Congenital Isolated ACTH Deficiency (TBX19-TPIT) and Other Genetic Causes

Congenital isolated corticotropin deficiency due to biallelic variants in TBX19 (TPIT), set within the other genetic causes of early-onset central adrenal insufficiency: pro-opiomelanocortin (POMC) deficiency, prohormone convertase 1/3 (PCSK1) deficiency, DAVID syndrome (NFKB2) and congenital hypopituitarism presenting with corticotropic deficiency

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

Isolated adrenocorticotropic hormone (ACTH, corticotropin) deficiency is defined by low cortisol with low or inappropriately normal ACTH, with the other anterior pituitary hormones preserved; the congenital form of neonatal onset is the main entity of this article, and the other genetic causes of ACTH deficiency are included as members of the same pathophysiological class [1–3].

Sources for the table: identifiers and inheritance [1, 2, 4–15]; GeneReviews [16]; MANE transcript [17, 18]; prevalences and cases [12–14, 19]; age and clinical features [3, 20–22]; reference network [23].

1. Introduction

1.1 Historical overview

Congenital isolated corticotropin deficiency was first described in 1954 and remained, for almost half a century, a poorly defined entity, known from a small number of reports of newborns with hypoglycaemia, jaundice and early death in families with more than one affected member [24, 25]. Among the older reports, OMIM records a 34-month-old boy described by Hung and Migeon in 1968 and two siblings described by Malpuech and colleagues in 1988: the first died at 14 hours of life with bilateral adrenal hypoplasia at autopsy, and in the next pregnancy measurement of maternal plasma oestriol allowed prenatal diagnosis and immediate treatment of the sister, who had small adrenals on ultrasound [4]. The first attempts at a molecular explanation looked for the defect in the hormone precursor itself or in its hypothalamic control. In 1993, Nussey and colleagues studied a girl with neonatal hypoglycaemia in whom ACTH was undetectable even after stimulation with corticotropin-releasing hormone (CRH), while the ACTH precursors (POMC, N-terminal pro-opiocortin and β-endorphin) were measurable, responded to CRH and were suppressed by glucocorticoids; the POMC coding sequence was normal and the authors suggested a defect of a cleavage enzyme [26]. In 1996, Kyllo and colleagues studied a pair of affected siblings of healthy parents, proposed autosomal recessive transmission, excluded by haplotype analysis linkage to the loci of POMC and of neuroendocrine convertases 1 and 2, and found compatibility with linkage to the region of the CRH gene on chromosome 8, a hypothesis not confirmed by later work [24, 27].

The explanation came from the study of pituitary differentiation. In 2001, Jacques Drouin's group in Montreal identified Tpit, a T-box family transcription factor present only in the two pituitary lineages that express POMC, the corticotrophs of the anterior pituitary and the melanotrophs of the intermediate lobe, and absent from other tissues, including hypothalamic POMC neurons; Tpit activates POMC transcription in cooperation with the homeobox factor Pitx1, bound to an adjacent site of the same regulatory element, and the same work described the first TPIT mutations in patients with isolated pituitary ACTH deficiency [28]. In the same year, Rosenfeld's group described the same gene, under the name Tbx19, as an early marker (from embryonic day 11.5) of the cells that would go on to express POMC [29]. In 2003, Pulichino and colleagues showed that the Tpit-null mouse reproduces human isolated ACTH deficiency, that TPIT mutations are frequently associated with early-onset forms and not with juvenile forms, and defined early-onset congenital deficiency as a relatively homogeneous clinical entity, recessively transmitted through loss-of-function mutations [30]; a second paper by the same group showed that Tpit is required for terminal differentiation of POMC cells, but not for lineage commitment, and that it represses gonadotroph differentiation [31].

The clinical series that followed established the phenotype. In 2004, Metherell and colleagues found TPIT mutations in two siblings with early onset, but not in two other early-onset patients or in three late-onset patients, and concluded that there was genetic heterogeneity [32]. In 2005, Vallette-Kasic and colleagues brought together 27 patients with neonatal isolated ACTH deficiency from 21 families, identified TPIT mutations in 17, all homozygous or compound heterozygous, with healthy carrier parents, and drew attention to the homogeneity of the presentation and to the possibility that the disorder is an underestimated cause of neonatal death [20]. In 2012, Couture and colleagues extended the series to 91 patients, distinguished three groups (complete neonatal, partial neonatal and late onset) and established that TPIT variants account for about two thirds of complete neonatal forms and none of the partial or late forms [3]. In the same year, among 22 patients of the French GENHYPOPIT network with ACTH deficiency without a TPIT mutation, Quentien and colleagues recognised the association with common variable immunodeficiency, which they named DAVID syndrome, later explained by NFKB2 variants [14, 21]. In 2022, Charnay and colleagues described the first founder variant in families originating from the Rif, in northern Morocco, and updated the published variant spectrum [17].

1.2 Nomenclature

The gene was named TPIT (pituitary-restricted T-box factor) by Lamolet and colleagues and Tbx19 by Liu and colleagues; the official symbol is TBX19, and the clinical literature uses both names [2, 28, 29]. OMIM records the disorder under number 201400 and Orphanet distinguishes two entities: congenital isolated ACTH deficiency (ORPHA:199296), of neonatal onset and autosomal recessive inheritance, and late-onset isolated ACTH deficiency (ORPHA:199299), considered acquired and of adult onset [1, 15]. The classification codes differ between sources: Orphanet assigns the congenital form the ICD-10 code E23.0 and the ICD-11 code 5A74.Y, whereas the GeneGuidance record gives E23.6; the late form has E23.6 and 5A61.0 [1, 2, 15].

1.3 Definitions and scope

Congenital isolated ACTH deficiency is defined by Orphanet as a rare endocrine disorder with neonatal hypoglycaemia, prolonged cholestatic jaundice and seizures, low plasma ACTH and cortisol, no structural pituitary defect and, sometimes, associated partial growth hormone (GH) deficiency [1]. In the classification of Couture and colleagues, the complete neonatal form has very low ACTH and cortisol, frequently below the limit of detection, and is the one associated with TBX19; the partial neonatal form and the late-onset form had no TBX19 variants in the series of 91 patients [3]. Pham and colleagues, in a French series of eight patients, used a practical division into an early form, before 1–2 years, and a late form, after 3 years [24]. The late-onset deficiency of Orphanet is an acquired entity, with fatigue, weight loss, anorexia, nausea and hypoglycaemia, sometimes associated with autoimmune disease such as Hashimoto's thyroiditis [15].

The scope of this article is the class of genetic causes of early-onset ACTH deficiency. TBX19 deficiency is covered in depth. POMC deficiency and PC1/3 deficiency have their corticotropic axis described here, in addition to causing monogenic obesity; DAVID syndrome is described in the differential diagnosis; the forms of combined congenital hypopituitarism in which ACTH deficiency coexists with other deficiencies, including septo-optic dysplasia, and the causes of adrenal insufficiency with raised ACTH (familial glucocorticoid deficiency, X-linked adrenal hypoplasia congenita and congenital adrenal hyperplasia) are also included in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1 The TBX19 gene and the TPIT protein

TBX19 lies at 1q24.2; the main transcript, NM_005149.3, is the MANE Select, has 8 exons and encodes a 448-amino-acid protein (NP_005140.1) with a DNA-binding T-box domain; the gene was cloned and mapped by Yi and colleagues in 1999, and the human protein shares 94% of its amino acids with mouse Tpit [2, 5, 17, 18]. TBX19 belongs to the T-box family, whose members cause, among others, Holt-Oram syndrome, ulnar-mammary syndrome, DiGeorge syndrome and X-linked cleft palate with ankyloglossia [5]. Expression is restricted to the two pituitary lineages that produce POMC, the corticotrophs and the melanotrophs [2, 28]. TPIT binds the T-box element of the POMC promoter and, alone or with Pitx1, has a small effect; together, the two factors produce synergistic activation, which a recent luciferase reporter assay demonstrated again in HEK293T cells [25, 28]. TPIT also recruits coactivators of the SRC/p160 family (SRC2), which mediate part of the stimulation of POMC transcription by CRH [33].

During development, TPIT is a positive regulator of late differentiation of POMC cells and of POMC expression, but it is not required for lineage commitment; in the Tpit-null mouse, the intermediate lobe loses almost all POMC cells and acquires gonadotrophs and clusters of Pit-1-independent thyrotrophs, which showed that Tpit represses gonadotroph differentiation, partly through trans-repression with the factor SF1 [31]. Liu and colleagues showed, in a complementary way, that Tbx19 can activate POMC and repress the promoters of the glycoprotein α-subunit and of the thyrotropin (TSH) β-chain [29]. Corticotrophs represent about 15% of anterior pituitary cells, so the loss of this lineage alters the volume of the gland very little [17].

2.2 From pituitary to adrenal: mechanism of the insufficiency

Biallelic loss of TPIT function prevents terminal differentiation of corticotrophs and ACTH synthesis, with the other pituitary axes intact [2, 30]. The result is secondary adrenal insufficiency: the adrenal cortex is structurally normal and the steroidogenic enzymes are intact, but the trophic stimulus is lacking, and the low cortisol is accompanied by low or undetectable ACTH, unlike primary insufficiency, in which ACTH rises above twice the upper reference limit [2, 34]. Hypoglycaemia results from the lack of cortisol, one of the counter-regulatory hormones on which maintenance of fasting glucose depends, and neonatal cholestasis, which regresses with hydrocortisone, is attributed to the cortisol deficiency itself, as shown by series in which cholestatic jaundice disappeared with replacement in both ACTH deficiency and familial glucocorticoid deficiency [35–37]. The hyponatraemia of secondary insufficiency is mainly due to free water retention, because cortisol no longer counteracts the effect of vasopressin [24, 38].

As ACTH is not the main regulator of the renin-angiotensin-aldosterone axis, mineralocorticoid function is, as a rule, preserved: renin and aldosterone were normal in the patients studied by Charnay and colleagues and in the series of Pham and colleagues, where aldosterone was normal or low [2, 17, 24]. This rule has documented exceptions. Hyponatraemia and hyperkalaemia were recorded in an infant with a TBX19 variant and normal renin and aldosterone [17], and Holterhus and colleagues, using liquid and gas chromatography coupled with mass spectrometry, demonstrated a combined reduction in glucocorticoid and mineralocorticoid biosynthesis in two patients homozygous for p.(Thr58Ala), one of them with neonatal hyponatraemia (lowest sodium 126 mmol/L) treated with hydrocortisone, fludrocortisone and sodium chloride; the authors propose that sufficient ACTH secretion is a prerequisite for regular mineralocorticoid biosynthesis [39]. Dehydroepiandrosterone sulfate (DHEAS), which is ACTH-dependent, is low in ACTH deficiency [24, 40].

2.3 Inheritance, penetrance and carriers

Transmission is autosomal recessive: all patients in the Montreal and Marseille series were homozygous or compound heterozygous, and the parents were healthy carriers [3, 20]. The sources consulted do not describe manifestations in heterozygous carriers, and there are no published data on penetrance in unaffected homozygotes; expressivity varies with the age at which the diagnosis is made and with the quality of treatment, more than with the genotype [17, 19]. The review by Dang and colleagues found no evidence of mosaicism in the published cases, without being able to exclude it with the methods used [19].

