Familial Glucocorticoid Deficiency and ACTH Resistance

Class of primary adrenal insufficiencies with predominant glucocorticoid deficiency: FGD1–5 (MC2R, MRAP, non-classic STAR, NNT, TXNRD2), MCM4 deficiency, triple A syndrome (AAAS), partial CYP11A1 deficiency and SGPL1 insufficiency

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

Familial glucocorticoid deficiency (FGD) designates a group of monogenic diseases of primary adrenal insufficiency (PAI) in which the gland does not respond to adrenocorticotropic hormone (ACTH) or loses the steroidogenic cells of the zona fasciculata, with low cortisol, markedly raised ACTH and, in the typical form, a preserved renin-aldosterone axis [1, 2]. The OMIM phenotypic series PS202200 is named "Familial glucocorticoid deficiency and ACTH resistance" [3].

0.1. Identifiers of the entities in the class

The identifiers come from GeneGuidance curation, from Orphanet (Orphadata, data of 23 June 2026) and from VariantValidator for the MANE transcripts [4–17]. ORPHA:361 also includes OMIM entries 202355 and 609197 and links STAR only as a "candidate gene tested", without assessment [13]. Entry 202355, without a prefix indicating a known molecular basis, corresponds to "adrenocortical unresponsiveness to ACTH with postreceptor defect", described in a 26-year-old Japanese man and his 29-year-old cousin, referred for hyperpigmentation, with raised ACTH, low cortisol and dehydroepiandrosterone, no steroidogenic response to exogenous ACTH, a normal aldosterone rise with furosemide and with a low-sodium diet, and ACTH receptors of normal number and affinity on monocytes, which led the authors to place the defect after the generation of cyclic AMP [18]. Entry 609197 is the OMIM designation of FGD type 3 (GCCD3, synonym FGD3) as a locus mapped to 8q11.2-q13.2 by homozygosity in 3 of 14 consanguineous families without MC2R variants; in the OMIM phenotypic series, non-classic STAR appears under entry 201710, and not under that designation [19, 20]. Entry 609197 records autosomal recessive inheritance, defines the phenotype as isolated glucocorticoid deficiency with very low cortisol, raised ACTH and a markedly reduced adrenal response to ACTH, without mineralocorticoid deficiency and with an intact renin-angiotensin system, and classifies the relationship only as a mapped locus, without a causal gene; the numbering results from a reassignment, because Genin and colleagues had called all FGD without MC2R variants type 2 and the new locus FGD2, and, after MRAP had been identified, OMIM reserved type 2 for MRAP and moved the 8q locus to type 3, keeping "GCCD2" as a former designation [20]. The 8q interval includes the cytoband of MCM4 (8q11.21), but the entry identifies no gene and does not relate the 3 families to MCM4; nor does it provide individual clinical data on those families [20]. In the OMIM designations, the series distinguishes GCCD1 (MC2R, 18p11.21), GCCD2 (MRAP, 21q22), GCCD3 (8q locus), GCCD4 with or without mineralocorticoid deficiency (NNT, 5p12) and GCCD5 (TXNRD2, 22q11) [19]; MCM4 is not linked to ORPHA:361, but to ORPHA:75391 [13, 21]. ORPHA:869 associates the genes AAAS, TRAPPC11 and GMPPA with triple A, although GMPPA disease runs with normal adrenal function [22, 23]. In OMIM, GMPPA disease (2q35; gene 615495) is the alacrima, achalasia and intellectual disability syndrome (AAMR, OMIM 615510), autosomal recessive and without adrenal insufficiency [24]. ORPHA:168558 records autosomal dominant and autosomal recessive inheritance, which corresponds to primary reports of both patterns [25–27]. The OMIM entries for the remaining entities confirm the numbers, cytobands and autosomal recessive inheritance in the table: GCCD2 (607398; MRAP, 21q22.11), GCCD4 with or without mineralocorticoid deficiency (614736; NNT, 5p12), GCCD5 (617825; TXNRD2, 22q11.21), marked with a question mark because it rests on a single family, immunodeficiency 54 (609981; MCM4, 8q11.21), which OMIM also designates NK cell and glucocorticoid deficiency with DNA repair defect (NKGCD) and familial isolated NK cell deficiency (NKCD), and triple A syndrome (231550; AAAS, 12q13.13), whose entry encompasses the achalasia and alacrima syndrome without adrenal insufficiency [28–32]. For CYP11A1, OMIM uses the title "congenital adrenal insufficiency with 46,XY partial or complete sex reversal" (synonym: P450scc deficiency; 613743, 15q24.1), does not assign it a single inheritance pattern and accepts as causal variants in the heterozygous, compound heterozygous or homozygous state, which agrees with the dual inheritance described in 2.8 [33].

0.2. Quick-reference clinical data

The European Reference Network on rare endocrine conditions (Endo-ERN) brings together more than 100 centres in 27 Member States and Norway, with thematic group 1 dedicated to adrenal diseases, and has published recommendations on replacement therapy and adrenal crisis [47]. The classification codes of ORPHA:361 are E27.1 in ICD-10 and 5A74.Y in ICD-11 [4].

1. Introduction

1.1. From clinical description to genetic heterogeneity

The clinical description that founded the concept appeared in 1959, when Shepard, Landing and Mason reported two sisters with "familial Addison's disease" and corticosteroid deficiency without hypoaldosteronism [48]. The combination of isolated glucocorticoid failure, familial occurrence and mineralocorticoid preservation distinguished this entity from autoimmune Addison's disease and from the congenital adrenal hyperplasias (CAH), and gave rise to the designations "congenital ACTH insensitivity", "hereditary ACTH resistance" and "isolated glucocorticoid deficiency" [49]. In 1978, Allgrove and colleagues described two pairs of siblings from different families with isolated glucocorticoid failure and achalasia of the cardia, with deficient tear production in three of them and signs of autonomic dysfunction in one, and proposed a familial disease of unknown cause, which became known as triple A syndrome or Allgrove syndrome [50].

Between 1968 and 1995, familial series accumulated that fixed the phenotype and anticipated the heterogeneity. Migeon and colleagues brought together in 1968 six patients, two of them siblings, with hypoglycaemia, hyperpigmentation, feeding difficulties in infancy, low urinary excretion of 17-hydroxycorticosteroids without an increase with ACTH and normal tolerance of salt restriction [19]. Franks and Nance described in 1970 two sisters and a brother born to first cousins, with markedly raised plasma ACTH, and, on reviewing eight other familial cases, the excess of boys and the scarcity of consanguinity suggested to them autosomal and X-linked forms; Kelch and colleagues, in 1972, brought together three families with variable adrenal pathology and proposed heterogeneity [19]. Thistlethwaite and colleagues described in 1975 two tall, hyperpigmented brothers with intermittent hypoglycaemia triggered by infections, normal electrolyte balance even on a low-sodium diet, raised ACTH and deoxycorticosterone and progressive loss of the response to ACTH in the elder; this progression led Moshang and colleagues, in 1973, to interpret the disease as an inherited degenerative process, whereas Spark and Etzkorn, in 1977, argued for a defect in or beyond the receptor [19]. In 1989, Allen and colleagues reported two siblings who died with a Reye syndrome-like picture at 3 years and 9 months and at 5.5 years; the adrenal cortex had cells arranged in a pseudoglandular pattern resembling the zona glomerulosa, with no identifiable fasciculata or reticularis cells [19]. The ACTH receptor of mononuclear leucocytes was used as a surrogate for the adrenal receptor: one patient had fewer high-affinity receptors on monocytes (Smith, 1987), two Japanese cousins had normal receptors and were attributed to a postreceptor defect (Yamaoka, 1992), and two Japanese siblings generated no adenylate cyclase in response to ACTH and had no high-affinity binding, without an identified causal variant (Yamamoto, 1995) [18, 19].

