel TBX19 variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "A functional study showed that the variants in our study result in a significant suppression of POMC transcriptional activity compared to wild-type TBX19."
      explanation: Patient TBX19 variants directly reduce POMC promoter activity in reporter assays.
- name: Loss of TPIT-PITX1 Activation of POMC Transcription
  description: >-
    In pituitary POMC-lineage cells TPIT binds a POMC regulatory element next to
    the homeoprotein PITX1, and the two factors cooperate to activate POMC
    transcription. TPIT is not expressed in hypothalamic POMC neurons or in
    other tissues, so its loss removes POMC expression specifically from the
    pituitary while sparing extra-pituitary POMC.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: corticotroph
    term:
      id: CL:0002309
      label: corticotroph
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:11290323
    reference_title: "A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In pituitary cells, Tpit activation of POMC gene transcription requires cooperation with Pitx1, the two factors binding to contiguous sites within the same regulatory element."
    explanation: Establishes that TPIT activates POMC transcription together with PITX1.
  - reference: PMID:11290323
    reference_title: "A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We identified Tpit, a novel T box factor only present in the two pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, and apparently in no other tissue, including hypothalamic POMC neurons."
    explanation: The restricted expression of TPIT explains why the deficiency is confined to pituitary POMC.
  - reference: PMID:39776042
    reference_title: Functional study of three cases with novel TBX19 variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TBX19 and PITX1 cooperated, resulting in a strong synergistic activation effect on POMC transcriptional expression."
    explanation: Confirms the TBX19-PITX1 synergy on the POMC promoter with the human protein.
  downstream:
  - target: Arrested Corticotroph Terminal Differentiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Tpit-deficient mice revealed that pituitary POMC cells do not reach terminal differentiation (POMC expression) but that precursors of POMC cells still form in absence of this factor (Pulichino et al. 2003)."
      explanation: Terminal differentiation of the POMC lineage is defined by and depends on TPIT-driven POMC expression.
- name: Arrested Corticotroph Terminal Differentiation
  description: >-
    TPIT is required for late differentiation of the POMC lineage but not for
    lineage commitment. In its absence, presumptive corticotrophs are present at
    about normal abundance and express early markers such as NeuroD1, but they
    do not reach terminal differentiation, so the anterior pituitary is left with
    very few ACTH-producing cells. In the mouse intermediate lobe, cells destined
    to be melanotrophs instead become gonadotrophs; the human intermediate lobe
    regresses during fetal life, so this fate switch has no clear human
    counterpart.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: corticotroph
    term:
      id: CL:0002309
      label: corticotroph
  biological_processes:
  - preferred_term: corticotropin hormone secreting cell differentiation
    term:
      id: GO:0060128
      label: corticotropin hormone secreting cell differentiation
    modifier: DECREASED
  locations:
  - preferred_term: adenohypophysis
    term:
      id: UBERON:0002196
      label: adenohypophysis
  evidence:
  - reference: PMID:12651892
    reference_title: Tpit determines alternate fates during pituitary cell differentiation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tpit is a positive regulator for late POMC cell differentiation and POMC expression, but it is not essential for lineage commitment."
    explanation: Tpit knockout mice show that TPIT acts at the terminal step of POMC-lineage differentiation.
  - reference: PMID:12651892
    reference_title: Tpit determines alternate fates during pituitary cell differentiation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "showing that the presumptive corticotroph cells are present (at about normal abundance) but are not able to reach terminal differentiation (POMC expression)."
    explanation: Corticotroph precursors persist but cannot complete differentiation without TPIT.
  - reference: PMID:12651892
    reference_title: Tpit determines alternate fates during pituitary cell differentiation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inactivation of the Tpit gene results in almost complete loss of POMC-expressing cells in this tissue, which now has a large number of gonadotrophs and a few clusters of Pit-1-independent thyrotrophs."
    explanation: In the mouse intermediate lobe, loss of TPIT also redirects precursors to the gonadotroph fate.
  downstream:
  - target: Pituitary ACTH Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Because Tpit mutant mice have very few remaining POMC (ACTH)-positive pituitary cells (Pulichino et al. 2003), we measured plasma ACTH levels in these mice."
      explanation: The near absence of POMC-positive cells is the basis for the low circulating ACTH measured in Tpit-null mice.
- name: Pituitary ACTH Deficiency
  description: >-
    Plasma ACTH is low or undetectable and CRH does not raise it. Other anterior
    pituitary hormones (GH, TSH, gonadotropins, prolactin) are produced normally
    and the pituitary is structurally normal, which separates this disorder from
    combined pituitary hormone deficiencies. Autopsy of an affected neonate
    showed a pituitary of normal morphology lacking ACTH immunoreactivity.
  biological_scale: ORGANISM
  locations:
  - preferred_term: adenohypophysis
    term:
      id: UBERON:0002196
      label: adenohypophysis
  evidence:
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous (−/−) mutant mice have very low, albeit detectable, plasma ACTH levels, whereas wild-type (+/+) and heterozygous (+/−) mice have similar normal levels (Fig. 1A)."
    explanation: Tpit-null mice reproduce the ACTH deficiency.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, acute or repeated treatment with CRH never elicited a response (Table 1, patients 2, 3, 5 and 6)."
    explanation: Absent response to CRH in patients localizes the defect to the pituitary corticotroph.
  - reference: PMID:22170728
    reference_title: Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones."
    explanation: Defines the isolated character of the pituitary deficiency.
  downstream:
  - target: Glucocorticoid Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Pituitary ACTH is the major stimulus for production of adrenal glucocorticoids and this action constitutes an important part of the hypothalamo-pituitary-adrenal axis."
      explanation: Loss of the main trophic stimulus of glucocorticoid production leads directly to glucocorticoid deficiency.
  - target: Adrenal Cortex Hypoplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results are clearly in support of a role of POMC-derived peptides in maintenance of adrenal tissue."
      explanation: Adrenal hypoplasia in ACTH-deficient Tpit-null mice shows the trophic dependence of the adrenal cortex on pituitary POMC peptides.
  - target: Decreased circulating ACTH concentration
    causal_link_type: DIRECT
- name: Adrenal Cortex Hypoplasia
  description: >-
    Chronic lack of ACTH trophic drive leaves the adrenal cortex hypoplastic,
    with the greatest loss in the glucocorticoid-producing zona fasciculata.
    The adrenals can still respond partially to repeated ACTH injections, showing
    that the gland is understimulated rather than intrinsically defective.
  biological_scale: TISSUE
  locations:
  - preferred_term: zona fasciculata of adrenal gland
    term:
      id: UBERON:0002054
      label: zona fasciculata of adrenal gland
  evidence:
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition, adrenal glands were found to be hypoplastic, with the most significant loss at the level of the glucocorticoid-producing fasciculata layer (Fig. 1C)."
    explanation: Tpit-null mice show adrenal hypoplasia centered on the zona fasciculata.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients did not show a cortisol response to acute injection of ACTH (Table 1), but in two cases (patients 2 and 3), repeated ACTH injection was found to significantly increase cortisol, indicating that adrenal function may be restored upon multiple challenges with ACTH."
    explanation: The adrenal defect in patients is secondary and partly reversible with repeated ACTH.
  downstream:
  - target: Glucocorticoid Deficiency
    causal_link_type: DIRECT
  - target: Adrenal hypoplasia
    causal_link_type: DIRECT
- name: Glucocorticoid Deficiency
  description: >-
    Cortisol is low or undetectable from birth. Glucocorticoid deficiency
    removes cortisol support of fasting glucose production and of hepatic and
    vascular function; this is the proximal cause of the neonatal hypoglycemia,
    the prolonged cholestatic jaundice and the risk of fatal adrenal crisis.
    Deficient fetal adrenal steroidogenesis can also lower maternal serum
    estriol during pregnancy.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: cortisol biosynthetic process
    term:
      id: GO:0034651
      label: cortisol biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The impact of low plasma ACTH on adrenal function was next assessed, and we observed undetectable plasma corticosterone in homozygous mutant, but not in wild-type or heterozygous mice (Fig. 1B)."
    explanation: Tpit-null mice have absent glucocorticoid production.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation of pituitary/adrenal function in IAD patients with TPIT mutations (Table 1) showed decreased/undetectable baseline plasma levels of ACTH and cortisol."
    explanation: Patients with TPIT mutations have low or undetectable cortisol together with low ACTH.