2.4 Variant spectrum

The first two variants, described in 2001, were p.(Arg286Ter) in the homozygous state in a boy of consanguineous parents, with the parents and a grandparent heterozygous without deficiency, and p.(Ser128Phe), at a residue conserved in all T-box genes, found in the heterozygous state without a second exonic variant in the surviving sister of the Malpuech family [5]. In the 2012 series, 21 variants were identified in 37 patients from 29 families with the complete neonatal form, most in the T-box; four missense variants studied in vitro had markedly reduced or absent transcriptional activity, and p.(Lys146Arg), homozygous in two siblings, abolished DNA binding [4, 5]. By 2022, 39 pathogenic variants had been described: 22 truncating (nonsense, frameshift, splicing and deletions of one or more exons), 33 located in the T-box domain, including all the missense variants, and variants in all exons except exon 8 [17]. The demonstrated loss-of-function mechanisms include nonsense-mediated messenger RNA decay, aberrant splicing, loss of DNA binding and defects of protein-protein interaction [3]. The p.(Met86Arg) variant, for example, does not alter monomer binding to DNA, but prevents binding as a homodimer and with Pitx1 and the recruitment of SRC2 [33]. In 2025, five variants (p.(Arg286Ter), p.(Pro126Leu), p.(Glu201Val), p.(His134Arg) and p.(Arg100His)) reduced POMC promoter activity by about 50% in a reporter assay [25].

A synonymous variant, c.288G>A p.(Thr96=), in a newborn of Romanian origin, creates a new splice acceptor site that removes 86 base pairs from exon 2; in a minigene, the truncated and normal transcripts appeared in a ratio of about 1:1, and the variant had been classified as benign by three protein-effect predictors [41]. The case shows that synonymous and intronic variants close to exon boundaries should be analysed for splicing before being discarded.

The following table brings together the variants cited, described according to Human Genome Variation Society (HGVS) nomenclature, normalised in VariantValidator on the MANE Select and cross-checked against ClinVar on 31 October 2026 [18, 42].

Two reports used the previous version of the transcript (NM_005149.2) with the same c. positions for the variants cited [25, 37]. In ClinVar there were 47 TBX19 records classified as pathogenic or likely pathogenic on the date of consultation [42].

2.5 Founder variants and genotype-phenotype correlation

The c.840del variant was found in four children from three apparently unrelated families, living in different regions of France, all originating from the same mountainous Rif region; two families were consanguineous, and the variant was absent from gnomAD v2.1.1, which supports a founder effect [17]. c.82C>T p.(Gln28Ter) is the other founder candidate: 43 of the 45 heterozygotes recorded in gnomAD were Finnish [17]. In an early series, the same mutation was found in five unrelated families [20]. The sources do not demonstrate a consistent genotype-phenotype correlation; Kardelen and colleagues and Kizilcan Cetin and colleagues stress that the number of cases does not allow one to be established, and the phenotype of the truncating and missense variants described overlaps [17, 43, 45].

2.6 Other genetic causes of ACTH deficiency

POMC is the precursor processed in a tissue-specific manner into ACTH, β-endorphin and α-, β- and γ-melanocyte-stimulating hormones; ACTH acts on the melanocortin 2 receptor (MC2R) of the adrenal cortex and α-melanocyte-stimulating hormone (α-MSH) on MC1R of melanocytes and on hypothalamic MC4R [12, 16]. Biallelic loss of POMC eliminates all these peptides and produces secondary adrenal insufficiency, pale pigmentation and hyperphagic obesity [12, 16]. In PC1/3 deficiency, prohormones are not processed: proinsulin accumulates with low or inappropriately normal mature insulin, and POMC precursors rise without sufficient formation of ACTH and α-MSH [13, 22]. In DAVID syndrome, NFKB2 variants prevent the processing of p100 into p52 in the non-canonical NF-κB pathway; the truncated protein retains the inhibitory region and the effect is not one of simple haploinsufficiency [14]. The demonstration that the endocrine phenotype of DAVID syndrome depends on NFKB2 was obtained in pituitary organoids derived from stem cells edited by CRISPR-Cas9, preclinical work [52]. The genes for CRH and its receptor have been proposed as candidates for isolated ACTH deficiency without the sources consulted describing confirmed pathogenic changes [24, 27].

3. Clinical Spectrum and Manifestations by System

3.1 Neonatal presentation (natural history)

The typical presentation of TBX19 deficiency is neonatal and can be fatal within days: severe hypoglycaemia, often with seizures, prolonged cholestatic jaundice, hypotonia and, in some patients, hyponatraemia [2, 20]. In the largest series, the family frequently reported neonatal deaths, and third-trimester miscarriages or neonatal deaths were reported in up to a quarter of cases [2, 17]. According to the description by Dang and colleagues of the 2012 series, the 91 patients included 37 newborns with a TBX19 variant, 32 newborns without a variant and 22 patients with a juvenile form without a variant; all newborns with a variant had neonatal hypoglycaemia and complete deficiency, and prolonged cholestasis and seizures were less frequent in the groups without a variant [3, 19]. OMIM summarises the same series: the 37 patients with a variant, from 29 families, had severe neonatal hypoglycaemia, frequently with seizures (about half of cases), and prolonged cholestatic jaundice, very low ACTH and cortisol and normal pituitary imaging; there were neonatal deaths in 25% of families, and only two patients had partial and transient GH deficiency [4]. In the 2005 series, cited by Pham and colleagues, hypoglycaemia was present in all patients with a mutation and in only one without a mutation; cholestatic jaundice with hepatomegaly, which disappeared with hydrocortisone, occurred in 11 of 17 patients with a mutation and in 1 of 10 without a mutation; mean ACTH was 6.8 pg/mL with a mutation and 12.1 pg/mL without a mutation; and consanguinity was reported in 5 of 13 and 1 of 8 families, respectively [20, 24].

Individual reports complete the picture. A 5-day-old newborn was admitted with hypoglycaemia, hypotonia and conjugated hyperbilirubinaemia, with cortisol of 0.1 µg/dL and ACTH below 5 pg/mL [53]. Another had respiratory arrest and hypoglycaemia at 15 hours of life, with jaundice on day 3 [41]. In a third, respiratory distress with pulmonary hypertension and haemodynamic instability minutes after birth required ventilation and noradrenaline, and severe hypoglycaemia and cholestasis accompanied the picture [17]. In the French series of Pham, one newborn girl was born in a state of "apparent death" and another had feeding difficulty, oedema and cold extremities on day 6 and hypothermia of 29 °C on day 14, both without an identified TBX19 variant [24]. Hyperkalaemia, characteristic of primary insufficiency, may occur in severe crises of ACTH deficiency [17], and a recent report describes hypokalaemia at presentation [45].

3.2 Presentations outside the neonatal period

Some patients with a TBX19 variant have an unremarkable neonatal period or unrecognised symptoms and reach diagnosis later. Charnay and colleagues made the diagnosis at 2 and 5 months in two of four patients, one of whom had neonatal hypoglycaemia and hypotonia that regressed spontaneously; the authors note that most cases diagnosed up to 5 years of age had symptoms before 1 year [17]. A 7-year-old child was admitted nine times for lower respiratory tract infections before ACTH and cortisol were measured [51]. A girl of first-cousin parents had admissions for seizures, abdominal pain and vomiting and was diagnosed at 4 years and 8 months with glucose of 1.4 mmol/L, cortisol of 0.1 µg/dL and ACTH below 5 pg/mL [49]. Two Russian patients with neonatal manifestations were only diagnosed at 8 and 22 months; in one of them, the liver disease included hepatomegaly, cytolysis and failure of hepatic protein synthesis, which normalised with hydrocortisone [46]. In three Chinese children, the presentation was recurrent hypoglycaemic seizures at 2 years, cholestasis with heart failure in the 1st month, and cardiorespiratory arrest during gastroenteritis at 28 months [25]. The Portuguese case from Coimbra, without hypoglycaemia or jaundice in the 1st month, presented at 9 months with a hypoglycaemic seizure during gastroenteritis and at 4 years with a severe crisis, described in section 10 [37].

3.3 Growth, morphology and other systems

Linear growth on treatment is usually normal, and several patients had tall stature or high weight: height +2.2 standard deviations at 4 years and 8 months [49], growth at or above the 97th centile [37, 54] and on the 99th centile at 3 years [17]. Kardelen and colleagues described, at long-term follow-up, short stature, microcephaly and sparse pubic hair in one patient, and dysmorphic features, Chiari type 1 malformation, tall stature and low bone mineral density in another [43]. Mild facial dysmorphism (long philtrum, depressed nasal bridge, epicanthus, prominent low-set ears, mild hypertelorism) was described in a newborn homozygous for p.(Arg286Ter) [45]. Charnay and colleagues recorded scaphocephaly in one patient and cardiac valve defects (bicuspid aortic valve, mitral regurgitation) in two, and argue that these malformations are frequent in the population and unlikely to result from the TBX19 defect, which is expressed only in the pituitary, allowing for other genetic defects associated with consanguinity [17]. The coexistence of two recessive diagnoses is documented: a boy from Sri Lanka was homozygous for pathogenic variants in TBX19 and DPYS (dihydropyrimidinase deficiency), with cerebral infarction, motor delay and epilepsy [48].

Transient abnormalities of other axes do not invalidate the diagnosis of isolated deficiency. TSH was transiently raised in several patients (16.79 mIU/L in an infant, with rapid normalisation; 7.28 mIU/L in a child in crisis) [17, 37, 54], free thyroxine (free T4) was transiently at the lower limit in a newborn [17], and Orphanet allows for associated partial GH deficiency [1]. Pituitary magnetic resonance imaging (MRI) is usually normal: the 11 patients studied in the 2012 series had a normal pituitary, and in the Charnay series the anterior pituitary was normal in two of three patients and moderately hypoplastic in one [2, 17]. In a child with TBX19 variants and pituitary stalk interruption syndrome, hypothyroidism and patent ductus arteriosus, the phenotype is not that of isolated deficiency and the association may have another cause [25].

3.4 Treated disease and sequelae

With early hydrocortisone, the reported patients had normal growth, neurodevelopment and quality of life [17, 45, 53]. A patient diagnosed on the 1st day of life had, at 22 years, normal physical, mental and neuromotor development, despite treated epileptic seizures and an arachnoid cyst, cortical atrophy and gliosis on MRI [50]. The main long-term morbidity is cognitive impairment, attributed to undiagnosed crises or poorly adjusted hydrocortisone [2, 17]. In a pair of siblings homozygous for p.(Arg286Ter), the first, in whom hydrocortisone was stopped at another hospital and replaced by antiepileptic drugs on suspicion of epilepsy, was left with developmental delay, whereas the second, treated from the neonatal period, had normal development [44]. In the review of 35 cases published in 2024, 15 had neurodevelopmental delay of variable degree, and 13 of these had started treatment after 1 year of age [19].

Source: Dang and colleagues, 2024 [19]. The review mixes patients with and without a TBX19 variant and depends on the quality of the individual reports.

3.5 Forms without a TBX19 variant and late-onset forms

About a third of the complete neonatal forms and all the partial and late forms in the 2012 series had no TBX19 variant [3]. In the Pham series, six patients had the late form, with first symptoms between 3 and 12.3 years and diagnosis between 3.3 and 14.4 years (0.3 to 4.8 years after the first symptoms); all had hypoglycaemia and four had seizures; the initial symptoms were vomiting or abdominal pain, fatigue, irritability, difficulty with physical activities and anorexia; school performance worsened in four, especially memory, and two were treated for depression, which was stopped when they started hydrocortisone; all had attended the emergency department one to three times and been discharged with diagnoses of encephalitis, gastroenteritis, asthma or fainting [24]. The TPIT coding sequence was normal in the eight patients of the series, including the two neonatal ones [24]. Late-onset isolated ACTH deficiency in adults is, according to Orphanet, acquired [15], and has been described in association with anti-corticotroph antibodies in a person with Down syndrome (single case) [55].