The first molecular basis was identified in 1993: Clark, McLoughlin and Grossman found, in a male proband and his affected sister, the missense variant p.Ser74Ile in the second transmembrane domain of the ACTH receptor, with heterozygous parents and an unaffected brother with normal sequence, and noted that this was only the second human disease associated with a mutation in a G protein-coupled hormone receptor [49]. As MC2R variants explained about 25% of cases, the remainder came to be designated FGD type 2. Heterogeneity was demonstrated by linkage: a microsatellite marker close to MC2R segregated with the disease in 4 families and independently of it in 3 (Weber and Clark, 1994), analysis of 11 families without variants in the coding region excluded a 12 cM region around the gene (Naville, 1998), and in 2002 Genin and colleagues mapped in 3 of 14 consanguineous families a locus at 8q11.2-q13.2, between markers D8S285 and D8S1718, which OMIM designates GCCD3, excluding it in 5 of the remaining families; the homozygosity interval was 8.8 cM [19, 20]. In 2005, Metherell and colleagues mapped a locus at 21q22.1 using single nucleotide polymorphism arrays and identified MRAP, which encodes a 19 kDa protein with a single transmembrane domain, required for trafficking of the receptor from the endoplasmic reticulum to the plasma membrane [51].

1.2. Expansion of the class

In 2006, Baker and colleagues defined non-classic congenital lipoid hyperplasia in three children from two families with PAI at 2–4 years and normal male genitalia, carrying the homozygous STAR variants p.Val187Met and p.Arg188Cys with about 20% residual activity, and presented it as a new cause of non-autoimmune Addison's disease [39]. In 2009, analysis of 80 probands with FGD identified a region of homozygosity on chromosome 8 that encompassed STAR and showed that the variants p.Arg188Cys and p.Arg192Cys produced a phenotype indistinguishable from FGD, which led to non-classic STAR being considered FGD type 3 [52]. In that cohort, MC2R and MRAP explained about 45% of cases [52].

In 2012 two new mechanisms were described. MCM4, which encodes a subunit of the replicative helicase, was identified in an Irish genetic isolate with hypocortisolaemia, growth delay, increased chromosomal breakage and natural killer (NK) cell deficiency, and, independently, in six related patients with growth delay, adrenal insufficiency and absence of the CD56dim NK subpopulation [53, 54]. In the same year, targeted exome sequencing identified NNT, which encodes a mitochondrial transhydrogenase, as a cause of FGD, inaugurating the group of causes due to redox imbalance (FGD type 4) [55]. In 2014, a consanguineous kindred of Kashmiri origin made it possible to identify TXNRD2, the first gene of the thioredoxin system with a homozygous mutation associated with human disease (FGD type 5) [42]. Partial CYP11A1 deficiency and SPLIS due to SGPL1 variants subsequently joined the genetic causes of PAI with predominant glucocorticoid deficiency [2, 27, 46].

1.3. Nomenclature and operational definitions

In current nomenclature, FGD is a genetically heterogeneous group whose mechanisms are ligand binding to the receptor, trafficking of the MC2R/MRAP complex, redox balance, cholesterol synthesis and sphingolipid metabolism [2]. The 2016 Endocrine Society guideline groups MC2R (type 1), MRAP (type 2), MCM4, NNT, TXNRD2 and AAAS under the "ACTH insensitivity syndromes" and classifies STAR and CYP11A1 among the steroidogenesis defects close to CAH [1]. The clinical criterion used in the Irish cohorts defines FGD as raised ACTH with low cortisol, normal renin and aldosterone and exclusion of the other causes of adrenal failure [34]. Mineralocorticoid preservation is not absolute: there is initial mineralocorticoid deficiency in a fraction of patients with NNT, MRAP, AAAS, STAR and CYP11A1 [37, 40, 44].

Within the class, FGD1 is PAI due to biallelic MC2R variants. FGD2 is PAI due to biallelic MRAP variants. FGD3 is predominantly glucocorticoid PAI due to STAR variants with residual activity, without the genital abnormalities of the classic form. In OMIM, however, GCCD3/FGD3 (609197) designates the 8q11.2-q13.2 locus without an identified gene, and non-classic STAR has its own entry (201710); in the tables and in the clinical text, FGD3 corresponds to the STAR form and GCCD3 to the 8q locus [20]. FGD4 and FGD5 are PAI due to biallelic loss of function of NNT and TXNRD2. MCM4 deficiency is a syndrome of growth restriction, PAI and NK cell deficiency. Triple A combines alacrima, achalasia, PAI and progressive neurological dysfunction. Partial CYP11A1 deficiency and SPLIS are biochemical phenocopies of FGD with distinguishing features (raised renin and gonadal abnormalities in the former; nephrotic syndrome, ichthyosis and immunodeficiency in the latter). Classic lipoid hyperplasia, 21-hydroxylase CAH and the other CAH, X-linked adrenoleukodystrophy, ACTH deficiencies of pituitary origin and the general approach to hypoglycaemia enter only as differential diagnosis. X-linked congenital adrenal hypoplasia (NR0B1) and the IMAGe, IMAGe-I and MIRAGE syndromes are covered in the differential diagnosis.

The term "congenital adrenal hypoplasia" is discouraged because it is confused with "congenital adrenal hyperplasia" (both abbreviated in English as CAH); "adrenal hypoplasia congenita" (AHC) is used instead [3]. The IMAGe association (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) only became a syndrome with the identification of its molecular basis in CDKN1C [56].

2. Molecular Genetics and Pathophysiology

2.1. ACTH signalling and vulnerability of the zona fasciculata

MC2R is the melanocortin 2 receptor, a G protein-coupled receptor expressed mainly in the adrenal cortex; unlike the other four melanocortin receptors, it is activated selectively by ACTH and couples to the Gs protein, with production of cyclic AMP (cAMP), activation of protein kinase A and stimulation of cortisol production, and is also required for adrenal development [4]. Expression of the receptor at the cell surface depends on MRAP, which accompanies MC2R from the endoplasmic reticulum and participates in signalling in response to ACTH [5, 51]. When this pathway fails, there is no cAMP-dependent steroidogenesis: cortisol falls, ACTH rises through loss of negative feedback and mineralocorticoid production is usually maintained [4, 36].

The second pathogenic pathway is oxidative injury. Mitochondrial steroidogenesis generates reactive oxygen species (ROS) and CYP11B1, which catalyses the last step of cortisol synthesis, accounts for about 40% of the NADPH electron flow that gives rise to ROS in steroidogenesis, which makes the zona fasciculata particularly vulnerable [42]. Detoxification depends on mitochondrial NADPH, which regenerates reduced glutathione (GSH) and reduced thioredoxin; NNT produces this NADPH and TXNRD2 reduces mitochondrial thioredoxin [42, 55]. Patients with MCM4 and NNT revealed a gland hypersensitive to replicative stress and oxidative stress, and both may develop pathology in other organs, which justifies extra-adrenal surveillance [57].