  downstream:
  - target: Neonatal hypoglycemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "In humans, adrenal insufficiency leads to severe hypoglycemia sometimes associated with seizures, reflecting the role of glucocorticoids in regulation of plasma glucose."
      explanation: States the causal link from glucocorticoid deficiency to hypoglycemia.
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "indicating that the ACTH- and glucocorticoid-deficient Tpit null mice are more susceptible to fasting-induced hypoglycemia."
      explanation: Glucocorticoid-deficient Tpit-null mice develop fasting hypoglycemia.
  - target: Prolonged cholestatic jaundice
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27535729
      reference_title: "Neonatal isolated ACTH deficiency (IAD): a potentially life-threatening but treatable cause of neonatal cholestasis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient was started on glucocorticoid replacement therapy after which his bilirubin and glucose levels normalised."
      explanation: Resolution of cholestasis with glucocorticoid replacement supports cortisol deficiency as its cause; the hepatic mechanism is not established.
  - target: Sudden neonatal death
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15613420
      reference_title: "Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency."
      explanation: Untreated glucocorticoid deficiency causes death through acute adrenal insufficiency.
  - target: Decreased circulating cortisol level
    causal_link_type: DIRECT
  - target: Adrenocorticotropin deficient adrenal insufficiency
    causal_link_type: DIRECT
  - target: Hyponatremia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Adrenocorticotropin deficient adrenal insufficiency
  category: Endocrine
  phenotype_term:
    preferred_term: Secondary adrenal insufficiency due to isolated ACTH deficiency
    term:
      id: HP:0011735
      label: Adrenocorticotropin deficient adrenal insufficiency
  frequency: OBLIGATE
  diagnostic: true
  description: Defining feature; adrenal insufficiency secondary to absent pituitary ACTH, with other pituitary axes intact.
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011735 | Adrenocorticotropin deficient adrenal insufficiency | Obligate (100%)"
    explanation: Orphanet annotates ACTH-deficient adrenal insufficiency as obligate.
  - reference: PMID:34564059
    reference_title: Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital isolated ACTH deficiency (IAD) is a rare cause of secondary adrenal insufficiency characterised by low plasma ACTH and serum cortisol in the setting of otherwise preserved anterior pituitary function."
    explanation: Describes the secondary adrenal insufficiency with preserved other pituitary function.
- name: Decreased circulating ACTH concentration
  category: Endocrine
  phenotype_term:
    preferred_term: Low plasma ACTH
    term:
      id: HP:0002920
      label: Decreased circulating ACTH concentration
  diagnostic: true
  evidence:
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation of pituitary/adrenal function in IAD patients with TPIT mutations (Table 1) showed decreased/undetectable baseline plasma levels of ACTH and cortisol."
    explanation: Low or undetectable plasma ACTH in patients with TPIT mutations.
  - reference: PMID:30747411
    reference_title: Evaluation of growth and puberty in a child with a novel TBX19 gene mutation and review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child was hypocortisolemic (0.1 μg/dl), and ACTH levels were extremely low (< 5.0 pg/ml)."
    explanation: Case report documenting extremely low ACTH with hypocortisolemia.
- name: Decreased circulating cortisol level
  category: Endocrine
  phenotype_term:
    preferred_term: Low plasma cortisol
    term:
      id: HP:0008163
      label: Decreased circulating cortisol level
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008163 | Decreased circulating cortisol level | Obligate (100%)"
    explanation: Orphanet annotates low cortisol as obligate.
  - reference: PMID:39664280
    reference_title: "Congenital isolated adrenocorticotropic hormone deficiency in a newborn caused by TBX19 mutation: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further endocrine examination showed low levels of cortisol (<0.1 µg/dl) and adrenocorticotropic hormone (ACTH, 2.l pg/ml), but the levels of growth hormone (GH), luteinizing hormone, and thyroid stimulating hormone were within normal limits (Table 1)."
    explanation: Undetectable cortisol with low ACTH and normal other pituitary hormones in a TBX19 case.
- name: Neonatal hypoglycemia
  category: Metabolic
  phenotype_term:
    preferred_term: Neonatal hypoglycemia
    term:
      id: HP:0001998
      label: Neonatal hypoglycemia
  frequency: OBLIGATE
  description: >-
    Severe, sudden and recurrent hypoglycemia in the first days or weeks of
    life is the usual reason the diagnosis is made.
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001998 | Neonatal hypoglycemia | Obligate (100%)"
    explanation: Orphanet annotates neonatal hypoglycemia as obligate.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal hypoglycemia was the major reason leading to diagnosis of ACTH deficiency."
    explanation: Hypoglycemia was the presenting feature in the first TPIT-mutant series.
  sequelae:
  - target: Hypoglycemic seizures
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "had very similar clinical presentation that included severe plasma ACTH and cortisol deficits, episodes of sudden and severe hypoglycemia sometimes associated with seizures"
      explanation: Seizures occur in association with the hypoglycemic episodes.
  - target: Apnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27535729
      reference_title: "Neonatal isolated ACTH deficiency (IAD): a potentially life-threatening but treatable cause of neonatal cholestasis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The apnoea episode was associated with low blood glucose level of 19 mg/dL; the infant was given 2 mL/kg bolus of dextrose 10% water solution."
      explanation: An apneic episode coincided with profound hypoglycemia and was treated with dextrose.
- name: Hypoglycemic seizures
  category: Neurological
  phenotype_term:
    preferred_term: Hypoglycemic seizures
    term:
      id: HP:0002173
      label: Hypoglycemic seizures
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002173 | Hypoglycemic seizures | Frequent (79-30%)"
    explanation: Orphanet annotates hypoglycemic seizures as frequent.
  - reference: PMID:32344415
    reference_title: "A Rare Cause of Adrenal Insufficiency - Isolated ACTH Deficiency Due to TBX19 Mutation: Long-Term Follow-Up of Two Cases and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After hydrocortisone treatment, there was resolution of the hypoglycemia and the convulsions were controlled."
    explanation: Convulsions accompanied hypoglycemia and resolved with glucocorticoid replacement.
  sequelae:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29858850
      reference_title: "A rare cause of neonatal hypoglycemia in two siblings: TBX19 gene mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This led to developmental delay, measured with the Denver Developmental Screening Test II (DDST-II), because of cessation of the hydrocortisone therapy."
      explanation: After hydrocortisone was stopped and seizures were treated as epilepsy, the child developed developmental delay.
- name: Prolonged cholestatic jaundice
  category: Hepatic
  phenotype_term:
    preferred_term: Prolonged neonatal cholestatic jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
  frequency: FREQUENT
  description: >-
    Conjugated hyperbilirubinemia with raised gamma-glutamyl transferase and
    bile acids that resolves after glucocorticoid replacement. Liver biopsy in
    reported cases showed intrahepatic biliary pigment accumulation and giant
    cell cholestatic hepatitis.
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006579 | Prolonged neonatal jaundice | Frequent (79-30%)"
    explanation: Orphanet annotates prolonged neonatal jaundice as frequent.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients suffered from prolonged neonatal cholestatic jaundice."
    explanation: Cholestatic jaundice in three of eight patients with TPIT mutations.
  - reference: PMID:15301051
    reference_title: Congenital early onset isolated adrenocorticotropin deficiency associated with a TPIT gene mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 5 day-old male infant was admitted for hypoglycemia, limpness and conjugated hyperbilirubinemia."
    explanation: Conjugated hyperbilirubinemia with hypoglycemia at presentation in a TPIT-mutant neonate.
  - reference: PMID:39664280
    reference_title: "Congenital isolated adrenocorticotropic hormone deficiency in a newborn caused by TBX19 mutation: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We initiated hydrocortisone (HC) replacement therapy when the infant was 31-days-old, after which the levels of bilirubin and bile acid gradually decreased, and the levels of ACTH and cortisol gradually increased (Table 1)."
    explanation: Cholestasis resolved with hydrocortisone replacement.
  sequelae:
  - target: Giant cell hepatitis
    causal_link_type: UNKNOWN
- name: Giant cell hepatitis
  category: Hepatic
  phenotype_term:
    preferred_term: Giant cell cholestatic hepatitis
    term:
      id: HP:0200084
      label: Giant cell hepatitis
  evidence:
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic needle biopsy in two cases revealed accumulation of biliary pigments in the liver cells and in the bile canaliculi, and also giant cells cholestatic hepatitis."
    explanation: Liver biopsy in two TPIT-mutant patients showed giant cell cholestatic hepatitis.
- name: Adrenal hypoplasia
  category: Endocrine
  phenotype_term:
    preferred_term: Adrenal hypoplasia
    term:
      id: HP:0000835
      label: Adrenal hypoplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000835 | Adrenal hypoplasia | Very frequent (99-80%)"