3.6 Other entities of the class

In the first report of POMC deficiency, in 1998, a girl with normal birth weight had cholestasis at 3 weeks and ACTH deficiency diagnosed at 23 days, with resolution of the cholestasis on hydrocortisone, and her older brother had died at 7 months of liver failure after severe cholestasis with adrenal insufficiency and hypoplasia [6]. In POMC deficiency, most children have exponential weight gain, hyperphagia, cholestasis and adrenal insufficiency in the first months, and by the end of the 1st year severe obesity without increased height; red hair and phototype 1 skin are common but not constant, and mild central hypothyroidism and GH and gonadotropin deficiency at puberty have been described [16]. The reports include a child of Turkish origin without red hair, a Hispanic girl with hypoglycaemia at 9 months and a North African boy with hypoglycaemia in the first days and diagnosis at 9 months, with dark hair but increased pheomelanin on chemical hair analysis [16]. The Oxford handbook summarises the neonatal presentation as adrenal crisis or cholestatic jaundice due to cortisol deficiency [22]. In PC1/3 deficiency, severe neonatal malabsorptive diarrhoea, which may require parenteral nutrition, is the earliest and most dangerous feature; it is followed by hyperphagic obesity and a progressive polyendocrinopathy with central hypothyroidism, GH deficiency, hypogonadotropic hypogonadism, central adrenal insufficiency, postprandial hypoglycaemia and, in some, central diabetes insipidus [13, 22]. In a series of 13 patients from 11 families with malabsorptive diarrhoea and PCSK1 variants, central adrenal insufficiency was diagnosed in 8, between 1 month and 5.5 years of age, and diabetes insipidus in 8, at a mean age of 18 months [8]. In DAVID syndrome, primary immunodeficiency began early in 46 of 50 patients in a review (mean age at onset 5.9 years), autoimmunity affected 80% and central adrenal insufficiency due to ACTH deficiency occurred in 44% [14]; in the original series of four patients, ACTH deficiency was diagnosed between 5 and 15 years with symptomatic hypoglycaemia, three had a hypoplastic pituitary and one had a subnormal GH response [21]. In septo-optic dysplasia, a series cited by the Oxford handbook found ACTH deficiency in 60% of patients, and seizures are often secondary to hypoglycaemia due to GH and cortisol deficiency [56].

4. Clinical Recognition and Red Flags

4.1 Before birth

Maternal serum unconjugated oestriol (uE3), used in some prenatal screening programmes, depends on fetal adrenal DHEAS production [24]. In a Californian programme with more than 100,000 pregnancies, 0.27% had a uE3 of 0.2 ng/mL or less (0.15 multiples of the median); the most common cause in a viable pregnancy is X-linked ichthyosis, and in a pregnancy with a female fetus the Oxford handbook advises considering, among other rare causes, ACTH deficiency [57]. In 1988, Malpuech and colleagues used maternal plasma oestriol for prenatal diagnosis in a family that had already lost a newborn [4]. Weintrob and colleagues, cited by Pham, made the diagnosis in utero in a second child on the basis of low maternal oestriol, after the first child had died at 7 weeks with suspected heart disease, and recommended that low oestriol with normal fetal ultrasound and growth, once placental sulfatase deficiency and Smith-Lemli-Opitz syndrome had been excluded, should raise suspicion of deficient fetal steroidogenesis [24]. Charnay and colleagues record the proposal, but note that prenatal diagnosis is not in routine use [17].

4.2 Newborn

The French National Diagnosis and Care Protocol (PNDS) for congenital pituitary deficiency lists the signs suggestive of corticotropic deficiency in the neonatal period: recurrent hypoglycaemia without hyperinsulinism, prolonged cholestatic jaundice, dilutional hyponatraemia without hyperkalaemia and a family history of perinatal mortality [58]. Profound and persistent hypoglycaemia not explained by neonatal conditions is a clear sign, especially if accompanied by jaundice or hypotension, but it may be isolated [24]. The combination of cholestasis and hypoglycaemia in an infant should lead to assessment of adrenal function [35, 45]. Physical examination helps to distinguish isolated deficiency from combined hypopituitarism: micropenis points to pituitary dysfunction, and midline anomalies, such as cleft palate, to GH, ACTH and cortisol deficiencies [36]. Newborn screening for congenital adrenal hyperplasia measures 17-hydroxyprogesterone, which does not rise in ACTH deficiency; a normal screen does not rule out this disorder [2].

4.3 Infant and child

Outside the neonatal period, the signs are non-specific: hypoglycaemic seizures during gastroenteritis or respiratory infection, recurrent respiratory infections, vomiting, abdominal pain, fatigue, difficulty with physical exertion, weight loss and declining school performance [19, 24, 37, 51]. Secondary insufficiency lacks the hyperpigmentation and salt wasting that point to primary insufficiency, which contributes to diagnostic delay [24]. The French PNDS and the National Institute for Health and Care Excellence (NICE) guideline indicate that corticotropic insufficiency should be considered in the presence of hyponatraemia without hyperkalaemia, unexplained hypoglycaemia, poor growth or a hypotensive crisis in children [58, 59]. The authors of the Portuguese case recommend measuring cortisol during hypoglycaemia whenever there is a Whipple triad or blood glucose below 60 mg/dL in a child who cannot express symptoms [37].

4.4 Emergency signs

Emergencies include hypoglycaemia with seizures or altered consciousness, shock or haemodynamic instability unresponsive to fluids, acute hyponatraemia and any deterioration during an infection or surgery in a patient with known deficiency; treatment with parenteral hydrocortisone begins as soon as the crisis is suspected, without waiting for results, after the diagnostic samples have been taken if this does not delay it [34, 38, 58]. In undiagnosed patients, refractory hypoglycaemia during a severe acute illness should raise the possibility of adrenal insufficiency, as in the Portuguese case [37].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no formal criteria published by a society for congenital isolated ACTH deficiency. The diagnosis rests on three elements: low cortisol with low or inappropriately normal ACTH, without prior corticosteroid therapy; normality of the other pituitary axes, which confirms the isolated nature; and, for the genetic form, biallelic variants in TBX19 or another gene of the class [2, 3, 24]. The absence of a classic circadian rhythm before 1 to 9 months of life and the physiologically low cortisol of the newborn make interpretation difficult and expose to overdiagnosis of isolated deficiency; the French PNDS recommends repeated measurements of cortisol and ACTH at different times and, if necessary, a low-dose (1 µg) tetracosactide test [24, 58].

5.2 Critical sample and baseline biochemistry

Hypoglycaemia is the strongest stimulus for ACTH and cortisol secretion, so the sample taken during spontaneous hypoglycaemia is the most informative: cortisol, ACTH, insulin (to exclude hyperinsulinism), GH and the other pituitary hormones, bearing in mind that thyroxine and GH are physiologically high in the newborn [2, 24]. Renin and aldosterone, sodium and potassium, conjugated bilirubin and liver function, and DHEAS complete the assessment [2, 24]. In a patient with a first acute presentation, the British paediatric guideline requires renal function, cortisol, renin, aldosterone, ACTH (ethylenediaminetetraacetic acid, EDTA, tube) and glucose to be taken before hydrocortisone, without delaying treatment [38]. The fasting test is contraindicated when ACTH deficiency is suspected, because it is dangerous [60].

In patients with a TBX19 variant, cortisol and ACTH were usually below the assay's limit of detection (for example, cortisol below 27 nmol/L and ACTH below 1.1 pmol/L) [17]. An ACTH within the reference range does not exclude the diagnosis when cortisol is undetectable: in the newborn with the synonymous variant p.(Thr96=), ACTH was 19 to 22 pg/mL with cortisol below 1 µg/dL during hypoglycaemia, and at 3.5 years ACTH was 3.85 pg/mL and the tetracosactide test produced no response [41]. The Brazilian guideline for adults stresses that ACTH alone has no diagnostic value in secondary insufficiency and that an undetectable ACTH, without cortisol, does not establish it [40]. Low DHEAS supports the diagnosis, but it is physiologically low in the first 5 years of life [24].

5.3 Cortisol thresholds and dynamic tests

Thresholds vary with age, time of sampling and assay, and the sources differ.

The tetracosactide stimulation test is the standard for primary insufficiency, but not for secondary insufficiency, because an adrenal deprived of ACTH for only a short time may still respond [34]; Pham and colleagues prefer basal cortisol at 8 a.m. and cite patients with a normal response to ACTH despite insufficiency [24]. In adults, the Endocrine Society guideline on hypopituitarism accepts the corticotropin test for intermediate morning values, with low grades of evidence (grade 2 suggestions), and points out that a random low-normal ACTH does not help to diagnose central insufficiency and that oral oestrogen increases corticosteroid-binding globulin (CBG) and, with it, total cortisol, which should be taken into account when assessing adrenal reserve or the adequacy of replacement [61]. Three paediatric studies from 2026 inform the interpretation of tests in suspected central insufficiency. In 177 children undergoing a 1 µg test, the peak occurred at 15 minutes in 48.6%, at 30 in 28.8%, at baseline in 10.7%, at 45 in 9.0% and at 60 in 2.8%; ending the test at 30 minutes would have classified as insufficient 11.9% of children with a later normal response, and time-specific thresholds reduced false positives about fivefold [62]. In 646 tests with 1 µg and a monoclonal immunoassay, sampling at 40 minutes was the best single time point, with fewer false negatives than at 60 minutes; a basal cortisol of 6.5 µg/dL or more had a sensitivity of 75.1% and a specificity of 57.5% [63]. In a Brazilian cohort of 904 children undergoing an insulin tolerance test or a glucagon test, central insufficiency was confirmed in 79 (8.7%); basal cortisol left 58% indeterminate, a basal value below 96.6 nmol/L had a specificity of 99% but a sensitivity of 5.3%, and the tests were safe in an experienced centre (mild hypoglycaemia in 46% on the insulin test, nausea or vomiting in 17.5% on the glucagon test, with no serious events) [64]. These studies used their own assays and thresholds and did not include patients identified as having a TBX19 variant. In the sick newborn with low cortisol and ACTH despite hypoglycaemia, Pham and colleagues start oral hydrocortisone and reassess the axis later in normoglycaemia [24].

5.4 Imaging

Pituitary MRI is usually normal in TBX19 deficiency, because corticotrophs are a small fraction of the gland; a normal MRI does not exclude the diagnosis, and mild hypoplasia of the anterior pituitary has been described [2, 17]. MRI serves mainly to exclude pituitary stalk interruption syndrome and other malformations that point to combined hypopituitarism [24, 58].

5.5 Genetic testing

The first-line test in complete neonatal isolated ACTH deficiency is sequencing of TBX19 with copy number variant analysis, alone or in a panel of hypopituitarism and adrenal insufficiency genes; the French network uses a panel that includes TBX19, NFKB2 and the genes of non-syndromic combined hypopituitarism, with coverage above 30-fold and Sanger confirmation [17]. Exome sequencing was the method in several recent reports [19, 25, 37, 49]. The limitations of the test are concrete: deletions of one or more exons, including a genomic deletion of about 31 kb (g.168,247,374 to g.168,278,264, according to the authors), require copy number analysis [3, 17, 54]; synonymous and intronic variants may alter splicing and be missed by protein-effect predictors [41]; and a negative result does not exclude the diagnosis of isolated deficiency, because about a third of the complete neonatal forms have no known TBX19 variant [3]. The proportion of patients with an identified variant in a referred series is not the sensitivity of the test in an unselected population.