2.2. MC2R (FGD1)

MC2R variants impair ACTH binding or trafficking of the receptor to the surface [4]. In the Barts and Queen Mary series (164 patients referred between 1993 and 2008 with a clinical diagnosis of FGD), analysis of 40 patients with FGD1 included 21 different MC2R variants, mostly missense with residual function, and p.Ser74Ile was present in 18 patients; p.Ser74Ile homozygotes had a median age at presentation of 3.2 years (0–16), with a severity spectrum from minimal to severe for the same variant, and the correlation between in vitro severity and clinical severity was weak [36]. In the British cohort of 155 young people with PAI of unknown cause, 20 of the 30 patients with MC2R had p.Ser74Ile, all of European ancestry from Ireland and Scotland, which corresponds to an Irish and Scottish founder effect [35]. In in vitro studies, MC2R missense variants reduce receptor expression at the cell surface by 20% to 100%, through intracellular retention, and homozygous frameshift variants, with severe loss of function, have been associated with transient mineralocorticoid insufficiency in addition to glucocorticoid deficiency [2].

In the Turkish cohort of 95 children with PAI of unknown cause, the deletion c.560del (described in the literature as c.560delT or p.V187Afs*29) was found in 10 patients from 9 families, with a broad distribution from east to west and previous description in northern Iran; in 13 of the 25 patients with MC2R the variants were severely disruptive and all presented in the first six months with hypoglycaemic seizures or respiratory distress [37]. This cohort described the first complete deletions of the MC2R locus (three patients) and multiple stillbirths in three families with severe variants; until then about 40 missense variants had been described [37]. In 2026 a Chinese patient was described who was compound heterozygous for NP_000520.1:p.(Leu151Pro) (inherited from the father) and NP_000520.1:p.(Glu28Ter) (inherited from the mother), protein designations published without c. notation, with reduced MC2R messenger RNA and protein and reduced ACTH-induced cAMP signal in luciferase assays [58]. In a zebrafish model with mc2r inactivated by CRISPR, interrenal steroidogenesis was impaired and hyperpigmentation appeared with increased melanophores and xanthophores, which suggests a role for the receptor in pigment cell development (preclinical data) [59].

2.3. MRAP (FGD2)

In the series of Chung and colleagues, the nine MRAP variants identified in 22 patients were all nonsense or splicing variants, abolishing the protein, in contrast to the predominance of missense variants in MC2R [36]. The intron 3 donor site is particularly vulnerable and is associated with early onset: the deletion NM_001379228.1:c.106+1del (described as c.IVS3ds+1delG) is recurrent in western Turkey, and in the United Kingdom p.(Met1?), c.106+2dup and c.106+1G>C predominate [35, 37]. Missense variants with partial function shift the ACTH dose-response curve without altering receptor trafficking (signalling defect) and cause late-onset FGD2: p.(Tyr59Asp) in a proband diagnosed at 4 years and p.(Val26Ala) in a patient diagnosed at 18 years [38]. The variant p.Val26Ala was published in the abstract as c.76T>C; VariantValidator returns a reference error for that notation and the correct description in the MANE transcript is NM_001379228.1:c.77T>C [17]. The amino-terminal variants p.(Lys30del) and p.(Leu53Pro) also presented late, between 3.5 and 13 years [37]. MRAP has a dual antiparallel topology: two molecules are required, one with the amino terminus outside and the other with the carboxy terminus outside, and truncating variants eliminate the transmembrane domain encoded by exon 3 [2]. In the mouse, Mrap and Mc2r messenger RNA is located in the zona fasciculata and also in a population of progenitor cells in the undifferentiated zone, between the glomerulosa and the fasciculata, which suggests a role in adrenocortical differentiation [2]. The MANE transcript of MRAP is NM_001379228.1; NM_178817.4, used in the literature, has the same c. numbering for the variants tested [17].

The gene was localised in a family whose disease did not cosegregate with MC2R or with the chromosome 8 region already associated with FGD: genome-wide single nucleotide polymorphism genotyping, with parents, affected individuals and healthy siblings, pointed to a single candidate region at 21q22.1, of about 2.75 Mb with a maximum lod score of 2.64, which homozygosity shared with a second consanguineous family reduced to 2.2 Mb [28]. The gene in that region encodes a protein of about 19 kDa with a single transmembrane domain, which associates with MC2R and intervenes in its route from the endoplasmic reticulum to the cell surface, and the initial families had seven different homozygous variants [28, 51].

2.4. STAR (FGD3 and lipoid hyperplasia)

The STAR protein transports cholesterol from the outer to the inner mitochondrial membrane, the rate-limiting step of steroidogenesis, where CYP11A1 converts it into pregnenolone [10]. The two-hit model explains the natural history: in the absence of STAR, STAR-independent steroidogenesis remains, but cholesterol esters accumulate, the gland enlarges and fills with lipid and secondary cell injury abolishes the residual production [10]. Variants with about 20% of normal activity (p.Val187Met, p.Arg188Cys, p.Arg192Cys) produce the non-classic form, with presentation at 2–4 years or later, predominant glucocorticoid deficiency and, in 46,XY, normal male genitalia, clinically indistinguishable from MC2R or MRAP FGD [39, 52]. In Turkey, NP_000340.2:p.(Ser13Pro) (published protein designation) was recurrent in three patients [37].

2.5. NNT (FGD4) and TXNRD2 (FGD5): the redox causes

NNT is an integral protein of the inner mitochondrial membrane that uses the proton gradient to transfer a hydride from NADH to NADP+, maintaining the NADPH needed to regenerate GSH through the glutathione peroxidases [55]. The gene was identified by polymorphism arrays in nine consanguineous probands (region 5p13-q12 linked in three families) and targeted exome sequencing, which revealed the homozygous variant NM_182977.3:c.1598C>T p.(Ala533Val); sequencing of 100 patients with FGD of unknown cause added 18 variants in 12 kindreds, for a total of 15 families [55]. NNT knockdown in the H295R adrenocortical line increased mitochondrial ROS and apoptosis and altered the GSH/GSSG ratio (29.95 ± 4.77 versus 18.82 ± 8.75; p <0.001); C57BL/6J mice, with a spontaneous deletion of five Nnt exons, have a disorganised zona fasciculata, more apoptosis and lower basal and stimulated corticosterone [55]. Reduced Nnt in this substrain also contributes to glucose intolerance, but this effect is not an established human phenotype of biallelic variants [6]. NNT is expressed mainly in the adrenal, heart, kidney, thyroid and adipose tissue, which explains the extra-adrenal manifestations [55].