    explanation: Orphanet annotates adrenal hypoplasia as very frequent.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation at autopsy of the dead sibling of family V revealed bilateral adrenal hypoplasia and normal pituitary morphology with the absence of ACTH immunoreactivity (Dechelotte et al. 1994), which is very similar to the phenotype of Tpit−/− mice."
    explanation: Autopsy of an affected sibling showed bilateral adrenal hypoplasia.
- name: Sudden neonatal death
  category: Mortality
  phenotype_term:
    preferred_term: Sudden neonatal death
    term:
      id: HP:0001699
      label: Sudden death
  description: >-
    Sudden death in the neonatal period from acute adrenal insufficiency when
    the diagnosis is missed; an earlier sibling's unexplained neonatal death is
    common in affected families. Mortality without recognition has been
    estimated at about 20 to 25 percent.
  evidence:
  - reference: PMID:15613420
    reference_title: "Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death."
    explanation: The disease is identified as an underestimated cause of neonatal death.
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients were the second children of the sibship, the eldest sibling having died suddenly at birth (families IV and V)."
    explanation: Prior sudden neonatal sibling deaths in families with TPIT mutations.
  - reference: PMID:27535729
    reference_title: "Neonatal isolated ACTH deficiency (IAD): a potentially life-threatening but treatable cause of neonatal cholestasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This diagnosis has a 20% mortality potential if unrecognised."
    explanation: Estimated mortality of unrecognized neonatal IAD.
  - reference: PMID:40727905
    reference_title: Long-term Follow-up of a Case with TBX19 Mutation, a Rare Cause of Isolated ACTH Deficiency and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in TBX19 cause early onset congenital isolated adrenocorticotrophic hormone (ACTH) insufficiency with a mortality rate of up to 25% in the neonatal period."
    explanation: Neonatal mortality estimate specific to TBX19 variants.
- name: Hyponatremia
  category: Metabolic
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  frequency: VERY_FREQUENT
  description: >-
    Hyponatremia occurs without hyperkalemia; Orphanet records hyperkalemia as
    excluded, consistent with preserved mineralocorticoid secretion in
    secondary adrenal insufficiency.
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002902 | Hyponatremia | Very frequent (99-80%)"
    explanation: Orphanet annotates hyponatremia as very frequent.
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002153 | Hyperkalemia | Excluded (0%)"
    explanation: Orphanet records hyperkalemia as excluded, which distinguishes this disorder from primary adrenal insufficiency.
- name: Hypotension
  category: Cardiovascular
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002615 | Hypotension | Very frequent (99-80%)"
    explanation: Orphanet annotates hypotension as very frequent.
- name: Fatigue
  category: Constitutional
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:199296
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012378 | Fatigue | Very frequent (99-80%)"
    explanation: Orphanet annotates fatigue as very frequent.
- name: Feeding difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Poor feeding
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:39664280
    reference_title: "Congenital isolated adrenocorticotropic hormone deficiency in a newborn caused by TBX19 mutation: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical manifestations were hypoglycemia, jaundice, convulsions, feeding difficulties, poor mental response, hypotonia, and growth retardation."
    explanation: Feeding difficulties are among the main manifestations in a pooled review of 35 cases.
- name: Apnea
  category: Respiratory
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:27535729
    reference_title: "Neonatal isolated ACTH deficiency (IAD): a potentially life-threatening but treatable cause of neonatal cholestasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was referred to our hospital for further evaluation and management because of signs of jaundice, hypoglycaemia, one episode of apnoea lasting about 20 s and poor feeding at day 11 of life."
    explanation: Apnea at presentation in a TBX19-confirmed neonate.
  - reference: PMID:34564059
    reference_title: Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks."
    explanation: Respiratory arrest with hypoglycemia at presentation in a TBX19 neonate.
- name: Global developmental delay
  category: Neurological
  phenotype_term:
    preferred_term: Developmental delay after delayed treatment
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Not intrinsic to the disease: developmental delay and cognitive impairment
    follow late diagnosis, interrupted replacement or repeated adrenal crises,
    and are absent in children treated early.
  evidence:
  - reference: PMID:39664280
    reference_title: "Congenital isolated adrenocorticotropic hormone deficiency in a newborn caused by TBX19 mutation: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 15 patients with different degrees of nervous system developmental delays, 13 initiated treatment when more than 1-year-old."
    explanation: Developmental delay clusters in patients whose treatment started late.
  - reference: PMID:36890856
    reference_title: A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Indeed, one of the main consequences of undiagnosed adrenal crises and inadequately adjusted hydrocortisone treatment in IAD due to TBX19 mutations is cognitive impairment (2, 4, 5, 20)."
    explanation: Cognitive impairment follows undiagnosed crises or inadequate treatment.
  - reference: PMID:31998673
    reference_title: "Congenital Isolated ACTH Deficiency Caused by TBX19 Gene Mutation: A Family Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The older brother developed subdural hematoma, intractable epilepsy, and developmental delays. In contrast, the younger sister received timely glucocorticoid replacement therapy and had no long-term complications while maintaining a good quality of life."
    explanation: Sibling comparison in which only the late-treated child developed delays.
genetic:
- name: TBX19
  gene_term:
    preferred_term: TBX19
    term:
      id: hgnc:11596
      label: TBX19
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    TBX19 (formerly TPIT) lies on chromosome 1q24.2 and its main transcript
    (NM_005149.3) has eight exons. TBX19 variants are found in about two thirds
    of neonatal-onset complete isolated ACTH deficiency and have not been found
    in partial or later-onset forms. No ClinGen gene-disease validity record for
    TBX19 is present in the repository's ClinGen cache.
  case_fractions:
  - population: Neonatal-onset complete isolated ACTH deficiency, international series of 91 IAD patients
    case_fraction_percent: 65.0
    notes: Proportion of neonatal-onset complete IAD with TPIT mutations; none were found in partial or late-onset IAD.
    evidence:
    - reference: PMID:22170728
      reference_title: Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD."
      explanation: Gene share among neonatal-onset complete IAD.
  - population: Neonatal-onset isolated ACTH deficiency, 21 unrelated families
    case_fraction_percent: 63.0
    cohort_size: 27
    notes: 17 of 27 patients carried TPIT mutations.
    evidence:
    - reference: PMID:15613420
      reference_title: "Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We found TPIT mutations in 17 of 27 patients."
      explanation: Gene share in an earlier neonatal IAD series.
  variants:
  - name: TBX19 c.856C>T (p.Arg286Ter)
    description: >-
      Recurrent nonsense variant (R286X) reported homozygous in multiple
      families of different origins; predicted to cause nonsense-mediated mRNA
      decay.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: TBX19
      term:
        id: hgnc:11596
        label: TBX19
    evidence:
    - reference: PMID:39776042
      reference_title: Functional study of three cases with novel TBX19 variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The TBX19 variant, c.856C>T (p.R286*) was classified as pathogenic according to ACMG"
      explanation: ACMG classification of the recurrent R286* variant.
    - reference: PMID:29858850
      reference_title: "A rare cause of neonatal hypoglycemia in two siblings: TBX19 gene mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both cases were homozygous for c.856 C>T (p.R286*), and hydrocortisone treatment was initiated."
      explanation: Homozygous R286* in affected siblings.
  - name: TBX19 p.Met86Arg
    description: >-
      Missense variant in the T-box that preserves monomer DNA binding but
      disrupts cooperative binding with PITX1 and recruitment of the SRC2
      coactivator; reported in compound heterozygosity with c.782delA.
    gene:
      preferred_term: TBX19
      term:
        id: hgnc:11596
        label: TBX19
    evidence:
    - reference: PMID:17652218
      reference_title: "The TPIT gene mutation M86R associated with isolated adrenocorticotropin deficiency interferes with protein: protein interactions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, TPIT M86R is deficient in the recruitment of the coactivator SRC2 that partly mediates the CRH stimulation of proopiomelanocortin transcription."
      explanation: Functional characterization of the M86R allele.
    - reference: PMID:15476446
      reference_title: "TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The missense mutation (Met86Arg) in exon 2 within the T-box (or DNA binding domain) is predicted to disrupt DNA binding."
      explanation: Identification of M86R in early-onset IAD siblings, who were compound heterozygous with a frameshift allele.
  - name: TBX19 c.840del (p.Glu280AspfsTer27)
    description: >-