The report should state the gene, the transcript and version (NM_005149.3), the HGVS nomenclature of the variants at DNA and protein level, zygosity, classification according to the criteria of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology, and parental segregation [17, 37]. Charnay and colleagues classified c.840del as pathogenic with PVS1, PM2 and PP4 and/or PP1 [17]. Confirmation that two variants are in trans requires parental testing, as in the Portuguese case [37]. Variants of uncertain significance should not be used for reproductive decisions; p.(Pro126Leu), for example, was considered of uncertain significance in one report and loss-of-function in a reporter assay the following year [19, 25].

5.6 Algorithm

5.7 Prenatal and preimplantation diagnosis

With the familial variants known, molecular prenatal diagnosis and preimplantation genetic testing are possible, and the Portuguese case discussed both with the parents [20, 37]. The aim described in the series is not only reproductive: identifying the affected fetus allows hydrocortisone to be started at birth, before the first crisis [2, 20].

6. Differential Diagnosis

The first step of the differential is ACTH paired with cortisol: with raised ACTH the insufficiency is primary, with low or inappropriately normal ACTH it is central [2, 34]. In the table, AR denotes autosomal recessive and AD autosomal dominant inheritance. Within the central forms, the distinction is made by the isolated or combined nature of the deficiency, by extra-pituitary signs and by genetics.

6.1 Primary adrenal insufficiency

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is diagnosed by raised 17-hydroxyprogesterone and raises ACTH; primary insufficiency of any cause, including adrenal hypoplasia congenita, shows ACTH above twice the upper limit with low cortisol and, in general, mineralocorticoid deficiency on renin and aldosterone [2, 34]. The GeneReviews chapter on POMC deficiency listed the inherited disorders of glucocorticoid metabolism to be considered in adrenal insufficiency with non-syndromic obesity: MC2R, MRAP, STAR and NNT deficiency, X-linked Addison disease, autoimmune polyendocrine syndrome type 1, natural killer (NK) cell and glucocorticoid deficiency with DNA repair defect, and combined pituitary hormone deficiency [16]. In a Saudi series of neonatal cholestasis with hypoglycaemia, two patients had familial glucocorticoid deficiency and two isolated ACTH deficiency, and the cholestasis regressed with hydrocortisone in all four [35].

6.2 POMC and PC1/3 deficiency

POMC deficiency shares with TBX19 deficiency neonatal secondary adrenal insufficiency and cholestasis, but adds, in the first months, hyperphagia and exponential weight gain, and often red hair and pale skin; the absence of typical pigmentation does not exclude it, as shown by cases with dark hair and increased pheomelanin on chemical analysis [16]. PC1/3 deficiency mimics the obesity and adrenal insufficiency of POMC deficiency, with other endocrinopathies and, in some patients, small bowel dysfunction with severe diarrhoea and malabsorption [13, 16]. Raised proinsulin relative to insulin is characteristic [22]. Treatment of the obesity of these two entities follows that of monogenic obesity.

6.3 DAVID syndrome

Among 22 French patients with ACTH deficiency without a TPIT mutation, three (13.6%) had common variable immunodeficiency, and in the original series of four patients ACTH deficiency was diagnosed between 5 and 15 years with symptomatic hypoglycaemia, after recurrent infections revealing the immunodeficiency between 2 and 8 years [21]. In the review of 50 patients with NFKB2 variants, 44% had central adrenal insufficiency, and GeneGuidance recommends assessing the pituitary-adrenal axis at diagnosis and repeating the assessment in all carriers of a pathogenic variant, including relatives identified by cascade testing [14]. OMIM records the entity as common variable immunodeficiency type 10 (CVID10), with the synonyms common variable immunodeficiency with central adrenal insufficiency and DAVID; the patients of the French series had low ACTH and cortisol without a response to synthetic ACTH, and the NFKB2 variants were identified by Chen and colleagues in four patients from two families and then in the original French families [10, 11]. Inheritance is autosomal dominant, unlike TBX19. The French PNDS mistakenly attributes the immune deficiency to TBX19 mutations; the association between ACTH deficiency and immunodeficiency is that of DAVID syndrome due to NFKB2 [14, 21, 58].

6.4 Congenital hypopituitarism and septo-optic dysplasia

In the combined forms, ACTH deficiency may be present at diagnosis or appear later, and the French PNDS recommends looking for it systematically and repeatedly during follow-up of any congenital hypothalamic-pituitary disorder [58]. In septo-optic dysplasia, one series found GH deficiency in 80%, ACTH deficiency in 60%, luteinising hormone (LH) and follicle-stimulating hormone (FSH) deficiency in 40% and diabetes insipidus in 35% of patients [56]. MRI with stalk interruption or marked hypoplasia, deficiencies of other axes and midline malformations rule out isolated deficiency; the transient TSH and free T4 abnormalities described in TBX19 deficiency are not enough to classify it as combined [17, 24].

6.5 Other causes of neonatal hypoglycaemia and cholestasis

Neonatal hypoglycaemia has a non-genetic cause in most cases (prematurity, low birth weight, sepsis, infant of a diabetic mother) [36]. Among the genetic causes, hyperinsulinism and fatty acid oxidation defects are distinguished by insulin and ketones in the critical sample, and congenital disorder of glycosylation type Ia may combine severe neonatal hypoglycaemia with cortisol deficiency in some cases, according to the experience of the authors of the Paris series [24, 60]. Beckwith-Wiedemann syndrome combines macrosomia with neonatal hypoglycaemia [16]. In the newborn of Dang and colleagues, the picture was initially treated as neonatal sepsis, hypoglycaemia and hyperbilirubinaemia, and the diagnosis was only made on day 31 [19]. In one of the siblings of Unal and colleagues, the hypoglycaemic seizures were interpreted as epilepsy [44].

7. Treatments and Risk Management Strategies

7.1 Principles and evidence base

There is no specific guideline for isolated ACTH deficiency due to TBX19 and there are no clinical trials in this disorder; the therapeutic evidence comes from cohorts and reports, and doses are applied by analogy from the guidelines on paediatric and central adrenal insufficiency [2, 65]. The references used are the French PNDS on congenital pituitary deficiency (2021), which includes isolated corticotropic deficiency, the 2023 British Society for Paediatric Endocrinology and Diabetes (BSPED) consensus on emergency and perioperative management, the 2024 NICE guideline NG243 and, by declared analogy, the 2016 Endocrine Society guideline on primary insufficiency, which excludes secondary insufficiency from its scope [34, 38, 58, 59]. For the adult with central insufficiency, the direct reference is the 2016 Endocrine Society guideline on hormone replacement in hypopituitarism, whose recommendations indicate strength (1, recommendation; 2, suggestion) and quality of evidence (from ⊕OOO, very low, to ⊕⊕⊕⊕, high) [61]. Hydrocortisone is the 1st-line glucocorticoid in children and adults, and treatment is lifelong in all constitutional corticotropic deficiencies [58]. Long-acting synthetic glucocorticoids (prednisolone, dexamethasone) should be avoided in children and reserved, according to the PNDS, for cases of insufficient efficacy of hydrocortisone, with expert advice [34, 58].

Hydrocortisone is the only targeted treatment; its aims are to correct the cortisol deficiency, provide quality of life, avoid chronic overdosing and prevent adrenal crisis, which results from underdosing or failure of adherence [58]. Started as soon as the disorder is suspected, it resolved the hypoglycaemia and cholestasis in the reported patients and allowed normal growth and development [2, 17, 53].

7.2 Treatment of adrenal crisis

The crisis is treated as soon as it is suspected, with intravenous (IV), intramuscular (IM) or subcutaneous (SC) hydrocortisone, without waiting for results, and the patient with known deficiency should carry an emergency card [38, 58]. Emergency doses differ between sources, as the table shows.

Sources: [34, 38, 58]. For young people aged 16–18 years followed in adult services, the BSPED refers to the Society for Endocrinology guideline, and NICE recommends for those aged 16 or over immediate IV or IM hydrocortisone (with no risk of overdose in an emergency), 1 L of 0.9% NaCl over 30 minutes, maintenance by 24-hour infusion or injections four times a day until stable and then at least 40 mg/day orally [38, 59]. The PNDS gives for adults 100 mg IM or IV immediately and a continuous infusion of 100 mg/24 h [58]. The Endocrine Society recommends, when a crisis due to secondary insufficiency is suspected in an adult, an immediate parenteral injection of 50–100 mg of hydrocortisone (grade 1, ⊕⊕⊕O), with the same glucocorticoid and fluid replacement as in primary insufficiency; it stresses that, despite preserved mineralocorticoid function, the risk of crisis in secondary insufficiency is similar to or greater than in primary insufficiency, that the crisis may be the first manifestation of the deficiency and that the incidence of crises did not depend on education, BMI, glucocorticoid dose or age at diagnosis [61]. In all sources, paediatric doses by weight and by age are approximations: the BSPED advises neonatal doses in infants who are very small for gestational age or have poor weight gain [38]. In secondary insufficiency, hyponatraemia is mainly dilutional and may justify some fluid restriction, unlike the salt wasting of primary insufficiency [38]; the PNDS limits correction of serum sodium to 1 mEq/kg/h [58].

The labels of the injectable forms give general doses that are not specific to this indication. Solu-Cortef® (hydrocortisone sodium succinate) is indicated in the USA for primary or secondary adrenal insufficiency when the oral route is not possible, with the IV route preferred in the initial emergency, 100 mg given over 30 seconds and high doses generally not continued beyond 48 to 72 hours, because of the risk of hypernatraemia [66]. The Portuguese Summary of Product Characteristics (SmPC) of Solu-Cortef® 100 mg/2 mL and that of Hidrocortisona Generis 100 mg powder for solution for injection indicate initial doses of 100 to 500 mg, repeatable every 2, 4 or 6 hours, and, in children, a dose reduced according to severity and response, never less than 25 mg per day [67, 68]. The BSPED and PNDS weight-based doses in the newborn and infant fall below this label daily minimum in some scenarios, and the clinical reference is that of the guidelines.

7.3 Maintenance replacement

The reference for maintenance in children is that of the guidelines, 8–10 mg/m²/day, with no maximum dose defined in those sources [38, 58, 59]. The doses of about 15 mg/m²/day used in the reported infants with TBX19 reflect the neonatal illness and hypoglycaemia, not a different target [2, 17]. The Portuguese SmPC of Hidrocortisona Roussel indicates 12–20 mg/m²/day, above the guidelines; the SmPC of Hidrocortisona Generis 10 mg tablets is indicated only for congenital adrenal hyperplasia from 12 years, and its use in ACTH deficiency is outside the SmPC [72, 73]. The dose is adjusted by clinical features and body surface area, because there is no reliable laboratory marker; the PNDS advises against post-dose cortisol as routine, reserving it for suspected inadequate adjustment [24, 58, 59].

In adults with ACTH deficiency, the Endocrine Society bases the 15–20 mg/day on a physiological cortisol production of 5–10 mg/m²/day and recommends the lowest tolerated dose, because higher doses have been associated with greater overall and cardiovascular mortality, with the greatest risk from 30 mg/day [61]. The quality-of-life data gathered by the guideline point in the same direction: in a cross-sectional study, doses above 30 mg/day were associated with worse self-rated health and three daily doses were not superior to two; in 2,737 adults with hypopituitarism, those receiving the equivalent of 10 mg/day or less had the best quality of life and those receiving 25 mg/day or more the worst, an association that may reflect dose increases in patients with complaints and not only an effect of the dose [61]. The guideline suggests low doses also to protect bone, based on a small crossover trial in men with hypopituitarism, in which 10 mg in the morning and 5 mg in the afternoon were associated with greater bone formation, and, in over-replaced men at risk of fracture, screening for vertebral fractures by spinal radiography or densitometry [61]. There is no reliable marker of dose: the daily cortisol curve has little practical value, urinary free cortisol has high variability, and prednisolone cross-reacts in many cortisol immunoassays [61]. The guideline's equivalence table (20 mg of hydrocortisone corresponds to 5 mg of prednisolone or prednisone, 4 mg of methylprednisolone, 0.75 mg of dexamethasone and 25 mg of cortisone) is based on anti-inflammatory effect and may overestimate the replacement dose [61].