In the French cohort of Roucher-Boulez and colleagues, NNT sequencing in 50 families with PAI without a molecular diagnosis (after exclusion of STAR, CYP11A1, MC2R, MRAP and, in boys, NR0B1) identified biallelic variants in 13 families (26%), with 18 patients; there was consanguinity in 8 of the 13 families and homozygosity in 11 [40]. Of the ten variants, seven were new: NM_182977.3:c.1009A>G p.(Met337Val), c.2588C>A p.(Ala863Glu), c.3G>A p.(Met1?), c.385C>T p.(Arg129Ter), c.1135C>T p.(Arg379Ter), c.1992_2005del p.(Val665ProfsTer29) and c.2106_2109dup p.(Ala704SerfsTer19) [40]. The authors numbered the variants on NM_012343.3; the correspondence with the MANE transcript was obtained in VariantValidator from the genomic coordinate, with identical c. numbering in both transcripts [40, 60]. p.(Arg129Ter) appeared in four families, all Algerian, which suggests a founder effect similar to that of p.(Gly200Ser) in Palestine [17, 40]. The two new missense variants affect conserved residues (Met337 in the NAD(H)-binding domain and Ala863 in transmembrane helix 14 of domain II) and were absent from population databases and from 100 controls of the same origin [40]. In a patient who appeared homozygous for p.(Arg71Ter), the mother was not a carrier, and comparative genomic hybridisation and long-range PCR showed a deletion of exons 2 and 3 on the other allele, which illustrates the risk of interpreting as homozygosity a variant that is hemizygous because of a deletion [40]. In individual reports, NM_182977.3:c.644T>C p.(Phe215Ser) was described in the homozygous state in a Japanese boy, absent from 120 Japanese controls, NM_182977.3:c.1163A>C p.(Tyr388Ser) in the homozygous state in an Israeli Jewish man and NM_182977.3:c.598G>A p.(Gly200Ser) in the homozygous state in two Palestinian families without known kinship, which share the haplotype carrying the variant (founder effect); among 200 controls of the same origin there was one carrier, which corresponds to an allele frequency of 0.0025 [29, 61]. In these patients' fibroblasts, biallelic loss of NNT increased reactive oxygen species, reduced ATP content and altered mitochondrial morphology, the first demonstration in patient cells of the proposed oxidative mechanism [61]. The correspondence between the OMIM protein notation (alleles 607878.0007 to 607878.0009) and the nucleotide notation in the MANE transcript was obtained in ClinVar and confirmed in VariantValidator; ClinVar classifies the first two as pathogenic and p.(Gly200Ser) as likely pathogenic [17, 60]. p.(Arg71Ter) (c.211C>T) was found in the homozygous state in a child of Pakistani ancestry in Scotland and in a child in Australia with a Pakistani mother [35]. The HGMD database listed 47 pathogenic NNT variants in 2022 (26 missense or nonsense, 11 deletions, 7 duplications and 3 splicing) [62]. The review of 23 patients from 16 families cited by Maharaj and colleagues recorded hyperpigmentation in 53% and coexisting mineralocorticoid deficiency in four; heterozygous loss-of-function NNT variants have been associated with left ventricular non-compaction, and two families with biallelic variants had cardiac involvement, which justifies, according to the authors, assessment of affected relatives and surveillance for extra-adrenal manifestations [2]. In 2026, three consanguineous Saudi families had the new variant c.1067C>T p.(Thr356Ile), classified as of uncertain significance (VUS), and the recurrent variants c.1025T>C p.(Val342Ala) and c.98dup p.(Leu33PhefsTer13), classified as pathogenic [63]; an 18-year-old Korean man, with PAI since 16 months and without a diagnosis after a targeted panel that did not include NNT, was diagnosed by genome sequencing, with the variants NM_182977.3:c.1820dup p.(Gly608TrpfsTer11) and c.1861C>T p.(Gln621Ter) in compound heterozygosity [64]; and a 10-year-old Chinese girl with epilepsy and hyperpigmentation had the homozygous variant c.645del p.(Phe215LeufsTer17) recorded in the appendix of a previous exome report [65].

TXNRD2 is a mitochondrial enzyme with FAD and selenocysteine, which functions as a homodimer and keeps mitochondrial thioredoxin reduced [7]. In the index kindred, exome sequencing of three affected individuals, after negative MC2R, MRAP, STAR and NNT testing, revealed as the only segregating variant NM_006440.3:c.1341T>G p.(Tyr447Ter) in exon 15, with complete absence of the protein; knockdown in H295R reduced the GSH:GSSG ratio [42]. In more than 1000 healthy British adults of Pakistani origin, the allele frequency was 1.04% (about 2% carriers) [42]. ClinVar records conflicting classifications for this variant [60]. Unlike patients, the Txnrd2-null mouse dies around embryonic day 13 with cardiac and haematopoietic defects [42]. The subsequent spectrum includes compound heterozygosity for p.(His464Arg) and p.(Arg381Trp) with reduced protein in a heterologous system [41], a homozygous splicing variant with genital, ophthalmological and neurological abnormalities, homozygous p.Val361Met with micropenis and cryptorchidism, and adrenal-like cells derived from a patient's induced pluripotent stem cells with loss of cortisol production and increased ROS [7]. In 2026 a Saudi proband was described with the homozygous variant c.575C>T p.(Pro192Leu) (NM_001282512), absent from more than 18,000 local exomes [66].

The 2025 European review on paediatric PAI also includes GPX1 and PRDX3, other genes of mitochondrial antioxidant defence, among the causes of FGD, with autosomal recessive or digenic inheritance and variable presentation, with or without mineralocorticoid deficiency; the sources consulted do not give the number of patients described [67].

2.6. MCM4

MCM4 is a subunit of the MCM2-7 hexamer, the replicative helicase that licenses replication origins in the CDC45-MCM-GINS complex; the ATPase sites form between neighbouring subunits and loss of MCM4 destabilises the ring [8]. Biallelic hypomorphic variants retain enough activity for life, but cause genomic instability in the tissues most dependent on cell division: the growing fetus, the adrenal cortex and the NK compartment [8]. The Irish founder variant was published by Hughes and colleagues as c.71-1insG, with predicted consequence p.Pro24ArgfsX4, and by Casey and colleagues as NM_005914.2:c.71-2A>G, a substitution that destroys the intron 1 acceptor site [53, 68]. ClinVar brings the three original articles together in a single record, NM_182746.3:c.71-2A>G (VCV 37234, OMIM allele 602638.0001, pathogenic), with c.71-1insG as an alternative designation; the MANE notation adopted is therefore c.71-2A>G, confirmed in VariantValidator, and not the duplication c.71-1dup that would result from a literal reading of the historical designation [60, 68]. The variant abolishes the main 96 kDa isoform and preserves a minor 85 kDa isoform [17, 53]. In the French pedigree, a splicing variant produces a premature stop codon, but translation is resumed from two downstream initiation codons, and the genomic instability of the fibroblasts was corrected by normal MCM4 [54]. In Mcm4-depleted mice, the adrenal cortex had non-steroidogenic GATA4+/Gli1+ cells [53]. Gene-disease validity was classified as moderate by the ClinGen severe combined and combined immunodeficiency panel, in August 2023 [8]. Chromosomal instability and the role of MCM4 in DNA replication led Maharaj and colleagues to accept an increased risk of neoplasia and to propose surveillance in these patients, an expert recommendation without a published risk estimate [2].

2.7. AAAS (triple A)

AAAS encodes ALADIN, a WD-repeat protein of the nuclear pore complex, anchored by NDC1, involved in the development of the peripheral and central nervous system and in the localisation of AURKA and NUMA1 during spindle formation [9]. ALADIN deficiency impairs nuclear import of DNA repair and antioxidant proteins, which brings triple A close to the redox causes; Aaas−/− mice have no phenotype [55]. Most alleles are truncating [9]. In the review of 133 genotyped cases there were 65 variants, 14 recurrent and 5 with regional clustering; truncating variants were associated with more frequent, earlier and more often presenting adrenal insufficiency, and non-truncating variants with more frequent, more often presenting and later-onset neurological dysfunction [44]. The splicing variant NM_015665.6:c.1331+1G>A is recurrent in the Maghreb and was found in the homozygous state in Colombia; c.1066_1067del p.(Leu356ValfsTer8) and c.1432C>T p.(Arg478Ter) were the most frequent in Turkey; c.787T>C p.(Ser263Pro) has a possible Slavic founder origin [43, 69–71]. In the review of 206 patients, neurological symptoms occurred in 33 of 34 carriers of p.Ser263Pro (97.1%) versus 133 of 172 with other variants (77.3%; p = 0.006) [43]. The MANE transcript is NM_015665.6; NM_001173466, cited in the GeneGuidance curation, is not the MANE transcript [17].