      Frameshift variant found in four patients from three families with roots
      in the same region of northern Morocco, suggesting a founder effect.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: TBX19
      term:
        id: hgnc:11596
        label: TBX19
    evidence:
    - reference: PMID:36890856
      reference_title: A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two of these families were consanguineous, and after investigations all of three were discovered to have roots in the same mountainous region of northern Morocco, suggesting a founder effect."
      explanation: Founder variant in northern Moroccan families.
  evidence:
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work defines congenital early onset IAD as a relatively homogeneous clinical entity caused by recessive transmission of loss-of-function mutations in the TPIT gene."
    explanation: Establishes TBX19 loss of function as the cause of congenital early-onset IAD.
  - reference: PMID:11290323
    reference_title: "A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TPIT gene mutations were found in patients with isolated deficiency of pituitary POMC-derived ACTH, in support of an essential role of Tpit for differentiation of the pituitary POMC lineage."
    explanation: First report of TPIT mutations in patients with isolated ACTH deficiency.
diagnosis:
- name: Morning ACTH and cortisol measurement
  description: >-
    Low or undetectable cortisol together with low plasma ACTH, measured in the
    morning or during spontaneous hypoglycemia, with normal results for the
    other anterior pituitary axes.
  evidence:
  - reference: PMID:27535729
    reference_title: "Neonatal isolated ACTH deficiency (IAD): a potentially life-threatening but treatable cause of neonatal cholestasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other hormone levels (luteinising hormone, follicle stimulating hormone, growth hormone, insulin-like growth factor 1, testosterone, thyroid-stimulating hormone, T4, T3) were within normal limits."
    explanation: Other pituitary axes are normal in a TBX19-confirmed case, establishing the isolated deficiency.
- name: ACTH and CRH stimulation testing
  description: >-
    Cortisol fails to rise after a single ACTH injection but can rise after
    repeated ACTH injections, while CRH elicits no response, localizing the
    defect to the corticotroph.
  evidence:
  - reference: PMID:12651888
    reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients did not show a cortisol response to acute injection of ACTH (Table 1), but in two cases (patients 2 and 3), repeated ACTH injection was found to significantly increase cortisol, indicating that adrenal function may be restored upon multiple challenges with ACTH."
    explanation: Characteristic response pattern to ACTH testing.
- name: Maternal serum estriol on prenatal screening
  description: >-
    An isolated low maternal unconjugated estriol on the triple-marker screen,
    with normal fetal ultrasound and after exclusion of steroid sulfatase
    deficiency and Smith-Lemli-Opitz syndrome, reflects deficient fetal adrenal
    steroidogenesis and has been reported as a prenatal clue in a TPIT-mutant
    pregnancy.
  evidence:
  - reference: PMID:16390921
    reference_title: Low estriol levels in the maternal triple-marker screen as a predictor of isolated adrenocorticotropic hormone deficiency caused by a new mutation in the TPIT gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A low estriol level in the context of normal fetal sonography and growth, after exclusion of placental sulfatase deficiency and Smith-Lemli-Opitz syndrome, should raise the suspicion of deficient fetal steroidogenesis, which leads to decreased production of adrenal dehydroepiandrosterone sulfate."
    explanation: Links low maternal estriol to deficient fetal adrenal steroidogenesis.
  - reference: PMID:16390921
    reference_title: Low estriol levels in the maternal triple-marker screen as a predictor of isolated adrenocorticotropic hormone deficiency caused by a new mutation in the TPIT gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the third pregnancy, a low level was found again, and the mother was referred to our tertiary center."
    explanation: Recurrent low maternal estriol in successive pregnancies with an affected fetus.
- name: TBX19 molecular testing
  description: >-
    Sequencing of TBX19, including splice regions and copy-number analysis,
    confirms the diagnosis and allows carrier testing and prenatal diagnosis in
    at-risk families. Synonymous exonic variants may act through missplicing.
  evidence:
  - reference: PMID:15613420
    reference_title: "Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy."
    explanation: Molecular diagnosis enables prenatal diagnosis and early treatment.
treatments:
- name: Hydrocortisone Replacement Therapy
  description: >-
    Lifelong oral hydrocortisone replacement, around 15 mg/m2/day in reported
    TBX19 cases, with increased doses during illness or other stress.
    Treatment reverses hypoglycemia, seizures and cholestasis, and early
    treatment allows normal growth and development.
  treatment_term:
    preferred_term: Glucocorticoid replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: CHEBI:17650
        label: cortisol
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Glucocorticoid Deficiency
    treatment_effect: BYPASSES
    description: >-
      Exogenous hydrocortisone replaces the cortisol the ACTH-deprived adrenal
      cortex cannot make, bypassing the pituitary defect.
    evidence:
    - reference: PMID:12651888
      reference_title: Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptoms of adrenal insufficiency disappeared after cortisol replacement therapy in all cases."
      explanation: Cortisol replacement resolved adrenal insufficiency in all TPIT-mutant patients.
  target_phenotypes:
  - preferred_term: Neonatal hypoglycemia
    term:
      id: HP:0001998
      label: Neonatal hypoglycemia
  - preferred_term: Prolonged neonatal jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
  evidence:
  - reference: PMID:36890856
    reference_title: A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hydrocortisone therapy was continued at 15 mg/m2/day (increased as appropriate in stress situations)."
    explanation: Maintenance dose with stress adjustment used in TBX19 patients.
  - reference: PMID:36890856
    reference_title: A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early diagnosis, timely treatment (hydrocortisone therapy) and preventive education allowed normal development, growth and quality of life in all patients."
    explanation: Early hydrocortisone with education gives normal outcomes.
  - reference: PMID:40727905
    reference_title: Long-term Follow-up of a Case with TBX19 Mutation, a Rare Cause of Isolated ACTH Deficiency and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early hydrocortisone replacement therapy is significant for survival without sequelae."
    explanation: Early replacement prevents death and sequelae.
  - reference: PMID:15301051
    reference_title: Congenital early onset isolated adrenocorticotropin deficiency associated with a TPIT gene mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On replacement therapy with hydrocortisone (15 mg/m2/day orally), cholestatic jaundice and hypoglycemia resolved and subsequent normal growth (weight, height and head circumference, 25th, 10th and 50th percentile, respectively) and development was achieved without recurrence of hypoglycemic episodes."
    explanation: Oral hydrocortisone at 15 mg/m2/day resolved cholestasis and hypoglycemia with normal growth and development.
- name: Genetic Counseling and Prenatal Diagnosis
  description: >-
    Identifying the familial TBX19 variants permits counseling of carrier
    parents and prenatal or immediate postnatal diagnosis, so that
    glucocorticoid replacement can start at birth.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:15613420
    reference_title: "Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy."
    explanation: Molecular diagnosis enables prenatal diagnosis and early treatment in at-risk families.
references:
- reference: ORPHA:199296
  title: Congenital isolated ACTH deficiency
datasets: []
notes: >-
  Scope. MONDO:0008720 (OMIM 201400, ORPHA:199296) names congenital isolated
  ACTH deficiency generally; Orphanet and OMIM attach a single causal gene,
  TBX19, and this entry describes the TBX19 neonatal-onset form. About one
  third of neonatal-onset complete IAD, and all reported partial or late-onset
  childhood IAD, carry no TBX19 variant. Differential diagnoses with their own
  genes are POMC deficiency and PCSK1 (prohormone convertase 1) deficiency, in
  which ACTH deficiency is accompanied by early-onset obesity; both are covered
  as gene subtypes of Obesity_Due_to_MC4R_Pathway_Disruption rather than here.
  ACTH deficiency within combined pituitary hormone deficiency is a separate
  disorder, as is DAVID syndrome (heterozygous NFKB2 variants, ACTH deficiency
  with common variable immunodeficiency), curated as a subtype of
  Common_Variable_Immunodeficiency. Familial glucocorticoid deficiency differs
  by its high ACTH and hyperpigmentation. MONDO lists combined pituitary hormone deficiencies, genetic form
  (MONDO:0013099) and isolated congenital hypogonadotropic hypogonadism
  (MONDO:0016553) as the parents of MONDO:0008720; neither describes an
  isolated corticotroph defect, so the free-text parents here are adrenal
  insufficiency and hypopituitarism. Orphanet notes that partial growth hormone
  deficiency is sometimes associated. Single case reports describe mild facial
  dysmorphism, tall stature, low bone mineral density or Chiari type 1
  malformation in TBX19 patients; these associations are not established and
  are not curated as phenotypes. No prevalence estimate has been published.
  No GeneReviews chapter covers this disorder (Bookshelf index snapshot
  2026-09-10 and a live PubMed title search).
📚