Mineralocorticoid therapy is not part of the usual treatment, because aldosterone is preserved; NICE recommends not offering a mineralocorticoid in secondary insufficiency from 1 year, and the Endocrine Society recommends not using fludrocortisone in secondary insufficiency in adults (grade 1, ⊕⊕⊕O) [2, 40, 59, 61]. The documented exception is the newborn girl of Holterhus and colleagues, with hyponatraemia and demonstrated mineralocorticoid deficiency, who received initial fludrocortisone and sodium chloride in addition to hydrocortisone [39]. In neonatal hyponatraemia that persists despite hydrocortisone, measurement of renin and aldosterone guides the decision.

The order of replacement matters in patients with associated or transient deficiencies: levothyroxine sodium should not be started before adrenal function has been assessed and insufficiency treated, because it may precipitate a crisis [16, 40]. The Endocrine Society explains that thyroid hormone accelerates cortisol clearance and, when the adrenal axis cannot be assessed beforehand, suggests empirical concurrent hydrocortisone until definitive assessment (grade 2, ⊕⊕OO); it also suggests assessing the axis before and after starting growth hormone in patients not on glucocorticoid, because GH reduces the conversion of cortisone to cortisol and may require higher doses or unmask low adrenal reserve (grade 2, ⊕OOO) [61].

7.4 Formulations and administration in children

Administration of small, divided doses is the practical problem of replacement in the infant. Alkindi® (hydrocortisone granules in capsules for opening, 0.5, 1, 2 and 5 mg) has been authorised in the European Union since 9 February 2018 for replacement in adrenal insufficiency from birth to 18 years; the granules are given on the tongue, on a spoon or sprinkled on cold soft food, followed by a drink, are not mixed into liquids and are not given via a nasogastric tube, because of the risk of obstruction [69]. The SmPC warns that the dose inaccuracy of conventional crushed or compounded formulations may lead to a relative fall in hydrocortisone exposure when switching to another formulation at the same nominal dose, with symptoms of insufficiency or crisis, and indicates the same total daily dose at transition [69]. If a dose is missed, it is given as soon as possible and the next at the usual time; if most of the granules are regurgitated, a new dose may be needed [69]. In the USA, Alkindi Sprinkle® was approved on 29 September 2020 for replacement in paediatric patients with adrenocortical insufficiency, with doses rounded to 0.5 or 1 mg [70]. Khindivi® (hydrocortisone oral solution 1 mg/mL) was approved by the Food and Drug Administration (FDA) on 28 May 2025 for replacement from 5 years of age; it is not approved for stress dosing and contains polyethylene glycol 400, propylene glycol and glycerin, whose absorption may cause hyperosmolality, metabolic acidosis, hypoglycaemia, hepatorenal injury and central nervous system toxicity, which is why it is not approved below 5 years [71].

In the absence of these formulations, the French PNDS describes the splitting of 10 mg tablets (divisible into 2 or, roughly, into 4) and the 1 mg/mL hospital oral suspension of hydrocortisone used in some centres [58]. In Brazil, the SBEM noted in 2021 that hydrocortisone and cortisone acetate were not widely available and advised against compounded preparations, because of doubts about origin, storage and bioequivalence; prednisone was more commonly prescribed in adults, at an equivalence of 1 mg of prednisone to 4 mg of hydrocortisone [40]. The open data of the Brazilian Health Regulatory Agency (ANVISA) of October 2026 list hydrocortisone products from several holders with active registration, without the pharmaceutical form being stated in the file, and several presentations of hydrocortisone sodium succinate for injection; active registration does not prove marketing [74].

7.5 Intercurrent illness and stress doses

Prevention of crisis rests on increasing the oral dose by the parents or the patient during intercurrent illness, infection, trauma, psychological stress or intense exercise [58]. The BSPED recommends a total dose of about 30 mg/m²/day divided into 4 equal doses during illness, to avoid long intervals with a hormone of short half-life [38]. The French PNDS proposes doubling or tripling the dose, or 30 mg/m²/day in 3 to 4 doses in children and 60 mg/day in 3 to 4 doses in adults [58]; the Alkindi® SmPC indicates doubling or tripling the daily dose in mild situations and switching to the parenteral route in severe ones (gastroenteritis with vomiting or diarrhoea, high fever, major accidents, surgery under general anaesthesia) [69]. NICE, for those aged 16 or over, recommends at least 40 mg/day of oral hydrocortisone in 2 to 4 doses during significant physiological stress and, if the patient vomits within 30 minutes of a dose, repeating it at double dose and, if vomiting recurs, giving IM hydrocortisone and attending the emergency department [59].

Source: [38]. The home IM emergency dose, when the oral route fails, is 25 mg below 1 year, 50 mg from 1 to 5 years and 100 mg from 6 years in the BSPED; the PNDS uses 25 mg below 1 year, 50 mg from 1 to 6 years and 50 mg repeated at 15 minutes from 6 years, and 100 mg in adults [38, 58]. Recurrent crises during infections, due to failure to increase the dose in time, are the cause of avoidable cognitive damage in this disorder; in one family, the management of the second child, after the parents had been educated, involved fewer crises than that of the first [2, 17].

7.6 Surgery, anaesthesia and procedures

Source: BSPED consensus [38]. The minimum dose of this regimen is about 84 mg/m²/day in the first 24 hours; fasting should not exceed 6 hours without fluids containing sodium chloride and glucose, and the child should be first on the operating list [38]. The French PNDS applies the crisis protocol in major surgery until feeding is resumed and then triples the oral dose; for minor surgery, fasting investigations or acute illness preventing the oral route, it proposes IV hydrocortisone 1 mg/kg every 6 hours or IM every 6 to 8 hours, not exceeding 25 mg every 6 hours [58]. For adults undergoing planned surgery, NICE refers to the tables of Woodcock and colleagues and the PNDS proposes 100 mg IM or IV on the day of surgery and, in major surgery, 100 mg/24 h or 25 mg every 6 hours, with tripled doses (at least 60 mg/day) on resumption [58, 59].

7.7 Education, card and emergency kit

Each child with confirmed insufficiency needs, before discharge, written information, a card with maintenance, sick-day and emergency doses, injection kits for home, school and other residences, injection training, open access to the paediatric service, registration with the ambulance service, an alert in the clinical record, an identification bracelet or necklace, a school plan and a scheduled appointment [38]. NICE recommends giving 2 or 3 kits to each person with primary or secondary insufficiency, each with an IM hydrocortisone injection (sodium phosphate 100 mg/1 mL or sodium succinate 100 mg powder with 5 or 10 mL of water for injections), injection equipment, illustrated instructions, emergency cards and, below 16 years, glucose gel, and checking expiry dates regularly [59]. The PNDS adds regular assessment of knowledge and adherence and an individualised care plan at school [58]. The Endocrine Society recommends, as practice, an emergency card, alert identification and an injection kit with education for all patients [34].

7.8 Regulatory status of the medicinal products

The NICE guideline, published in August 2024, considered modified-release tablets off-label below 18 years; the current Efmody® SmPC, with an indication from 12 years, is later [59, 76]. Authorisation of a medicinal product does not mean marketing or reimbursement, and the sources consulted do not document the marketing status in Portugal or Brazil.

7.9 Clinical trials

Source: Alkindi® SmPC [69]. There are no efficacy trials in TBX19 ACTH deficiency: searches on ClinicalTrials.gov in October 2026 found no studies involving TBX19, and the four studies on isolated ACTH deficiency did not address the congenital form [65]. The Alkindi® study is pharmacokinetic, single-dose, without a comparator and with a single patient with insufficiency of pituitary origin; it serves to support the formulation, not to compare regimens. The evidence on doses comes from case series and consensus statements, and a negative registry search does not prove that no research is under way.

7.10 Developments in the last 12 months

7.11 Pregnancy, lactation and transition

The disorder affects women of reproductive age who reach adulthood on treatment. The French PNDS recommends increasing hydrocortisone by 30% in the 3rd trimester, giving 100 mg of injectable hydrocortisone at delivery and not measuring cortisol in pregnancy, as it is physiologically raised [58]. NICE recommends follow-up by a multidisciplinary team, considering a dose increase in the 3rd trimester according to symptoms, sodium and postural blood pressure, an immediate additional dose of 20 mg of hydrocortisone and the sick-day rules in the event of fever, infection, trauma or vomiting, 100 mg IM and attendance at the emergency department in hyperemesis gravidarum, 200 mg IV/24 hours or 50 mg four times daily in the admitted woman, sick-day doses for 48 hours post partum and gradual reduction to the previous dose [59]. The Endocrine Society prefers hydrocortisone in pregnancy, advises against dexamethasone, which is not inactivated by the placenta, and recommends stress doses in active labour, similar to those for major surgery [34]. The same society's guideline on hypopituitarism repeats these recommendations for central insufficiency (dexamethasone, grade 1, ⊕⊕OO; stress doses at delivery, grade 1, ⊕⊕OO), advises adjusting hydrocortisone to the individual clinical course, with higher doses especially in the 3rd trimester (an increase of 20–40% is the alternative cited, close to the 30% of the PNDS), and monitoring for signs of under- and over-replacement, such as weight gain, fatigue, postural hypotension or hypertension and hyperglycaemia [61]. It also points out that the diagnosis may be missed in the 1st trimester, that a morning cortisol < 3 µg/dL with typical clinical features is diagnostic and that, in the 2nd and 3rd trimesters, the rise in CBG may give a falsely normal cortisol [61]. The sources consulted give no specific recommendations on breastfeeding in central insufficiency.

Transition to adult services is a period of increased risk, and NICE recommends reviewing information and support at transitions (starting school, university, change of service) and more frequent appointments during that phase [59]. In adults, the reference doses become 15–25 mg/day (NICE), 10–20 mg/day (PNDS) or 15–20 mg/day (SBEM and Endocrine Society), with the largest dose in the morning; doses above 20 mg/day maintained for long periods have been associated, in hypopituitarism, with an unfavourable metabolic profile, Cushingoid morbidity and increased mortality [40, 58, 59, 61].

7.12 Precautions and agents to avoid

Khindivi® is not suitable for stress dosing and should not be used below 5 years [71]. Alkindi® granules are not given via a nasogastric tube, unlike the oral solution [69, 71]. Levothyroxine sodium is not started before hydrocortisone in a patient with corticotropic deficiency [16, 40]. Dexamethasone should be avoided in pregnancy, because it is not inactivated by the placenta [34, 61]. Long-acting synthetic glucocorticoids should be avoided in children [34]. High doses of hydrocortisone sodium succinate maintained for more than 48 to 72 hours may cause hypernatraemia [66, 67]. Chronic overdosing causes excess weight, metabolic syndrome and cardiovascular risk and, in children, slowing of growth and puberty [58]. Exogenous glucocorticoids, including inhaled ones and those in products with undeclared corticosteroid, interfere with diagnosis and may mask the manifestations, as in the Portuguese case, in which inhaled fluticasone may have attenuated the symptoms [37, 59].