The locus was mapped to 12q13 by linkage analysis in eight families, with a maximum lod score of 10.81 and no evidence of heterogeneity, and linkage was confirmed in four small Puerto Rican families without known consanguinity and in 12 mostly North African families, in which most affected chromosomes descended from a single founder chromosome [32]. In 2000, Tullio-Pelet and colleagues identified the gene in 14 families, with five homozygous truncating variants, and found that nine of ten North African families shared the same splicing variant, with an estimated age of more than 2400 years; Handschug and colleagues independently described eight variants in nine patients and expression of the gene in neuroendocrine and gastrointestinal structures [32, 72, 73]. The two groups assigned 547 and 546 amino acids, respectively, to the predicted protein, and most of the initial variants were truncating, consistent with loss of function [72, 73]. In a series of six patients with a classic picture, only three had biallelic variants, one had a single variant and two had none, which leaves open genetic heterogeneity or mechanisms that sequencing does not detect [32].

2.8. CYP11A1: recessive and dominant inheritance

CYP11A1 (P450scc) hydroxylates carbons 22 and 20 of cholesterol and cleaves the C20–C22 bond in the inner mitochondrial membrane, with electrons supplied by ferredoxin reductase and the ferredoxins; as it is the first step of all steroidogenesis, its deficiency does not lead to precursor accumulation and 17-hydroxyprogesterone (17-OHP) is low [11]. Partial forms result from variants with residual activity: p.(Arg451Trp) (NM_000781.3:c.1351C>T), with about 30% activity, was described in the homozygous state in two 46,XY siblings with isolated PAI and normal genitalia and is the most common variant, recurrent in eastern and central Turkey [27, 37, 45]; c.940G>A p.(Glu314Lys) (rs6161) causes aberrant splicing and a partial phenotype and was found in compound heterozygosity with a severe variant in 10 of 12 British patients with CYP11A1 [35]. Its pathogenicity was demonstrated by Maharaj's group in a cohort of 19 patients from 13 families with PAI of unknown cause: the variant, previously regarded as benign, was in trans with a second disruptive CYP11A1 alteration in 17 patients and with one of two rare synonymous variants, p.(Thr330=) and p.(Ser391=), in the remainder, and all three caused aberrant splicing; an independent minigene assay showed exon 5 skipping in four compound heterozygous patients [2]. In 2026, reanalysis of clinical sequencing data revealed c.644T>C p.(Phe215Ser) and c.1187G>A p.(Arg396Lys) in compound heterozygosity in two siblings, with phase confirmed by long-read sequencing [74].

Inheritance is autosomal recessive in the great majority of families, but there are reports of disease with a single heterozygous variant. Tajima and colleagues described a 46,XY child with sex reversal and PAI with a de novo in-frame Gly-Asp insertion between Asp271 and Val272, totally inactive and without a dominant-negative effect on cotransfection, and proposed haploinsufficiency combined with the two-hit model; the child lived four years without replacement until a life-threatening AI [26]. Papadimitriou and colleagues described a Greek family with three carriers of the heterozygous variant NM_000781.3:c.235G>A p.(Val79Ile): a 46,XY boy with AI at 3 months and severe faltering weight gain, his twin sister with adrenal crisis hours after birth and the father with reported neonatal faltering growth, and concluded that dominant transmission was possible [75]. The systematic review by Phadte and colleagues included monoallelic p.Val79Ile among the genotypes associated with typical male genitalia [76]. Orphanet records both patterns under ORPHA:168558 [25]. Interpretation of an isolated heterozygote requires exclusion of a second undetected variant (deep intronic or copy number variation), and the sources do not estimate the penetrance of this dominant form.

2.9. SGPL1

SGPL1 encodes sphingosine-1-phosphate lyase, which irreversibly degrades sphingosine-1-phosphate; its deficiency increases plasma sphingosine-1-phosphate and the sphingosine/sphinganine ratio [77]. About half of the variants described cause complete loss of function, and patients with biallelic loss of function without kidney transplantation have a survival of 28% [46]. Loss-of-function SGPL1 variants also cause, without adrenal involvement, an axonal neuropathy with recurrent mononeuropathies described as an atypical form of Charcot-Marie-Tooth disease, and three patients with congenital nephrotic syndrome, hypogonadism and prenatal adrenal calcifications (only one with congenital PAI) had the homozygous variants p.(Arg505Ter) and p.(Leu312PhefsTer30), with increased sphingosine-1-phosphate and sphingosine in blood and fibroblasts [2]. p.(Arg222Gln) (NM_003901.4:c.665G>A) accounts for 29–30% of variants, almost always in the homozygous state, with a mean age at presentation of 8 years and survival of 77% in non-transplanted patients versus 44% with other variants; p.(Tyr416Cys) (c.1247A>G) is a founder variant in the Dariusleut Hutterite colony, with survival of 66.7% and a carrier frequency of 6.67% (10 in 150) in that colony, versus 0 in 140 in the Lehrerleut and 0 in 100 in the Schmiedeleut [46].

2.10. Proportion of cases by gene

Reviews estimate that MC2R explains about 25% of FGD, MRAP about 20% and STAR 5–10%, together about half; MCM4, NNT, TXNRD2, CYP11A1 and SGPL1, identified by exome sequencing in negative cases, add about 10%, and about 40% of cases remained without a genetic diagnosis in 2019 [2]. These proportions refer to cohorts of clinical FGD in research laboratories; in cohorts of paediatric PAI of unknown cause the distribution varies with the population (see section 9).

2.11. Normalised reference variants

Recurrent or founder variants were normalised in VariantValidator (GRCh38, MANE Select transcript, query of 26 October 2026), with the literature nomenclature alongside [17, 60].

The MANE transcript of TXNRD2 is NM_006440.5; the original article used NM_006440.3, with the same c. numbering for this variant [17, 42]. VariantValidator issues a selenoprotein warning for TXNRD2, because the UGA codon may be read as selenocysteine; the codon created by p.(Tyr447Ter) is UAG, which is not subject to this recoding [17].

2.12. Allelic disorders, genotype-phenotype and modifiers

NNT has an allelic disorder with an opposite mechanism: the heterozygous gain-of-function missense variant NM_182977.3:c.2063T>G p.(Leu688Trp), described in three families with dominant transmission, increases the NADPH/NADP+ ratio and glutathione, reduces ROS and ferroptosis and causes premature diffuse familial sebaceous hyperplasia [80]. In TXNRD2, two heterozygous missense variants were found in 3 of 227 patients with dilated cardiomyopathy and in none of 683 controls, with a proposed dominant-negative effect, and there is one mother-son report; ClinGen has not assessed this relationship, GenCC classifies it as limited and OMIM lists no cardiac phenotype [7]. The homozygotes of the FGD5 kindred had no cardiomyopathy or conduction disease on echocardiography and electrocardiography (ECG), despite the absence of TXNRD2 [42]. On this evidence, a heterozygous TXNRD2 variant should not be reported as a cause of dilated cardiomyopathy [7].

CDKN1C (IMAGe syndrome) and SAMD9 (MIRAGE syndrome) have dominant inheritance, with maternal imprinting in the former and gain of function, usually de novo, in the latter; NR0B1 is X-linked [3, 56, 81]. In CDKN1C, all IMAGe variants are located in an eight-amino-acid segment of the PCNA-binding domain on the maternally expressed allele, whereas loss of function outside that domain causes Beckwith-Wiedemann syndrome and the variants p.Arg279Leu and p.Arg279Ser (published protein designations) cause Silver-Russell syndrome without AI [56]. For MC2R, MRAP, MCM4, AAAS, STAR and SGPL1, the sources consulted describe only recessive inheritance.