References & Deep Research

References

1
ORPHA:199296
Congenital isolated ACTH deficiency
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Congenital_Isolated_ACTH_Deficiency · 2026-10-15T02:34:01Z · View source

New entry for congenital isolated ACTH deficiency (MONDO:0008720), scoped to the neonatal-onset TBX19 (TPIT) form. The stub stubs/Congenital_Isolated_Adrenocorticotropic_Hormone_Deficiency.yaml is deleted. Evidence comes from PubMed primary papers (Lamolet 2001 PMID:11290323, Pulichino 2003 PMID:12651888 and PMID:12651892, Vallette-Kasic 2005 PMID:15613420, Couture 2012 PMID:22170728, later case reports) and the Orphanet record ORPHA:199296, which supplied the phenotype frequencies. All 82 snippets verify against references_cache. The OpenScientist deep-research report (research/Congenital_Isolated_ACTH_Deficiency-deep-research-openscientist.md) was used as a lead source: 25/25 references resolved, none off topic; term validation needs_review because of five mislabelled CURIEs (HP:0011736, CL:0000152, CL:0002097, CHEBI:3650, CHEBI:17754), none of which is bound here. The report also gives a wrong Orphanet code (ORPHA 442); the entry uses ORPHA:199296 from the MONDO cross-reference. just preflight-dr returned WARN because POMC (the TPIT target gene and a differential diagnosis) and NFKB2 (DAVID syndrome differential) outnumber TBX19 mentions; the report is about the intended disease (OMIM 201400 matches) and only TBX19 content was curated. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER). Pathograph: TBX19 loss of function, loss of TPIT-PITX1 activation of POMC, arrested corticotroph terminal differentiation, pituitary ACTH deficiency, adrenal cortex hypoplasia, glucocorticoid deficiency, then phenotypes; all 15 phenotypes are causally connected. HP:0003811 Neonatal death and HP:0008073 Low maternal circulating estriol concentration fall outside the PhenotypeTerm enum, so sudden neonatal death is bound to HP:0001699 Sudden death and maternal estriol is recorded as a diagnosis row. MONDO's parents (combined pituitary hormone deficiencies, genetic form; isolated congenital hypogonadotropic hypogonadism) do not describe an isolated corticotroph defect, so free-text parents are Adrenal Insufficiency and Hypopituitarism. The Orphanet cache file was rebuilt from local Orphadata files whose checksums differ from the manifest pin, so its Source line carries release 2026-06-23.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 2026-10-15T02:14:42.250726

1. Disease Information

Overview. Congenital Isolated ACTH Deficiency (IAD) is a rare monogenic form of secondary (central) adrenal insufficiency characterized by low or undetectable serum cortisol due to deficient pituitary adrenocorticotropic hormone (ACTH) production, with preservation of all other anterior pituitary hormones (GH, TSH, LH/FSH, prolactin) and normal pituitary anatomy. The best-defined form is neonatal-onset, complete IAD caused by biallelic loss-of-function variants in TBX19/TPIT (PMID 22170728, 15613420). It is clinically important because, untreated, it can cause neonatal death from acute adrenal crisis, yet it is fully treatable with glucocorticoid replacement.

Key identifiers. - MONDO: MONDO:0008720 - OMIM: #201400 (Adrenocorticotropic hormone deficiency / isolated ACTH deficiency); gene TBX19 OMIM 604614 - Orphanet: ORPHA 442 (Isolated ACTH deficiency) - ICD-10: E23.0 (Hypopituitarism, includes isolated deficiency of pituitary hormones); ICD-11: 5A61.0 (Hypofunction of pituitary gland / ACTH deficiency) - MeSH: "Adrenocorticotropic Hormone" / "Hypopituitarism"; "Adrenal Insufficiency" - Gene (HGNC):* TBX19 (HGNC:11596), alias TPIT; also NFKB2 (HGNC:7795), POMC (HGNC:9201)

Synonyms / alternative names. Isolated ACTH deficiency; IAD; TPIT deficiency; congenital isolated adrenocorticotropin deficiency; isolated adrenocorticotropic hormone deficiency; isolated corticotropin deficiency.

Information source. Derived predominantly from aggregated disease-level resources (OMIM, Orphanet) and individual-patient case reports/series (e.g., the 91-patient TPIT series, PMID 22170728). No population EHR datasets were used here.

2. Etiology

Primary cause: genetic (Mendelian). IAD is not infectious or environmentally acquired. The principal molecular cause of neonatal-onset complete IAD is biallelic (homozygous or compound heterozygous) loss-of-function (LOF) in TBX19/TPIT, a pituitary-restricted T-box transcription factor required for corticotroph terminal differentiation and POMC transcription (PMID 15476446, 15613420, 22170728). In the largest series, TPIT mutations were found in 65% of neonatal-onset complete IAD but 0% of partial or late-onset IAD (PMID 22170728).

"we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers." (PMID 22170728, human clinical)

Genetic risk factors / genetic heterogeneity. Other monogenic causes of congenital/childhood central ACTH deficiency: - NFKB2 (DAVID syndrome) — heterozygous, usually de novo C-terminal mutations; ACTH deficiency + common variable immunodeficiency (PMID 37322808, 25524009). - POMC — biallelic LOF; adrenal insufficiency with early-onset obesity and red hair (not truly "isolated") (PMID 35775692). - Rare/other hypopituitarism genes may present with ACTH deficiency within broader combined pituitary hormone deficiency.

Environmental risk factors. None established as causal for the congenital genetic disease. Consanguinity increases the chance of homozygous TPIT/POMC LOF (autosomal recessive). Family history of an affected sibling/neonatal death is a major risk indicator.

Protective factors. No genetic or environmental protective modifiers are established. The main "protective" intervention is presymptomatic diagnosis (prenatal/cascade testing in at-risk families) enabling immediate glucocorticoid replacement.

Gene–environment interactions. Not applicable as a cause. Clinically, physiological stressors (infection, fasting, surgery) unmask/precipitate adrenal crisis on the genetic background of cortisol deficiency — a genotype × stressor interaction at the level of clinical decompensation rather than disease causation.

3. Phenotypes

Neonatal TPIT-related IAD has a highly homogeneous presentation (PMID 15613420). Onset is typically within hours to days of birth.

Phenotype Type HPO term Onset Severity Frequency
Hypoglycemia (recurrent, severe; seizures, limpness, apnea/respiratory arrest) Lab + clinical sign HP:0001943 (Hypoglycemia); HP:0001998 (Neonatal hypoglycemia) Neonatal Severe Very frequent (hallmark)
Low/undetectable serum cortisol Lab abnormality HP:0008163 (Decreased circulating cortisol) Neonatal Severe Near-universal
Inappropriately low/normal plasma ACTH Lab abnormality HP:0011736 (Decreased circulating ACTH) Neonatal — Defining feature
Prolonged conjugated (cholestatic) jaundice Clinical sign / lab HP:0002908 (Conjugated hyperbilirubinemia); HP:0001396 (Cholestasis) Neonatal Moderate–severe Frequent
Seizures Clinical sign HP:0001250 (Seizure) Neonatal Severe Frequent (secondary to hypoglycemia)
Adrenal insufficiency / adrenal crisis Clinical HP:0000846 (Adrenal insufficiency) Neonatal–lifelong Life-threatening Core
Hypokalemia / electrolyte disturbance Lab HP:0002900 (Hypokalemia) Neonatal Variable Reported
Hyponatremia (dilutional, cortisol-dependent) Lab HP:0002902 (Hyponatremia) Variable Variable Reported (esp. later/adult cases)
Facial dysmorphism (long philtrum, depressed nasal root, epicanthus, low-set ears, mild hypertelorism) Physical HP:0000271 (Abnormal facial shape) Congenital Mild Occasional (reported in some cases)
Prolonged/severe infections, lethargy, poor feeding, failure to thrive Clinical HP:0004322/HP:0001508 Neonatal–infancy Variable Variable
  • Severity/progression: Episodic life-threatening decompensations (hypoglycemia, adrenal crisis) on a chronic lifelong deficiency; metabolic/hepatic features are fully reversible on hydrocortisone.
  • Important distinction: Because ACTH is low, there is no hyperpigmentation (unlike primary adrenal insufficiency/FGD). No salt-wasting/mineralocorticoid deficiency (aldosterone preserved).
  • Quality-of-life impact: With treatment, generally normal growth, development and QoL; residual burden stems from chronic medication dependence, risk of adrenal crisis, and the vigilance required for sick-day management (QoL instruments: AddiQoL, SF-36, EQ-5D — disease-specific data limited).