7.13 Treatment in the other entities of the class

In POMC deficiency, neonatal adrenal insufficiency is treated with hydrocortisone in the same way, and the obesity can now be treated with setmelanotide, a melanocortin 4 receptor agonist authorised in the USA and the EU from 2 years of age for obesity due to genetically confirmed POMC, PCSK1 or leptin receptor (LEPR) deficiency; in the POMC deficiency trial, 8 of 10 participants (80%) lost at least 10% of their weight in about 1 year [12, 13, 16]. In PC1/3 deficiency, treatment includes enteral or parenteral nutritional support for the neonatal diarrhoea, replacement of the missing hormones and setmelanotide [13]. In DAVID syndrome, immunoglobulin replacement is the mainstay of treatment, central adrenal insufficiency is treated with hydrocortisone and the axis should be reassessed over time [14].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

In TBX19 deficiency, autosomal recessive inheritance gives heterozygous parents a 25% risk in each pregnancy of having an affected child [17, 37]. Carrier parents have no signs of ACTH deficiency [17, 20]. Consanguinity increases the risk, and there are founder variants in northern Morocco and, probably, in Finland; carrier frequency in these populations has not been estimated [17]. In POMC and PC1/3 deficiency, inheritance is also recessive; heterozygotes for a null POMC allele are not at risk of adrenal insufficiency but are predisposed to obesity, and some heterozygous variants at critical sites of POMC have been associated with early-onset obesity without adrenal insufficiency [16]. In DAVID syndrome, dominant inheritance gives a 50% risk to each child of a carrier [14].

8.2 Cascade testing and at-risk siblings

Identification of the familial variants allows siblings to be tested prenatally or at birth, so that replacement can be started before the first crisis [2, 20]. The GeneReviews chapter on POMC deficiency recommended, when the variants were not known or there had been no prenatal diagnosis, assessing all at-risk newborns for adrenal insufficiency and starting glucocorticoid as soon as it was demonstrated [16]. Charnay and colleagues stress that access to paediatric intensive care at birth is essential in families with a history [17]. In family 3 of the French series, the second affected child was diagnosed at 10 days, after neonatal hyponatraemia and hypotonia [17]. In DAVID syndrome, the corticotropic axis should also be assessed in carrier relatives identified by cascade testing [14]. The sources consulted do not address carrier testing in healthy minor siblings; in TBX19 deficiency, carrier status has no clinical consequence for the carrier [17, 20].

8.3 Prenatal and preimplantation diagnosis

With the variants known, molecular prenatal diagnosis and preimplantation genetic testing are options to be discussed, as they were in the Portuguese case [37]. The 2005 series stressed that identification of TPIT mutations made prenatal diagnosis possible in at-risk families, with the aim of starting glucocorticoid replacement early [20]. Low maternal oestriol was used in an in utero diagnosis, but it is not a routine test and has several other causes [24, 57]. In a treatable disorder, the decision to use prenatal or preimplantation diagnosis depends on the family's values, and the information should include the prognosis with early treatment.

8.4 Mosaicism

The sources consulted do not describe germline or somatic mosaicism in TBX19 deficiency; in a recessive disorder, recurrence depends on the parents' carrier status, which should be confirmed by testing [19, 37].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

There is no estimate of the population prevalence or incidence of congenital isolated ACTH deficiency; Orphadata has no epidemiological data for ORPHA:199296, and Pham and colleagues consider the prevalence unknown [1, 24]. The available figures count described patients, not frequency: 27 neonatal patients from 21 families in 2005, with a mutation in 17 [20]; 91 patients in 2012, of whom 37 newborns with a TBX19 variant according to Dang's description [3, 19]; 42 paediatric cases published up to 2011 [24]; 39 pathogenic variants up to 2022 [17]; 35 cases published up to December 2023 in Dang's review, 24 with a variant [19]; and 47 pathogenic or likely pathogenic TBX19 records in ClinVar in 2026 [42]. The disorder is described as an underestimated cause of neonatal death, because undiagnosed crises leave no diagnosis [20, 24]. For primary and secondary adrenal insufficiency as a whole, of all causes and mostly acquired, the European estimate is 20 to 50 per 100,000 [79]; POMC deficiency and PC1/3 deficiency have prevalence classes below 1 per 1,000,000 in Orphanet [12, 13].

9.2 Founder populations and geographical distribution of reports

The c.840del variant is concentrated in families originating from the Rif, in northern Morocco, living in France [17]; c.82C>T p.(Gln28Ter) is almost exclusive to the Finnish population among gnomAD heterozygotes and was found in the homozygous state in a Russian patient [17, 46]. The published reports come from France and the European network (Montreal and Marseille series) [3, 17, 20], Turkey [43–45, 49, 50, 53], China [19, 25, 47, 80], Germany [39], Russia [46], the United Kingdom [32], Cyprus [51], the USA [81], Saudi Arabia [35] and Sri Lanka [48], and include a patient of Romanian origin [41]. The distribution reflects the activity of the centres and the consanguinity of the populations studied, not the relative frequency of the disorder.

9.3 Portugal and Brazil

The published Portuguese case, from Coimbra, is a girl with compound heterozygosity p.(Arg100His)/p.(Arg286Ter), non-consanguineous parents, diagnosis at 4 years and severe neurological sequelae [37]. In the French series of Pham, one of the six patients with the late form, without a TPIT variant, was of Portuguese origin [24]. In Brazil, the Ribeirão Preto cohort of 904 children assessed for central insufficiency provides data on the performance of dynamic tests, without TBX19 genetic testing [64], and the SBEM documented in 2021 the limited availability of hydrocortisone in the country [40]. The sources consulted include no Brazilian cases with a TBX19 variant, which does not demonstrate that none exist.

9.4 European Reference Network and patient associations

Endo-ERN, the European Reference Network for rare endocrine conditions, has thematic groups for the adrenal and pituitary [23]. The BSPED makes the consensus and the paediatric emergency card available online [82]. Patient associations indicated by the sources include the Pituitary Foundation and the Addison's Disease Self-Help Group, in the United Kingdom, and the National Adrenal Diseases Foundation, in the USA [16, 38]. In France, the PNDS was drawn up by the HYPO (Marseille) and CRMERCD (Paris) reference centres [58].

10. Illustrative Clinical Case

10.1 Three families with the same founder variant (Charnay et al., 2022)

Charnay and colleagues described four children from three families living in different regions of France, all homozygous for NM_005149.3:c.840del p.(Glu280AspfsTer27) and with asymptomatic heterozygous parents originating from the Rif [17]. The pedigrees are in figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC9987334/figure/f1/) and the map of pathogenic TBX19 variants on the MANE transcript in figure 3 (https://pmc.ncbi.nlm.nih.gov/articles/PMC9987334/figure/f3/) [17].

In family 2, a boy had respiratory distress with pulmonary hypertension minutes after birth, with intubation for 3 days, non-invasive ventilation for 11 days and haemodynamic instability treated with fluids and noradrenaline; he also had severe hypoglycaemia, prolonged cholestatic jaundice and axial hypotonia, with normal brain MRI and electroencephalogram [17]. Two months later, he was brought to the emergency department with weakness and anorexia during severe bronchiolitis, with blood glucose of 0.2 g/L, hyponatraemia and hyperkalaemia; cortisol (< 3 nmol/L) and ACTH (< 0.6 pmol/L) were below the limit of detection, aldosterone and renin were normal, and so were the other pituitary axes and free thyroid hormones [17]. With hydrocortisone at 15 mg/m²/day, increased in stress situations, improvement was rapid; pituitary MRI showed a moderately hypoplastic anterior pituitary, and examination revealed a bicuspid aortic valve [17]. At 5 years he was well, without severe infections or new crises, and psychomotor development did not appear to have been affected by the hypoglycaemia and hyponatraemia of the first year [17].

In family 3, a girl had repeated hypoglycaemia (0.10 g/L) from 8 hours of life, with undetectable cortisol and ACTH, and started oral hydrocortisone on day 6; MRI at 18 days and at 6 years was normal, and by 7 years she had already had three crises with hypoglycaemia and seizures during infections, attributed to failure to adjust the dose in time [17]. Her brother, born 6 years later, had an Apgar score of 2, hypotonia, feeding difficulty and sodium of 130 mmol/L, recovered partially in intensive care and had febrile orchitis requiring surgery; at 10 days, cortisol and ACTH were below the limit of detection, hydrocortisone at 15 mg/m²/day produced rapid improvement, and a year later he was well [17]. The authors attribute the more favourable course of the second child to the education of the parents [17].

The case illustrates the variability of presentation with the same genotype, normal renin and aldosterone despite hyponatraemia and hyperkalaemia, and the weight of stress-dose management on prognosis. The dose of 15 mg/m²/day used in these infants is higher than the guideline maintenance dose of 8–10 mg/m²/day, which is the reference for maintenance outside the acute phase [17, 58, 59].

10.2 Late diagnosis in a Portuguese case (Vieira et al., 2022)

A girl born at 41 weeks in Portugal, weighing 4220 g, had in the neonatal period a patent ductus arteriosus and possible atrial septal defect treated with oral ibuprofen, without hypoglycaemia or jaundice; the parents were not consanguineous [37]. At 9 months she had a hypoglycaemic seizure during gastroenteritis, with blood ketones of 1.3 mmol/L attributed to the illness, and was discharged with blood glucose monitoring; over the next three years only one blood glucose below 55 mg/dL was recorded, during bronchiolitis, and she received inhaled fluticasone [37]. Weight and height remained on the 97th centile, with motor delay and mild language delay [37]. At 4 years she had a tonic-clonic seizure with fever and diarrhoea, haemodynamic instability, anuria, a Glasgow score of 8 falling to 5, blood glucose of 43 mg/dL, C-reactive protein of 64 mg/dL and procalcitonin of 84 ng/mL; she was ventilated and treated with antibiotics and with stress-dose IV hydrocortisone for refractory hypoglycaemia, and progressed to multiple organ failure and disseminated intravascular coagulation [37]. During hypoglycaemia (39 mg/dL), cortisol was below 1.0 µg/dL and ACTH below 5 pg/mL, with TSH of 7.28 mIU/L and normal free T4 [37]. Computed tomography and MRI showed extensive cortical lesions, predominantly posterior, compatible with severe hypoglycaemia and hypoxic-ischaemic injury (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9513655/figure/fig1/) [37]. Exome sequencing identified NM_005149.2:c.299G>A p.(Arg100His) and c.856C>T p.(Arg286Ter) in trans, with the same positions on the MANE transcript (NM_005149.3:c.299G>A p.(Arg100His); NC_000001.11:g.168291255G>A) [18, 37]. At 12 years, on hydrocortisone and anticonvulsants, she walked with difficulty, smiled and followed with her eyes, but did not speak; puberty was regular, with menarche at 11 years and 10 months [37]. The 25% risk was explained to the parents and prenatal diagnosis and preimplantation testing were discussed [37].

The case shows that a symptom-free neonatal period does not exclude the disorder, that hypoglycaemia during an acute illness should be investigated with cortisol and ACTH in the critical sample, and that inhaled corticosteroid therapy may attenuate and delay the presentation [37].

11. Prognosis and Long-term Follow-up

11.1 Prognosis

Without treatment, congenital isolated ACTH deficiency can kill in the first days of life; third-trimester miscarriages or neonatal deaths were reported in up to 25% of families in the largest series, and several sources estimate neonatal mortality at about 20% to 25% when diagnosis is late [2, 17, 25, 50, 54, 81]. With early diagnosis and hydrocortisone, growth, neurodevelopment and quality of life were normal in Charnay's patients (follow-up from 7 months to 6 years), in a patient followed up to 22 years and in another up to 3.2 years [17, 45, 50]. Three patients in the Pham series reached target height (172, 180 and 171.5 cm), and schooling normalised with treatment [24]. The neurological prognosis depends on the timing of diagnosis and the prevention of crises: in the review of 35 cases, 15 had neurodevelopmental delay and 13 of these had started treatment after 1 year [19], and the cases with severe sequelae had a late diagnosis [37] or discontinuation of hydrocortisone [44]. Crises during infections continue after diagnosis if the parents do not adjust the dose in time [17]. In a Swiss cohort of adults, admissions for adrenal crisis increased between 2012 and 2022, mainly in central insufficiency, and crisis was associated with a greater risk of intensive care admission (incidence rate ratio 1.99; 95% confidence interval 1.8–2.21) [78]; in Europe, 5 to 10 crises per 100 patients with adrenal insufficiency per year and a crisis mortality of 0.5 per 100 patient-years are estimated [40]. These data from adults with insufficiency of various causes cannot be transposed directly to congenital TBX19 deficiency.