The most consistent genotype-phenotype correlations are earlier onset with MRAP null variants than with MC2R missense variants [36], early presentation with hypoglycaemic seizures in disruptive MC2R variants [37], late onset of MRAP missense variants and of the partial forms of STAR and CYP11A1 [38, 39, 45], and the relationship between AAAS truncation and early adrenal insufficiency [44]. Intrafamilial heterogeneity is frequent: relatives with the same NNT genotype may differ in phenotype, and in SPLIS there is variability within the same family [40, 46]. A digenic modifier was proposed in a boy with compound heterozygous NNT and glucocorticoid and mineralocorticoid deficiency, who also had two common missense variants of the malic enzyme 3 gene (ME3) in compound heterozygosity, NM_001161586.3:c.972G>C p.(Lys324Asn) (rs1042780) and c.1252G>A p.(Ala418Thr) (rs3182235); as ME3 also produces mitochondrial NADPH, the authors suggested that a modest functional variation in this gene aggravates the effect of severe NNT variants, a hypothesis supported by a single patient [29, 79]. OMIM records the first as K234N, but the original article gives c.G972C p.K324N and VariantValidator, from the genomic coordinate of rs1042780, confirms codon 324 on the MANE transcript [29, 79]. Both variants are frequent (minor allele frequency of 0.4 and 0.02 in the 1000 Genomes project), and prediction tools classified p.(Lys324Asn) as benign and p.(Ala418Thr) discordantly; there was no functional study [79]. The contrast that motivated the hypothesis was clinical: the French-Canadian girl with isolated glucocorticoid deficiency (hypoglycaemia of 0.7 mmol/L at 14 months, calcified adrenals) had two truncating NNT variants, NM_182977.3:c.63del p.(Ser22ProfsTer7) and c.1864-1G>T, whereas the boy with combined deficiency (at 13 months, sodium of 126 mmol/L, potassium of 8.2 mmol/L and renin of 202 ng/L during a retropharyngeal abscess) had one truncating variant, c.1107_1110del p.(His370Ter), and one missense variant, c.3027T>G p.(Asn1009Lys), the latter absent from both parents and probably de novo; the formal severity of the NNT variants did not, therefore, explain the difference in phenotype [79].

2.13. Animal models

Mouse models reproduce FGD completely or partially [2]. Mc2r−/− mice are born in Mendelian proportion, but about three quarters die before weaning, most in the first 48 hours, with hypoglycaemia and reduced hepatic gluconeogenesis; survivors have undetectable corticosterone, raised ACTH, a hypoplastic zona fasciculata and, unlike patients, low aldosterone. Mrap−/− mice (exon 1 deletion) have almost complete neonatal lethality (322 of 325) owing to pulmonary immaturity, preventable with corticosterone given to the pregnant mother; survivors reproduce FGD2, with isolated glucocorticoid deficiency and normal mineralocorticoid function, and show altered zonation, a thick capsule, lower expression of Sf1 and the steroidogenic enzymes (except Cyp11b2) and dysregulation of the WNT4/β-catenin and sonic hedgehog pathways [2]. Star-null and Cyp11a1-null mice have adrenal insufficiency with progressive lipid accumulation and, in males, undervirilisation; the Mcm4-null mouse dies before implantation, and the hypomorphic model shows capsular hyperplasia with non-steroidogenic GATA4+/Gli1+ cells invading the cortex. C57BL/6J mice lacking Nnt have a reduced corticosterone response and a 65% reduction in Cyp11a1 protein, and Txnrd2-null mice die in the embryonic period without a described adrenal phenotype, with cardiomyopathy in cardiac inactivation models, whereas the FGD5 patients studied had normal cardiac function [2]. Most Sgpl1−/− mice die in the first days; survivors reproduce the altered adrenal zonation and glomerular injury with progressive proteinuria, and have dyslipidaemia, lymphopenia and impaired T lymphocyte maturation [2]. Discrepancies between species, such as low aldosterone in Mc2r−/− mice and the embryonic lethality of Mcm4- and Txnrd2-null mice, limit the transfer of these models to the clinic [2].

3. Clinical Spectrum and Manifestations by System

3.1. Common picture and natural history without treatment

The usual presentation of FGD occurs in the neonatal period or early childhood with hypoglycaemia, sometimes with seizures and permanent neurological injury, faltering weight gain, recurrent or severe infections, hyperpigmentation, prolonged neonatal jaundice or cholestasis, and adrenal crisis with shock [4, 36]. Biochemistry shows markedly raised ACTH, low cortisol and preserved mineralocorticoid production [36]. Without treatment, children die of hypoglycaemia or overwhelming infection [51]. In the Turkish cohort of 95 children with rare PAI, hyperpigmentation was present in 94%, salt-wasting crisis or electrolyte imbalance in 51%, hypoglycaemia with or without seizures in 47%, vomiting or abdominal pain in 26%, prolonged jaundice in 24%, fatigue in 18%, neonatal respiratory distress in 17%, frequent infections in 11% and faltering weight gain in 7%; a history of unexplained death in childhood in the extended family was frequent [37]. In the Italian cohort of 803 children with PAI, the 121 patients without 21-hydroxylase deficiency had fatigue in 67%, hyperpigmentation in 50.4%, dehydration in 33%, hypotension in 31%, raised ACTH in 96.4%, hyponatraemia in 55%, hyperkalaemia in 32.7% and hypoglycaemia in 33.7%, with an age at presentation of 6.5 ± 5.1 years and symptoms 5.6 ± 11.6 months before diagnosis [82].

3.2. FGD1 and FGD2

A comparison of 40 patients with FGD1 and 22 with FGD2 showed a median age at presentation of 2.0 years (0–16; mean 3.11 ± 3.40) in FGD1 and 0.08 years (0–1.6; mean 0.31 ± 0.51) in FGD2 (p <0.01) [36]. Height at presentation was greater in FGD1 (SDS +1.76 ± 1.52 versus +0.12 ± 1.35; p <0.001), with no significant difference in weight; the authors propose that raised ACTH acts on melanocortin receptors in bone and the growth plate and that early treatment in FGD2 prevents this acceleration [36]. Median ACTH at presentation was 1409 ng/L (250–6888) in FGD1 and 1250 ng/L (108–4500) in FGD2, and median basal cortisol 50 nmol/L in both (FGD1 8–502; FGD2 5.5–200), with no significant differences [36]. The sources had insufficient data on bone age, final height and adrenal androgens [36].

In the Turkish cohort, tall stature (more than 2 standard deviations or two centiles above the parental target) occurred in 7 of 25 patients with MC2R (28%) and short stature in 4 [37]. Hypoglycaemic seizures at presentation occurred in 22 of 25 patients with MC2R (88%) and in 5 of 9 with MRAP (56%), versus 5 of 43 with other causes (12%; p <0.0001) [37]. Salt wasting requiring mineralocorticoid affected 2 of 25 patients with MC2R (8%), to whom 4 with transient hyponatraemia should be added, and 2 of 9 with MRAP (22%) [37]. Minor dysmorphic features and transient abnormalities of other adrenal zones or of the thyroid have been described in isolated cases of FGD1 [4].

In FGD2, hyperpigmentation may be the first sign, even at birth: a term newborn, born to consanguineous parents, had marked scrotal hyperpigmentation with normal newborn screening, initial glucose and electrolytes, very low cortisol and markedly raised ACTH, and required fludrocortisone for a short time because of transient hyperkalaemia with low-normal aldosterone [78]. The MRAP missense forms presented late: in the family with p.(Tyr59Asp), the proband was diagnosed at 4 years, an older brother was well and another had cerebral palsy due to undiagnosed hypoglycaemic seizures; the patient with p.(Val26Ala) was diagnosed at 18 years because of fatigue, weight loss and depression [38]. Until that report no FGD2 had presented after 1.6 years [38].