Evidence: PMID 15613420 (homogeneous presentation), 15301051 (hypoglycemia + conjugated hyperbilirubinemia resolving on hydrocortisone), 34564059 (neonatal onset at 15 h, undetectable cortisol with normal-range ACTH), 40990269 (hypoglycemic seizures, hypokalemia, cholestasis, dysmorphism).

4. Genetic / Molecular Information

Causal gene (principal): TBX19 / TPIT — HGNC:11596; OMIM 604614; locus 1q24.2; T-box transcription factor family. Encodes a corticotroph/melanotroph-restricted DNA-binding transcription factor. TPIT was discovered by Lamolet et al. (2001, Cell; PMID 11290323) as a T-box factor present only in pituitary POMC lineages (corticotrophs, melanotrophs) and "apparently in no other tissue, including hypothalamic POMC neurons," that activates POMC transcription cooperatively with PITX1 and can initiate* POMC-lineage differentiation; the same study reported TPIT mutations in patients with isolated POMC-derived ACTH deficiency.

Other causal genes: NFKB2 (HGNC:7795; 10q24.32; DAVID syndrome), POMC (HGNC:9201; 2p23.3; adrenal insufficiency–obesity–red hair).

Pathogenic variant spectrum (TBX19). All variant classes reported, all loss-of-function: - Missense (e.g., p.Met86Arg within the T-box, disrupting protein–protein interaction/DNA binding; PMID 17652218, 15476446) - Nonsense (e.g., p.Arg286Ter; PMID 40990269) - Frameshift / small indels (e.g., c.782delA; PMID 15476446) - Splice-site and synonymous/exonic splice-disrupting (e.g., p.Thr96= c.288G>A causing exon-2 missplicing; PMID 34564059) - Large deletions (PMID 22170728)

Functional consequences / mechanisms of LOF (PMID 22170728): nonsense-mediated mRNA decay, aberrant splicing, loss of DNA binding, and loss of protein–protein interactions (e.g., with PITX1 and coactivator SRC2). The M86R mutation impairs cooperative DNA binding (homodimers, PITX1 heterodimers) and SRC2 recruitment despite retaining monomeric DNA binding (PMID 17652218, in vitro).

Variant classification (ACMG/AMP). Reported variants are predominantly pathogenic/likely pathogenic (functional assays + recessive segregation + absent/rare in population databases). Allele frequencies are very low in gnomAD (e.g., rs376493164 ~1×10⁻⁵, no homozygotes; PMID 34564059).

Origin: germline, biallelic (AR) for TBX19/POMC; heterozygous (often de novo) for NFKB2. No somatic involvement.

Modifier genes. None established. Partners/functionally related factors (PITX1, NEUROD1, PAX7, ETV1, CREB3L2, NR4A/Nur family) shape the corticotroph program but are not reported disease modifiers in IAD (PMID 26792828, 21622576, 31481663, 23070814).

Epigenetics. No disease-specific methylation signature established in patients. Mechanistically, the POMC locus is controlled by pioneer-factor chromatin remodeling (PAX7) and lineage enhancers on which TPIT acts (PMID 23070814, 26792828) — relevant to normal regulation rather than a documented epigenetic lesion in IAD.

Chromosomal abnormalities. Not characteristic; large TBX19 deletions occur but gross cytogenetic abnormalities are not a feature.

5. Environmental Information

  • Environmental/toxic factors: None causal for congenital IAD.
  • Infectious agents: None causal. Intercurrent infection is the most common precipitant of adrenal crisis (not a cause of the disease).
  • Lifestyle factors: Not applicable to disease causation. Relevant to management: adherence, stress-dosing behavior, carrying emergency hydrocortisone.

(Note: acquired/late-onset isolated ACTH deficiency in adults can be autoimmune/hypophysitis-related or drug-related, e.g., immune-checkpoint-inhibitor hypophysitis — but that is a separate, non-congenital entity.)

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic LOF variant in TBX19/TPIT (germline) results in absent or non-functional TPIT transcription-factor protein (nucleus). [demonstrated: functional assays, PMID 22170728, 17652218]
  2. Loss of TPIT leads to failure of terminal differentiation of pituitary corticotrophs (and melanotrophs) and failure to activate the POMC gene via the TPIT/PITX1 regulatory element. [demonstrated in human + mouse, PMID 11290323, 26792828, 15525497]
  3. Failed POMC program results in absent/deficient POMC precursor and its product ACTH in anterior-pituitary corticotrophs. [demonstrated]
  4. Low circulating ACTH leads to loss of MC2R (ACTH receptor) + MRAP1 activation on adrenocortical (zona fasciculata) cells. [downstream; receptor biology demonstrated, PMID 36588120]
  5. Loss of MC2R/cAMP–PKA signaling results in failure of adrenal steroidogenesis → cortisol (glucocorticoid) deficiency. [inferred from HPA physiology + clinical cortisol absence]
  6. Cortisol deficiency leads to the clinical phenotype — via branches:
  7. 6a. Impaired hepatic gluconeogenesis/glycogenolysis → neonatal hypoglycemia → seizures/apnea. [inferred/clinical]
  8. 6b. Impaired bile flow/hepatic adaptation → neonatal cholestasis/conjugated hyperbilirubinemia. [clinical association, reversible on replacement]
  9. 6c. Loss of permissive glucocorticoid effects on vascular tone/stress response → hypotension, vulnerability to adrenal crisis → potential neonatal death. [clinical, PMID 15613420]
  10. Because TPIT is lineage-restricted, other pituitary hormones are spared → the deficiency is isolated (selective ACTH loss). [demonstrated]

Branch (NFKB2/DAVID): heterozygous C-terminal NFKB2 mutation → defective non-canonical NF-κB p100→p52 processing → corticotroph dysfunction and B-cell/immune defect → ACTH deficiency + hypogammaglobulinemia (PMID 25524009, 37322808, organoid support PMID 39607428).

Supporting detail

  • Molecular pathways: POMC transcriptional regulation (TPIT–PITX1–NEUROD1; NR4A/Nur-mediated CRH response; glucocorticoid-receptor negative feedback) (PMID 26792828); downstream cAMP–PKA steroidogenic signaling at MC2R (PMID 36588120); non-canonical NF-κB (NFKB2 branch).
  • Cellular processes: arrest of corticotroph terminal differentiation; TPIT also drives a cell-cycle-control switch and secretory/translational scale-up via CREB3L2 (PMID 31481663, 35524583). BDNF autocrine loop couples precursor engagement to glucocorticoid feedback (PMID 42392084).
  • Protein dysfunction: TPIT missense (e.g., M86R) → impaired cooperative DNA binding and coactivator (SRC2) recruitment (PMID 17652218). Structural note: M86 lies at the T-box dimer interface.
  • Immune involvement: only in the NFKB2/DAVID branch (hypogammaglobulinemia/CVID). TPIT-IAD is not immune-mediated.
  • Metabolic changes: cortisol-dependent failure of gluconeogenesis → hypoglycemia; no primary enzyme defect.

GO terms: GO:0045944 (positive regulation of transcription by RNA Pol II), GO:0003700 (DNA-binding transcription factor activity), GO:0030855/GO:0030154 (epithelial/cell differentiation), GO:0042446 (hormone biosynthetic process), GO:0006704 (glucocorticoid biosynthetic process), GO:0051458 (corticotropin secretion), GO:0007267 (cell–cell signaling). CL terms: CL:0000152 (corticotroph / corticotropic cell), CL:1000298? melanotroph (CL:0002487), CL:0000164 (endocrine cell), adrenal cortical cell (CL:0002097 zona fasciculata cell).