11.2 Follow-up

Follow-up has three aims: adjusting the hydrocortisone dose to growth and clinical features, avoiding under- and over-replacement; maintaining education on stress doses; and monitoring the other axes, because deficiencies may appear over time in congenital hypothalamic-pituitary disorders and because transient TSH and GH abnormalities have been described in TBX19 deficiency [17, 37, 58, 59]. Signs of under-replacement include weight loss, early satiety, lack of appetite, nausea, fatigue affecting activities and muscle weakness; signs of over-replacement include increased weight and appetite, disturbed sleep, thin skin, hypertension, diabetes, a Cushingoid appearance, acne, skin infections and fragility fractures; in children, growth velocity and the timing of puberty are additional markers [58, 59].

The Brazilian guideline for adults with pituitary disease advises against hydrocortisone doses above 20 mg/day maintained for long periods, because of the association with metabolic morbidity and mortality [40]. The Endocrine Society recommends the lowest tolerated hydrocortisone dose in adults with central insufficiency, to reduce metabolic and cardiovascular risk, and does not recommend the cortisol day curve or urinary free cortisol as routine guides to dosing [61].

12. Summary and Final Considerations

Congenital isolated ACTH deficiency due to biallelic TBX19 variants is a secondary adrenal insufficiency of neonatal onset, caused by failure of terminal differentiation of corticotrophs, with the other pituitary axes preserved. The typical presentation is severe hypoglycaemia with seizures, prolonged cholestatic jaundice and hypotonia in the first hours or days of life, with cortisol and ACTH often undetectable, renin and aldosterone normal in most and a normal pituitary MRI. TBX19 variants account for about two thirds of the complete neonatal forms and have not been found in the partial or late forms. The disorder is rare, with no prevalence estimate, and there are founder variants in northern Morocco and, probably, in Finland.

Diagnosis requires a critical sample of cortisol and ACTH during hypoglycaemia and demonstration of the isolated nature of the deficiency; an ACTH within the reference range does not exclude it when cortisol is undetectable, the fasting test is contraindicated, and newborn screening for congenital adrenal hyperplasia does not detect this disorder. Genetic testing should include copy number analysis and assessment of splicing variants, and a negative result does not rule out isolated deficiency.

Treatment is lifelong hydrocortisone at maintenance doses of 8–10 mg/m²/day in the paediatric guidelines, without mineralocorticoid in most patients, with sick-day doses of about 30 mg/m²/day, emergency parenteral hydrocortisone by age or weight, perioperative cover and parental education. The prognosis with early treatment is good, and neurological sequelae are associated with late diagnosis and poorly managed crises. Genetic counselling follows recessive inheritance, with a 25% recurrence risk, and allows siblings to be tested so that replacement can begin at birth. The other genetic causes of the class are distinguished by extra-pituitary signs: early obesity and pale pigmentation in POMC deficiency, neonatal diarrhoea and polyendocrinopathy in PC1/3 deficiency, immunodeficiency in DAVID syndrome and deficiencies of other axes in combined hypopituitarism.