3.3. FGD3 and the spectrum of STAR lipoid hyperplasia

The non-classic form presents at 2–4 years or later with predominant glucocorticoid deficiency; in 46,XY the genitalia are normal male and in 46,XX ovarian function is maintained, with normal puberty and spontaneous or clomifene-induced pregnancy in four women described [10, 39]. In the United Kingdom, five patients with the non-classic form presented between 9 months and 4 years, mainly with glucocorticoid deficiency, without evident genital abnormalities, and most received mineralocorticoid [35]. Late-onset non-classic forms of STAR and CYP11A1 are a frequent cause of undiagnosed PAI, and mild forms may appear in adulthood under the label of "Addison's disease" [83].

The classic form serves as a contrast. In the multicentre Korean OUTSPREAD cohort (31 patients, 29 with the classic form), the median age at diagnosis was 36.5 days, with salt wasting in 58.6% and hyperpigmentation in 71%; all 46,XY (12) and 46,XX (17) patients had a female phenotype [84]. In the 46,XX patients, spontaneous thelarche occurred in 11 (median 11.0 years) and menarche in 5 (12.4 years), and 3 of 8 assessed by imaging had unilocular ovarian cysts, one with rupture [84]. The two non-classic patients (46,XY, genotypes NM_000349.3:c.772C>T p.(Gln258Ter)/c.559G>A p.(Val187Met) and c.653C>T p.(Ala218Val)/c.661G>A p.(Gly221Ser)) were diagnosed at 1.6 and 3.3 years with male genitalia, and one had spontaneous puberty at 10.6 years [84]. In Turkey, all six 46,XY patients with STAR had differences of sex development (DSD), five with a female phenotype and salt-wasting crisis, and a boy with severe hypospadias developed hypergonadotrophic hypogonadism at puberty [37].

3.4. FGD4 (NNT)

In the review of 23 patients, the median onset was about 12 months (3 days to 39 months), with hypoglycaemia frequently ketotic and with seizures, faltering growth, recurrent infections, collapse and cutaneous and mucosal hyperpigmentation, which is often the first sign and precedes the crisis [6]. In the French cohort (18 patients from 13 families), diagnosis was late, between 8 and 18 months after severe hypoglycaemia, and 5 patients had mineralocorticoid deficiency at onset [40]. The median age at onset was 11.5 months (1.5 months to 4 years); severe hypoglycaemia, sometimes with coma, inaugurated the picture in 16 of the 18 patients, often during an infection and with melanoderma that, according to the history, preceded it, and two presented with salt wasting without hypoglycaemia [40]. Onset was earlier in patients with global insufficiency than in those with isolated glucocorticoid deficiency (Kruskal-Wallis test, p = 0.034 in the cohort and p = 0.004 with the published cases), with no difference between truncating and non-truncating variants [40]. The article is not consistent in its count of presentations: 13 patients with FGD and 5 with global insufficiency in the introduction and abstract, 11 and 7 in the discussion [40]. During follow-up of 16 patients, aged between 4 and 57 years at the end of the study, one patient had salt wasting at 15 years and again at 18, and another eight required mineralocorticoid or salt because of raised renin or low aldosterone [40]. Two boys had testicular nodules at 5 years and precocious puberty with raised testosterone and low or undetectable gonadotrophins; in one of them surgery revealed a Leydig interstitial cell adenoma, and after excision and a short course of GnRH analogue testosterone returned to prepubertal values [40]. One man had at 18 years testicular inclusions compatible with TART and azoospermia, with FSH of 18 IU/L, LH of 9 IU/L, testosterone of 5.8 nmol/L and a 46,XY karyotype without Y microdeletion, and increasing the glucocorticoid dose neither reduced the inclusions nor improved spermatogenesis [40]. Another had at 23 years severe asymmetric left ventricular hypertrophy, with a maximum thickness of 36 mm in the basal septum; two had hypothyroidism with an orthotopic thyroid (one congenital), two operated cryptorchidism, three recurrent urinary infections and four learning difficulties, possibly a consequence of the hypoglycaemic episodes; none had glucose intolerance and growth in those who reached adulthood was normal [40]. During prolonged follow-up of the same cohort, 14 of the 18 patients eventually also had mineralocorticoid deficiency, two sibling pairs had discordant phenotypes (one with glucocorticoid deficiency only and the other with combined deficiency) and in 5 of the 13 families other children had died, probably of adrenal insufficiency with severe hypoglycaemia [29]. In the original description, the patients from the 15 families were diagnosed between 6 and 40 months, with normal renin and aldosterone [29]. Individual reports broadened the spectrum: a Japanese boy presented at 19 months with hyponatraemia, markedly raised ACTH and increased renin, with no adrenal glands visible on computed tomography, and at 17.5 years had age-appropriate secondary sexual characteristics; an Israeli boy had severe hyponatraemia with hyperkalaemia and natriuresis at 10 months, peripheral puberty at 6 years with pubertal testosterone and increased testicular volume, with a biopsy interpreted by the authors as an adrenal rest tumour, which regressed with intensification of glucocorticoid [85], central puberty at 10 years and, at 20 years, absence of crises and of adrenal rest tumours on ultrasound, and two older brothers had died at 3 and 4 months with a picture recorded as gastroenteritis; in two Palestinian families, three children had a neonatal or first-year Addisonian crisis and required glucocorticoid and mineralocorticoid [29, 61]. In Turkey, the NNT forms appeared at different ages in the first two years and 2 of 7 patients (28%) required mineralocorticoid [37]; in the United Kingdom, presentation occurred between 4 months and 2.5 years and 3 of 10 patients had precocious puberty [35]. Extra-adrenal manifestations include precocious puberty, cryptorchidism, testicular inclusions and testicular adrenal rest tumours (TART), Leydig cell adenoma, azoospermia, hypothyroidism (including congenital) and hypertrophic cardiomyopathy [40]. The lesion is progressive: in a presymptomatic sibling, ACTH was already raised at 6 months with normal urinary cortisol metabolites [62]. In 2026 a 10-year-old girl with epilepsy for four years, long-standing hyperpigmentation, primary hypothyroidism and metabolic encephalopathy, who improved with glucocorticoid, thyroxine and antiepileptic drugs, was described [65], as well as three Saudi families with hypoglycaemia and adrenal crises [63].

3.5. FGD5 (TXNRD2)

In the index kindred, the proband, daughter of first cousins, was diagnosed at 10.8 years because of hyperpigmentation during febrile illnesses (09:00 ACTH of 160 ng/L, normal <50; cortisol <10 nmol/L); her sister was diagnosed at 4.5 years after two years of hyperpigmentation, and the proband's children, screened from birth, between 0.1 and 6.9 years [42]. All had a poor response to 125 µg of intramuscular (IM) tetracosactide and normal mineralocorticoid production; one boy also had truncus arteriosus and a ventricular septal defect, the only comorbidity in the kindred [42]. Initial biochemistry may normalise before diagnosis: one homozygous child was well at 7.4 years under surveillance after an ACTH of 124 ng/L with cortisol of 305 nmol/L in the neonatal period, and a sister had raised ACTH in childhood that normalised before diagnosis [42]. The spectrum includes cases with genital (micropenis, cryptorchidism), ophthalmological and neurological abnormalities, a case of compound heterozygosity with a possible association with electrocardiographic abnormalities and a proband with epilepsy and basal ganglia abnormalities on magnetic resonance imaging (MRI) [7, 41, 66]. The OMIM entry is still based only on the index family and therefore keeps the gene-phenotype relationship as provisional [30].