7. Anatomical Structures Affected

  • Organ level (primary): Anterior pituitary / adenohypophysis (UBERON:0002196 / anterior pituitary UBERON:0002196; adenohypophysis UBERON:0002196) — specifically the corticotroph population. Secondary (functional): Adrenal cortex (UBERON:0001235), which is hypofunctional/atrophic due to lack of ACTH trophic drive (adrenal hypoplasia in Tpit-null mice, PMID 15525497).
  • Body systems: Endocrine system (hypothalamic–pituitary–adrenal axis); secondary impacts on hepatobiliary (cholestasis), metabolic/CNS (hypoglycemic seizures), cardiovascular (hypotension in crisis). In the NFKB2 branch, the immune system is involved.
  • Tissue/cell level: pituitary corticotroph cells (CL:0000152) and melanotrophs (intermediate lobe, vestigial in humans); adrenocortical cells of the zona fasciculata (CL:0002097).
  • Subcellular (GO Cellular Component): nucleus (GO:0005634, site of TPIT action/DNA binding); secretory pathway / dense-core secretory granules for ACTH (GO:0030141); plasma membrane MC2R receptor complex on adrenal cells (GO:0005886).
  • Localization/lateralization: midline pituitary; bilateral adrenal glands. No lateralization.

8. Temporal Development

  • Onset: Congenital, typically presenting in the neonatal period (first hours to days of life) for TPIT-complete IAD; NFKB2/DAVID typically presents in childhood (mean ACTH-deficiency diagnosis ~8.6 y, often after infections/alopecia) (PMID 37322808). Onset pattern: acute decompensation (hypoglycemia/crisis) superimposed on a congenital deficiency.
  • Progression: The hormonal deficiency is stable and lifelong (not progressive in the TPIT form), but the clinical course is episodic, punctuated by stress-precipitated adrenal crises. Metabolic/hepatic features remit rapidly with glucocorticoid replacement (treatment-induced remission of manifestations; the underlying deficiency does not remit).
  • Critical periods: The neonatal window is the period of highest vulnerability (risk of death) and of greatest benefit from early diagnosis/replacement. Lifelong vigilance during intercurrent illness/surgery.
  • Duration: Chronic, lifelong; requires lifelong replacement.

9. Inheritance and Population

  • Epidemiology: Very rare. Congenital IAD has no robust prevalence/incidence estimates (Orphanet: prevalence unknown/<1/1,000,000 order of magnitude; reported as an "underestimated cause of neonatal death," PMID 15613420). The literature consists of case reports and a few multinational series (largest = 91 IAD patients; TPIT mutations in 17/27 then expanded, PMID 15613420, 22170728).
  • Inheritance patterns:
  • TBX19/TPIT: Autosomal recessive (homozygous/compound heterozygous; unaffected heterozygous carrier parents) (PMID 15613420, 22170728).
  • POMC: autosomal recessive.
  • NFKB2 (DAVID): autosomal dominant, frequently de novo (PMID 25524009).
  • Penetrance: For biallelic TPIT LOF, complete/high penetrance with early lethal potential if untreated; NFKB2 shows variable expressivity (endocrine vs immune features vary within families; some carriers show only immune phenotype) (PMID 25524009).
  • Expressivity: TPIT-IAD is phenotypically homogeneous; NFKB2 is variable.
  • Genetic anticipation: Not applicable (no repeat expansion).
  • Germline mosaicism: Not specifically documented; de novo events occur for NFKB2.
  • Founder effects / consanguinity: Consanguinity contributes to homozygous TPIT cases; a recurrent TPIT mutation was seen in multiple unrelated families (PMID 15613420). A POMC 5′-UTR founder mutation was described in the Perm Tatar population (PMID 35775692) — relevant to the POMC-deficiency differential.
  • Carrier frequency: Very low; TPIT pathogenic alleles are rare in gnomAD.
  • Demographics / sex ratio: No strong sex predilection for TPIT-IAD (autosomal). Reported across diverse ethnicities/geographies; no defined endemic region.

10. Diagnostics

Biochemical (first-line). - Low/undetectable serum cortisol (e.g., <1 µg/dL; LOINC 2143-6) with inappropriately low or normal plasma ACTH (LOINC 2141-0) — the defining combination of secondary adrenal insufficiency (PMID 34564059). - Hypoglycemia (LOINC 2345-7), sometimes hyponatremia/hypokalemia. - Normal mineralocorticoid axis: normal/near-normal aldosterone and plasma renin activity (distinguishes from primary AI). - Dynamic testing: low-dose/standard ACTH (Synacthen) stimulation may show adrenal response if atrophy is not advanced; insulin tolerance test / CRH test / metyrapone assess central axis (used cautiously in neonates). ACTH-stimulation can transiently increase cortisol early (PMID 15301051). - Normal other pituitary hormones (GH, TSH/free T4, gonadotropins, prolactin) confirms "isolated."

Imaging. Pituitary MRI is typically normal (no structural lesion) in TPIT-IAD — an important feature separating it from structural hypopituitarism.

Genetic testing (confirmatory). - Approach: targeted single-gene (TBX19) testing in neonatal complete IAD; gene panels for adrenal insufficiency/hypopituitarism (TBX19, POMC, NFKB2, and FGD genes MC2R, MRAP, STAR, NNT, TXNRD2) via NGS/WES; WES/WGS for undiagnosed cases (HaloPlex/NGS arrays used in practice, PMID 34564059). - CMA/karyotype/FISH, mtDNA, repeat-expansion testing are not indicated (not a CNV/mitochondrial/repeat disorder).

Clinical criteria / differential diagnosis. - Primary (ACTH-high) adrenal insufficiency: Familial Glucocorticoid Deficiency (MC2R/MRAP/STAR/NNT/TXNRD2) — high ACTH, hyperpigmentation, preserved mineralocorticoid (PMID 37352919); Addison disease; congenital adrenal hyperplasia (elevated 17-OHP/androgens). - Central causes: combined pituitary hormone deficiency/panhypopituitarism (multiple deficits, abnormal MRI); POMC deficiency (obesity/red hair, PMID 35775692); NFKB2/DAVID (hypogammaglobulinemia, infections, alopecia, PMID 37322808). - Key discriminator: the ACTH level (low/normal = central IAD; high = primary).

Screening. No population newborn screening exists for IAD; cascade genetic testing and, in families with a known variant, prenatal/preimplantation testing enable presymptomatic management (PMID 15613420).

11. Outcome / Prognosis

  • With early diagnosis + glucocorticoid replacement: excellent prognosis — hypoglycemia and cholestasis resolve, and normal growth/development is achieved (PMID 15301051). Long-term follow-up of TPIT cases supports good outcomes on replacement (PMID 40727905).
  • Without treatment: potentially fatal in the neonatal period from acute adrenal insufficiency; IAD is described as an underestimated cause of neonatal death (PMID 15613420).
  • Principal ongoing risk / mortality driver: adrenal crisis during intercurrent illness/stress — in adrenal-insufficiency populations, adrenal crisis mortality is ~0.5/100 patient-years and a leading cause of death (PMID 40416465). Rare severe complications include reversible cardiomyopathy during crisis (PMID 39935712).
  • Morbidity/QoL: chronic medication dependence, need for emergency preparedness; neurodevelopmental sequelae possible if recurrent severe neonatal hypoglycemia is not prevented.
  • Prognostic factors: time to diagnosis, prevention of hypoglycemic brain injury, adherence, quality of sick-day/stress-dosing education.

12. Treatment

Pharmacotherapy (mainstay — lifelong hormone replacement). - Hydrocortisone, oral, physiological dosing (~8–15 mg/m²/day divided 2–3×; neonates/infants often need individualized dosing) — rapidly reverses hypoglycemia and cholestasis and restores growth (PMID 15301051). NCIT: Hydrocortisone C379; Glucocorticoid C821; Hormone Replacement Therapy C62604. - Mineralocorticoid (fludrocortisone) is generally NOT required — aldosterone is preserved in central/secondary AI (contrast with primary AI). NCIT: Fludrocortisone C29089. - Stress/sick-day dosing: double–triple oral hydrocortisone during febrile illness; parenteral (IM/IV) hydrocortisone for vomiting, severe illness, surgery, or adrenal crisis (emergency kit + medical alert). Structured stress-dosing protocols reduce crises (PMID 40416465, 40696758, 40214077). - Emergency adrenal crisis management: immediate parenteral hydrocortisone, IV dextrose for hypoglycemia, fluids/electrolyte correction.

Advanced/experimental therapeutics. No gene therapy, cell therapy, RNA therapy, or targeted/immunotherapy exists for IAD; treatment is replacement only. Modified-release hydrocortisone formulations (e.g., Plenadren, Chronocort) aim for more physiological cortisol rhythms (PMID 26683495) — relevant to adrenal insufficiency broadly. In the NFKB2/DAVID branch, immunoglobulin replacement addresses the immune deficiency (PMID 37322808).

Surgical/rehabilitative: not applicable (no surgical target). Supportive care = nutrition, infection management, caregiver education.