13. References

1. Orphanet. Congenital isolated ACTH deficiency (ORPHA:199296). https://www.orpha.net/en/disease/detail/199296
2. GeneGuidance. TBX19 gene and OMIM 201400 condition record (accessed 2026-09-26).
3. Couture C, Saveanu A, Barlier A, Carel JC, Fassnacht M, Flück CE, et al. Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations. J Clin Endocrinol Metab. 2012;97(3):E486-95. doi:10.1210/jc.2011-1659. PMID: 22170728.
4. Online Mendelian Inheritance in Man, OMIM®. MIM Number 201400: ACTH deficiency, isolated; IAD. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/201400
5. Online Mendelian Inheritance in Man, OMIM®. MIM Number 604614: T-box transcription factor 19; TBX19. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/604614
6. Online Mendelian Inheritance in Man, OMIM®. MIM Number 609734: Obesity, early-onset, with adrenal insufficiency and red hair; OBAIRH. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/609734
7. Online Mendelian Inheritance in Man, OMIM®. MIM Number 176830: Proopiomelanocortin; POMC. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/176830
8. Online Mendelian Inheritance in Man, OMIM®. MIM Number 600955: Proprotein convertase 1/3 deficiency. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/600955
9. Online Mendelian Inheritance in Man, OMIM®. MIM Number 162150: Proprotein convertase, subtilisin/kexin-type, 1; PCSK1. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/162150
10. Online Mendelian Inheritance in Man, OMIM®. MIM Number 615577: Immunodeficiency, common variable, 10; CVID10. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/615577
11. Online Mendelian Inheritance in Man, OMIM®. MIM Number 164012: Nuclear factor kappa-B, subunit 2; NFKB2. Baltimore (MD): Johns Hopkins University. https://www.omim.org/entry/164012
12. GeneGuidance. POMC gene record (accessed 2026-09-26).
13. GeneGuidance. PCSK1 gene record (accessed 2026-09-26).
14. GeneGuidance. NFKB2 gene record (accessed 2026-09-26).
15. Orphanet. Late-onset isolated ACTH deficiency (ORPHA:199299). https://www.orpha.net/en/disease/detail/199299
16. Challis BG, Millington GWM. Proopiomelanocortin Deficiency (RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY). In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–. Initial posting 2013 Dec 12 (retired chapter). PMID: 24354022. https://www.ncbi.nlm.nih.gov/books/NBK174451/
17. Charnay T, Mougel G, Amouroux C, Gueorguieva I, Joubert F, Pertuit M, et al. A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin. Front Endocrinol (Lausanne). 2022;13:1080649. doi:10.3389/fendo.2022.1080649. PMID: 36890856. PMC9987334.
18. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166. https://variantvalidator.org
19. Dang Y, Zhang J, Wang F. Congenital isolated adrenocorticotropic hormone deficiency in a newborn caused by TBX19 mutation: a case report and literature review. Front Pediatr. 2024;12:1493387. doi:10.3389/fped.2024.1493387. PMID: 39664280. PMC11631573.
20. Vallette-Kasic S, Brue T, Pulichino AM, Gueydan M, Barlier A, David M, et al. Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations. J Clin Endocrinol Metab. 2005;90(3):1323-31. doi:10.1210/jc.2004-1300. PMID: 15613420.
21. Quentien MH, Delemer B, Papadimitriou DT, Souchon PF, Jaussaud R, Pagnier A, et al. Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections. J Clin Endocrinol Metab. 2012;97(1):E121-8. doi:10.1210/jc.2011-0407. PMID: 22013103.
22. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 255–256 (Obesity with and without developmental delay).
23. European Reference Network on Rare Endocrine Conditions (Endo-ERN). https://endo-ern.eu/
24. Pham LL, Garot C, Brue T, Brauner R. Clinical, biological and genetic analysis of 8 cases of congenital isolated adrenocorticotrophic hormone (ACTH) deficiency. PLoS One. 2011;6(10):e26516. doi:10.1371/journal.pone.0026516. PMID: 22028893. PMC3196582.
25. Lei N, Qiu X, Li W, Liu Y, Hu R, Li C, et al. Functional study of three cases with novel TBX19 variants. Endocrine. 2025;88(1):273-284. doi:10.1007/s12020-024-04153-z. PMID: 39776042. PMC11933146.
26. Nussey SS, Soo SC, Gibson S, Gout I, White A, Bain M, et al. Isolated congenital ACTH deficiency: a cleavage enzyme defect? Clin Endocrinol (Oxf). 1993;39(3):381-5. doi:10.1111/j.1365-2265.1993.tb02381.x. PMID: 8222301.
27. Kyllo JH, Collins MM, Vetter KL, Cuttler L, Rosenfield RL, Donohoue PA. Linkage of congenital isolated adrenocorticotropic hormone deficiency to the corticotropin releasing hormone locus using simple sequence repeat polymorphisms. Am J Med Genet. 1996;62(3):262-7. doi:10.1002/(SICI)1096-8628(19960329)62:3<262::AID-AJMG11>3.0.CO;2-I. PMID: 8882784.
28. Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, et al. A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell. 2001;104(6):849-59. doi:10.1016/s0092-8674(01)00282-3. PMID: 11290323.
29. Liu J, Lin C, Gleiberman A, Ohgi KA, Herman T, Huang HP, et al. Tbx19, a tissue-selective regulator of POMC gene expression. Proc Natl Acad Sci U S A. 2001;98(15):8674-9. doi:10.1073/pnas.141234898. PMID: 11447259. PMC37494.
30. Pulichino AM, Vallette-Kasic S, Couture C, Gauthier Y, Brue T, David M, et al. Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency. Genes Dev. 2003;17(6):711-6. doi:10.1101/gad.1065603. PMID: 12651888. PMC196015.
31. Pulichino AM, Vallette-Kasic S, Tsai JP, Couture C, Gauthier Y, Drouin J. Tpit determines alternate fates during pituitary cell differentiation. Genes Dev. 2003;17(6):738-47. doi:10.1101/gad.1065703. PMID: 12651892. PMC196016.
32. Metherell LA, Savage MO, Dattani M, Walker J, Clayton PE, Farooqi IS, et al. TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency. Eur J Endocrinol. 2004;151(4):463-5. doi:10.1530/eje.0.1510463. PMID: 15476446.
33. Vallette-Kasic S, Couture C, Balsalobre A, Gauthier Y, Metherell L, Dattani M, et al. The TPIT gene mutation M86R associated with isolated adrenocorticotropin deficiency interferes with protein: protein interactions. J Clin Endocrinol Metab. 2007;92(10):3991-9. doi:10.1210/jc.2007-0284. PMID: 17652218.
34. Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-89. doi:10.1210/jc.2015-1710. PMID: 26760044. PMC4880116.
35. Al-Hussaini A, Almutairi A, Mursi A, Alghofely M, Asery A. Isolated cortisol deficiency: a rare cause of neonatal cholestasis. Saudi J Gastroenterol. 2012;18(5):339-41. doi:10.4103/1319-3767.101137. PMID: 23006463. PMC3500024.
36. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 182 (Hypoglycaemia in neonate and infant).
37. Vieira IH, Mourinho Bala N, Ramos F, Dinis I, Cardoso R, Caetano JS, et al. A serious and unusual presentation of congenital isolated ACTH deficiency due to TBX19 mutation, beyond the neonatal period. Endocrinol Diabetes Metab Case Rep. 2022;2022. doi:10.1530/EDM-22-0277. PMID: 36070412. PMC9513655.
38. Mushtaq T, Ali SR, Boulos N, Boyle R, Cheetham T, Davies JH, et al. Emergency and perioperative management of adrenal insufficiency in children and young people: British Society for Paediatric Endocrinology and Diabetes consensus guidance. Arch Dis Child. 2023;108(11):871-878. doi:10.1136/archdischild-2022-325156. PMID: 37045585. PMC10646833.
39. Holterhus PM, Roll C, Gaida B, Richter-Unruh A, Kulle AE, et al. Global Adrenal Insufficiency in Two Independent Patients Carrying the Same Homozygous c.172A>G, p.(Thr58Ala) Mutation in the TBX19 Gene. Horm Res Paediatr. 2025;98(6):633-638. doi:10.1159/000539796. PMID: 38952103.
40. Garmes HM, Boguszewski CL, Miranda PAC, Martins MRA, da Silva SRC, Abucham JZ Filho, et al. Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism. Arch Endocrinol Metab. 2021;65(2):212-230. doi:10.20945/2359-3997000000335. PMID: 33905631. PMC10065316.
41. Maudhoo A, Maharaj A, Buonocore F, Martos-Moreno GA, Argente J, Achermann JC, et al. Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency. Endocrinol Diabetes Metab Case Rep. 2021;2021. doi:10.1530/EDM-21-0128. PMID: 34564059. PMC8495723.
42. National Center for Biotechnology Information. ClinVar: TBX19[gene], pathogenic/likely pathogenic classifications. https://www.ncbi.nlm.nih.gov/clinvar/?term=TBX19%5Bgene%5D
43. Kardelen Al AD, Poyrazoğlu Ş, Aslanger A, Yeşil G, Ceylaner S, Baş F, et al. 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. Horm Res Paediatr. 2019;92(6):395-403. doi:10.1159/000506740. PMID: 32344415.
44. Unal E, Yıldırım R, Taş FF, Tekin S, Sen A, Haspolat YK. A rare cause of neonatal hypoglycemia in two siblings: TBX19 gene mutation. Hormones (Athens). 2018;17(2):269-273. doi:10.1007/s42000-018-0028-2. PMID: 29858850.
45. Kizilcan Cetin S, Siklar Z, Aycan Z, Ozsu E, Ceran A, Berberoglu M. Clinical insights of the TBX19 C.856 C>T variant: a case report and literature review on neonatal isolated ACTH deficiency. J Pediatr Endocrinol Metab. 2026;39(1):96-101. doi:10.1515/jpem-2025-0381. PMID: 40990269.
46. Skorodok YL, Kozhevnikova AV, Plotnikova EV, Ioffe IY, Tiulpakov AN. [Two cases of congenital isolated adrenocorticotropic hormone deficiency due to pathogenic variants in TBX19]. Probl Endokrinol (Mosk). 2025;71(3):51-55. doi:10.14341/probl13519. PMID: 40734300. PMC12319635.
47. Wu S, Chen Q, Shen L, Wei H, Chen Y. [Analysis of TBX19 gene variant in a child with congenital isolated adrenocorticotropic hormone deficiency]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021;38(1):59-62. doi:10.3760/cma.j.cn511374-20191107-00563. PMID: 33423260.
48. Mohideen SB, Fernando PMS, Beetz C, Schroder S, Pereira C, Gunatilleke S, et al. Dihydropyrimidinase enzyme deficiency and congenital isolated adrenocorticotrophin deficiency: dual genetic diagnosis in a Sri Lankan boy. Lab Med. 2025;56(1):93-96. doi:10.1093/labmed/lmae058. PMID: 39126710.
49. Abali ZY, Yesil G, Kirkgoz T, Kaygusuz SB, Eltan M, Turan S, et al. Evaluation of growth and puberty in a child with a novel TBX19 gene mutation and review of the literature. Hormones (Athens). 2019;18(2):229-236. doi:10.1007/s42000-019-00096-7. PMID: 30747411.
50. Ceran A, Aycan Z, Şıklar Z, Özsu E, Kızılcan Çetin S, Berberoğlu M. Long-term Follow-up of a Case with TBX19 Mutation, a Rare Cause of Isolated ACTH Deficiency and Literature Review. J Clin Res Pediatr Endocrinol. 2025;. doi:10.4274/jcrpe.galenos.2025.2024-12-18. PMID: 40727905.
51. Akcan N, Serakıncı N, Turkgenc B, Bundak R, Bahceciler N, Temel SG. A Novel TBX19 Gene Mutation in a Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Respiratory Tract Infections. Front Endocrinol (Lausanne). 2017;8:64. doi:10.3389/fendo.2017.00064. PMID: 28458651. PMC5394421.
52. Fauquier T, Mac TT, Castinetti F, Brue T. Pituitary organoids as models for congenital pituitary deficiencies. Presse Med. 2025;54(4):104299. doi:10.1016/j.lpm.2025.104299. PMID: 40645445.
53. Atasay B, Aycan Z, Evliyaoğlu O, Adiyaman P, Günlemez A, Unal S, et al. Congenital early onset isolated adrenocorticotropin deficiency associated with a TPIT gene mutation. J Pediatr Endocrinol Metab. 2004;17(7):1017-20. doi:10.1515/jpem.2004.17.7.1017. PMID: 15301051.
54. Weijing K, Liping Z, Tiantian Z, Pei Z, Yan M. A Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Caused by Two Novel Mutations in the TBX19 Gene. Front Endocrinol (Lausanne). 2019;10:251. doi:10.3389/fendo.2019.00251. PMID: 31057487. PMC6482258.
55. Watanabe M, Urai S, Bando H, Yamamoto M, Iguchi G, Ogawa W. Evidence of anti-corticotroph autoantibodies in Down syndrome with isolated adrenocorticotropic hormone deficiency: findings from a single case. Endocrine. 2026;91(1). doi:10.1007/s12020-026-04629-0. PMID: 42068444.
56. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 321 (Structural intracranial anomalies — septo-optic dysplasia).
57. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 748 (Low maternal serum oestriol).
58. Haute Autorité de Santé; Centre de référence des maladies rares d'origine hypophysaire (HYPO); Centre de référence des maladies endocriniennes rares de la croissance et du développement (CRMERCD). Protocole National de Diagnostic et de Soins (PNDS): Déficit hypophysaire congénital. Saint-Denis La Plaine: HAS; 2021 Sep. Available from: https://www.has-sante.fr/
59. National Institute for Health and Care Excellence. Adrenal insufficiency: identification and management. NICE guideline NG243. London: NICE; 2024 Aug 28. https://www.nice.org.uk/guidance/ng243
60. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 3, Diagnostic Procedures, 3.2.1 Fasting Test.
61. Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(11):3888-3921. doi:10.1210/jc.2016-2118. PMID: 27736313.
62. Tepe D, Çetin SK, Gökdemir İ, Kocaay P, Deligozoglu D, Gürbüz F. Avoiding false-positive adrenal insufficiency diagnoses in children: insights from cortisol kinetics during pediatric low-dose ACTH stimulation test. Eur J Pediatr. 2026;185(6). doi:10.1007/s00431-026-07129-5. PMID: 42228004.
63. Gürpınar Tosun B, Arıkan Gacemer H, Helvacıoğlu D, Turan S, Bereket A, Güran T. The 40(th) Minute Cortisol Measurement is the Key Time-Point in the Low-Dose Synacthen Stimulation Test: A Large, Assay-Specific Pediatric Validation Study. J Clin Res Pediatr Endocrinol. 2026;18(3):394-401. doi:10.4274/jcrpe.galenos.2026.2026-1-17. PMID: 42043277. PMC13554950.
64. Halah MP, Teodózio ACM, Aragon DC, Elias PCL, de Castro M, Moreira AC, et al. Challenges in Diagnosing Central Adrenal Insufficiency in Children: Cortisol-Stimulating Tests are Safe and Often Required. Clin Endocrinol (Oxf). 2026;105(4):408-415. doi:10.1111/cen.70164. PMID: 42144695. PMC13532148.
65. ClinicalTrials.gov. API v2 search: "TBX19", "isolated ACTH deficiency". https://clinicaltrials.gov
66. Pharmacia & Upjohn Company LLC (Pfizer). SOLU-CORTEF (hydrocortisone sodium succinate for injection). Prescribing information. NDA 009866; version 2025-08-21. https://dailymed.nlm.nih.gov/
67. INFARMED. Solu-Cortef 100 mg/2 ml pó e solvente para solução injetável: Resumo das Características do Medicamento. 1st MA 2000-09-13. Infomed med_id 30174. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=30174&tipo_doc=rcm
68. INFARMED. Hidrocortisona Generis 100 mg pó para solução injetável: RCM. 1st MA 2001-01-24. Infomed med_id 31554. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=31554&tipo_doc=rcm
69. European Medicines Agency. Alkindi (hydrocortisone) granules in capsules for opening: EPAR – product information. EMEA/H/C/004416; EU/1/17/1260. 1st MA 2018-02-09; renewal 2022-11-09; marketing authorisation holder Immedica Pharma AB. https://www.ema.europa.eu/en/medicines/human/EPAR/alkindi
70. Eton Pharmaceuticals. ALKINDI SPRINKLE (hydrocortisone) oral granules. Prescribing information. NDA 213876 (initial approval 2020-09-29); version 2026-04-21. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=26c13a5f-7119-4c6a-bf10-fda4e07d7682
71. Eton Pharmaceuticals. KHINDIVI (hydrocortisone oral solution) 1 mg/mL. Prescribing information. NDA 218980 (approval 2025-05-28); version 2026-04-01. https://dailymed.nlm.nih.gov/
72. INFARMED. Hidrocortisona Roussel 10 mg comprimidos: RCM. Phoenix Labs; 1st MA 2013-04-17; renewal 2022-03-08. Infomed med_id 571140. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=571140&tipo_doc=rcm
73. INFARMED. Hidrocortisona Generis 10 mg comprimidos: RCM. 1st MA 2022-07-29. Infomed med_id 662384. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=662384&tipo_doc=rcm
74. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos — DADOS_ABERTOS_MEDICAMENTOS.csv. Brasília: ANVISA; extract of 2026-10-26. https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
75. Pharmacia & Upjohn Company LLC (Pfizer). CORTEF (hydrocortisone tablets, USP). Prescribing information. NDA 008697; version 2025-02-17. https://dailymed.nlm.nih.gov/
76. European Medicines Agency. Efmody (hydrocortisone) modified-release hard capsules: EPAR – product information. EU/1/21/1549. 1st MA 2021-05-27; renewal 2026-01-09. https://www.ema.europa.eu/en/medicines/human/EPAR/efmody
77. European Commission. Union Register of medicinal products: Efmody (EU/1/21/1549). https://ec.europa.eu/health/documents/community-register/html/h1549.htm
78. Gafner S, Leitner K, Schuetz P, Mueller B, Laager R, Struja T, et al. Incidence and hospital outcomes of acute adrenal crisis in a Swiss-wide cohort study. Eur J Endocrinol. 2026;194(4):441-453. doi:10.1093/ejendo/lvag056. PMID: 41894571.
79. Nowotny H, Ahmed SF, Bensing S, Beun JG, Brösamle M, Chifu I, et al. Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis. Endocrine. 2021;71(3):586-594. doi:10.1007/s12020-021-02649-6. PMID: 33661460. PMC7929907.
80. Du M, Liu ZQ, Song FY, Qian K, Chen XB. [Clinical and genetic characteristics of congenital isolated adrenocorticotropic hormone deficiency]. Zhonghua Er Ke Za Zhi. 2022;60(7):706-709. doi:10.3760/cma.j.cn112140-20211222-01067. PMID: 35768360.
81. Alsaleem M, Saadeh L, Misra A, Madani S. Neonatal isolated ACTH deficiency (IAD): a potentially life-threatening but treatable cause of neonatal cholestasis. BMJ Case Rep. 2016;2016. doi:10.1136/bcr-2016-215032. PMID: 27535729. PMC5015154.
82. British Society for Paediatric Endocrinology and Diabetes. BSPED Adrenal Insufficiency Consensus Guidelines. https://www.bsped.org.uk/adrenal-insufficiency