Pharmacogenomics: none specific to IAD.

Treatment strategy / personalized medicine: genotype-informed (TPIT vs POMC vs NFKB2) management — e.g., add Ig replacement for NFKB2; weight/obesity and pigmentation surveillance for POMC; otherwise identical glucocorticoid-replacement backbone.

13. Prevention

  • Primary prevention: Not possible for the germline genetic disease. Genetic counseling for at-risk (carrier) couples; options include prenatal diagnosis and preimplantation genetic testing where a familial variant is known (AR recurrence risk 25%) (PMID 15613420).
  • Secondary prevention (early detection): Cascade/presymptomatic genetic testing of newborn siblings in affected families permits immediate glucocorticoid prophylaxis and prevents neonatal death/hypoglycemic injury (PMID 15613420). No population newborn-screening program currently targets IAD.
  • Tertiary prevention (preventing complications): structured adrenal-crisis prevention — patient/caregiver education, written stress-dosing plans, emergency hydrocortisone injection kits, medical-alert identification; address knowledge gaps that drive preventable crises/deaths (PMID 40696758, 40214077, 40416465).
  • Immunization / public health / environmental: standard childhood immunization (reduces infections that precipitate crisis); in NFKB2/DAVID, vaccine responses may be impaired and Ig replacement considered.
  • Counseling: genetic counseling re: AR inheritance (TPIT/POMC) vs AD/de novo (NFKB2) and recurrence risks.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: Mouse Tbx19/Tpit (NCBI Taxon 10090; MGI ortholog) is the principal comparative model; TPIT and the POMC regulatory program are evolutionarily conserved across mammals (PMID 26792828). PAX7 expression in melanotropes is conserved in human and dog (PMID 23070814).
  • Natural disease in animals: No well-established spontaneous TPIT-mutation disease analog is documented in companion animals/livestock (OMIA: not a classically catalogued natural animal disease). Canine pituitary biology is referenced comparatively (Cushing's/adenoma context), not as a natural IAD model.
  • Comparative biology: Mouse Tpit-null endocrine phenotype closely mirrors human IAD (reduced ACTH, undetectable corticosterone, adrenal hypoplasia) — strong mechanistic conservation (PMID 15525497).
  • Zoonotic potential: Not applicable (non-infectious genetic disease).

15. Model Organisms

  • Mouse (Mus musculus, NCBI Taxon 10090):
  • Tpit-null (knockout) — recapitulates IAD: "plasma ACTH is greatly reduced … plasma corticosterone is undetectable and the adrenals are hypoplastic" (PMID 15525497, model organism). Demonstrates Tpit as positive regulator of POMC-cell differentiation and negative regulator of alternate (gonadotroph) fate.
  • Pax7 knockout — defines chromatin/enhancer context of Tpit action (melanotrope identity) (PMID 23070814).
  • POMC-knockout and adrenalectomized mice — reveal compensatory corticotrope-precursor accumulation and BDNF/Tpit precursor biology (PMID 42392084).
  • Resources: MGI/IMPC/IMSR.
  • In vitro / cellular: AtT-20 corticotroph tumor cell line (POMC/Tpit functional assays, PMID 21622576); heterologous expression systems for TPIT mutation functional testing and splicing assays (PMID 17652218, 34564059).
  • Human iPSC-derived pituitary organoids: model corticotroph deficiency and support the functional role of NFKB2 in DAVID syndrome (PMID 39607428, in vitro human).
  • Phenotype recapitulation: strong for the endocrine core (ACTH/corticosterone deficiency, adrenal hypoplasia). Limitations: neonatal cholestasis, dysmorphism, and human-specific developmental/clinical features are not fully modeled; mouse intermediate-lobe (melanotrope) biology differs from humans.
  • Applications: dissecting corticotroph differentiation, POMC transcriptional control, testing differentiation signals (BDNF, CREB3L2), and modeling genotype-specific mechanisms.

Supported vs. Refuted Hypotheses

Supported: - Biallelic TBX19/TPIT LOF is the principal cause of neonatal-onset complete IAD (65% of such cases) — PMID 22170728. - Highly homogeneous neonatal phenotype (hypoglycemia, cholestasis, undetectable cortisol with low/normal ACTH), fatal if untreated, reversible with hydrocortisone — PMID 15613420, 15301051. - Mechanistic chain TPIT→POMC/ACTH→MC2R→cortisol, with isolated (lineage-restricted) deficiency — PMID 26792828, 36588120. - Tpit-null mouse recapitulates the endocrine phenotype — PMID 15525497.

Refuted / bounded: - TPIT mutations do NOT explain partial or late-onset IAD (0% in those groups) — PMID 22170728; implies additional, partly unknown genetic/acquired causes. - IAD is not a mineralocorticoid-deficient, hyperpigmented, or ACTH-high disorder — these features indicate primary AI/FGD instead — PMID 37352919.

Limitations & Future Directions

  • No large-scale prevalence/incidence or registry data; epidemiology is case-series-based.
  • Genetic cause of partial/late-onset IAD remains largely unexplained (gene-discovery opportunity via WES/WGS).
  • Limited QoL and long-term neurodevelopmental outcome data specific to IAD.
  • Mechanistic links from cortisol deficiency to neonatal cholestasis remain incompletely defined (largely inferred/clinical).
  • No disease-modifying/curative therapy; replacement is lifelong — future directions include physiological cortisol delivery and, speculatively, corticotroph cell/gene-based restoration.

Ontology quick-reference

  • Disease: MONDO:0008720; OMIM #201400; ORPHA:442; ICD-10 E23.0
  • Genes: TBX19 (HGNC:11596, OMIM *604614), NFKB2 (HGNC:7795), POMC (HGNC:9201)
  • HPO: HP:0001943, HP:0001998, HP:0008163, HP:0011736, HP:0001396, HP:0002908, HP:0000846, HP:0001250, HP:0002900
  • GO: GO:0045944, GO:0003700, GO:0030154, GO:0006704, GO:0051458
  • CL: CL:0000152 (corticotroph), CL:0002097 (zona fasciculata cell)
  • UBERON: UBERON:0002196 (adenohypophysis/anterior pituitary), UBERON:0001235 (adrenal cortex)
  • CHEBI: CHEBI:17650 (cortisol), CHEBI:3650 (ACTH), CHEBI:17754 (glucocorticoid class)
  • NCIT: C379 (Hydrocortisone), C821 (Glucocorticoid), C62604 (Hormone Replacement Therapy)

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 25
On topic 18
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 39
Resolved 35
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 22
Terms named correctly 11
Terms named as a different term 5
Terms whose name is worth a second look 6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0011736 (2 mentions) - the report calls it "Decreased circulating ACTH"; HP calls it Primary hyperaldosteronism
  • CL:0000152 (3 mentions) - the report calls it "corticotroph / corticotropic cell", "Tissue/cell level: pituitary corticotroph cells", "corticotroph"; CL calls it exocrine cell**
  • CL:0002097 (3 mentions) - the report calls it "zona fasciculata", "zona fasciculata cell"; CL calls it cortical cell of adrenal gland
  • CHEBI:3650 (1 mention) - the report calls it "ACTH"; CHEBI calls it chlorpropamide
  • CHEBI:17754 (1 mention) - the report calls it "glucocorticoid class"; CHEBI calls it glycerol

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0008163 (2 mentions) - the report calls it "Decreased circulating cortisol"; HP calls it Decreased circulating cortisol level
  • HP:0000271 (1 mention) - the report calls it "Abnormal facial shape"; HP calls it Abnormality of the face, and lists "Abnormal face" among its other names
  • GO:0045944 (2 mentions) - the report calls it "positive regulation of transcription by RNA Pol II"; GO calls it positive regulation of transcription by RNA polymerase II
  • GO:0030154 (2 mentions) - the report calls it "epithelial/cell differentiation"; GO calls it cell differentiation
  • CL:0000164 (1 mention) - the report calls it "endocrine cell"; CL calls it enteroendocrine cell
  • UBERON:0002196 (4 mentions) - the report calls it "adenohypophysis/anterior pituitary"; UBERON calls it adenohypophysis, and lists "anterior pituitary" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • CL:0000152 - called "corticotroph / corticotropic cell", "Tissue/cell level: pituitary corticotroph** cells", "corticotroph"
  • CL:0002097 - called "zona fasciculata", "zona fasciculata cell"
  • UBERON:0001235 - called "Adrenal cortex", "adrenal cortex"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.