3.6. MCM4 deficiency

The triad consists of severe intrauterine and postnatal growth restriction with short stature and microcephaly, FGD-type PAI (often the presenting problem) and selective NK cell deficiency, with absence of the mature CD56dim subpopulation and relative preservation of the CD56bright cells; T and B lymphocyte numbers are not altered [8, 54]. Recurrent viral infections, mainly respiratory and herpesvirus infections, may cause respiratory failure [8]. The authors consider an increased neoplastic risk due to genomic instability plausible, without an established frequency [53]. In the Irish Traveller community, the nine children with FGD without MC2R or MRAP variants described by O'Riordan had later onset because the initial investigation showed normal cortisol (422–575 nmol/L) and ACTH <34 ng/L; the gene of these families was later identified as MCM4 by the same group [34, 53]. The first description of the Irish kindred came from immunology [86]: four members of three sibships, first cousins, had a selective and profound deficiency of NK cells in blood, one of them with Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the small intestine at 2 years and 9 months, surgically removed, and two with severe pneumonitis of probable viral cause; the deficiency was mapped to the centromeric region of chromosome 8 (8p11.23-q11.21, maximum LOD 4.51) [86] and, at follow-up, all had NK counts below 5% of normal, growth restriction, microcephaly and AI on replacement [31]. In three Irish Traveller clans, 8 of 10 homozygous patients had been born small for gestational age, all had short stature and most microcephaly, faltering weight gain and hyperpigmentation; one of the families was referred for suspected Silver-Russell syndrome before hyperpigmentation led to the diagnosis of FGD [31, 68]. In this series, hyperpigmentation appeared after 2 years and ACTH rose progressively, with low-normal cortisol, until the diagnosis of FGD at a mean age of 5 years; pigmentation regressed in patients who took hydrocortisone regularly [68]. The authors noted that, in some families with poor adherence, stopping hydrocortisone had not caused adrenal crisis and interpreted FGD as a possibly secondary phenotype; this is a descriptive observation in a few families, which does not justify stopping replacement [68]. Chromosomal fragility was at one point classified as mosaic Fanconi anaemia, but the pattern did not match: DNA damage was greater than in healthy individuals and less than in Fanconi mosaicism, affected a minority of cells, and the patients did not have the expected clinical picture [31]. In the seven children from three kindreds described by Hughes and colleagues, glucocorticoid failure appeared after a period of normal adrenal function, and only one had recurrent infections; in O'Riordan's series, the mean age at diagnosis was 5 years [31].

3.7. Triple A syndrome

In the review of 133 genotyped cases, alacrima occurred in 99%, achalasia in 93%, AI in 91% and neurological dysfunction in 79%; alacrima appears from birth and is the earliest sign, AI and achalasia precede the neurological involvement, mineralocorticoid deficiency is rare (12.5%) and the median age at presentation is 5 years (1–42) [44]. In an Indian cohort of 8 patients, the median was 4.75 years, with alacrima and AI in 8, achalasia in 7 and neurological involvement in 4, without mineralocorticoid deficiency [44]. Recent cohorts show the variability of presentation:

Neurological signs include peripheral neuropathy with pes cavus and distal atrophy, pyramidal signs (hyperreflexia, Babinski sign, spastic toe-walking), cognitive impairment, cerebellar dysfunction, dysautonomia (anhidrosis), neuro-ophthalmological signs (including optic atrophy), and bulbar and facial involvement with nasal speech [35, 88, 89, 91]. Peripheral muscle weakness, nasal speech and hyperreflexia without other spasticity are considered pathognomonic [35]. The electromyographic pattern of distal axonal motor polyneuropathy with rare sensory involvement requires differentiation from hereditary spastic paraplegia and motor neurone disease [88]. Onset may be delayed until adulthood: a 51-year-old Austrian man with achalasia, PAI since childhood, total alacrima on the Schirmer test and mild peripheral and central neuropathy was the first documented case in Austria [92]. There are incomplete forms, such as a 5-year-old girl with alacrima from birth, hyperpigmentation, hypoglycaemia, hyponatraemia and mineralocorticoid deficiency, without achalasia [93].

The progressive nature of the neurological involvement was established by follow-up of Allgrove's patients, who developed polyneuropathy with sensory, motor and autonomic components, long tract degeneration, parkinsonism and mild dementia; glucocorticoid replacement does not appear to modify the onset or progression of the neurological manifestations [32]. In 1980, Lanes and colleagues proposed the designation "triple A" in relation to an 8-year-old Saudi girl with glucocorticoid and partial mineralocorticoid deficiency; in 1995, Gazarian and colleagues found in three children tested an abnormal heart rate variation on deep breathing in all, an abnormal Valsalva ratio in two and an abnormal orthostatic blood pressure response in one, and proposed including autonomic dysfunction in the designation "4A"; orthostatic hypotension with compensatory tachycardia was subsequently described in adolescents [32]. The adult spectrum includes a Portuguese woman with progressive bulbospinal amyotrophy and dysautonomia at 33 years, with the triad present from birth and the nonsense variant NM_015665.6:c.1432C>T p.(Arg478Ter) in the homozygous state [60, 94], other patients with spastic tetraparesis and peripheral motor neuropathy, and a man with achalasia at 47 years, orthostatic hypotension, AI, progressive gait disturbance from 59 years with signs of motor neurone disease and cerebellar, frontal and basal ganglia atrophy, who died at 78 years of aspiration pneumonia, homozygous for NM_015665.6:c.464G>A p.(Arg155His) (OMIM allele 605378.0011; pathogenic or likely pathogenic in ClinVar) and with reduced ALADIN in nervous tissue [32]. Incomplete expression is frequent: there are patients with achalasia and neurological involvement only, recognised through gene testing, a 14-year-old girl with axonal motor neuropathy, alacrima and plantar hyperkeratosis without AI, and consanguineous sibships with achalasia and alacrima without AI, which were at one point proposed as a distinct entity; the observation of siblings with the same variant, one with the triad and the other with achalasia and alacrima only, justifies the inclusion of this form in the triple A entry [32]. For this reason, the diagnosis rests on AAAS testing and may encompass patients with one or two of the three cardinal manifestations [32].

3.8. Partial CYP11A1 deficiency

The severe neonatal form runs with early salt-wasting PAI and complete feminisation of the external genitalia, regardless of karyotype; partial forms present in childhood with ketotic hypoglycaemia, hyperpigmentation and mainly glucocorticoid deficiency, with mild zona glomerulosa deficiency in about half of the British cases [11, 35]. In the Turkish cohort of 22 p.(Arg451Trp) homozygous patients from 16 families, the age at presentation was 4.8 ± 4.2 years (1–14.6), three were diagnosed by family screening, 20 had mineralocorticoid deficiency (83% according to the authors) with recovery in two, and one patient without initial deficiency had a salt-wasting crisis during an acute illness; no 46,XY patient had atypical genitalia, three had micropenis and one cryptorchidism, and two required sex steroids for later hypergonadotrophic hypogonadism, with growth in line with genetic potential and normal puberty in the rest [45]. In the review of 52 probands, 46,XY patients with typical male genitalia had spontaneous puberty in 9 of 9 and normal pubertal testosterone in 9 of 11, versus 0 of 3 in those with atypical genitalia (p = 0.0045 and p = 0.027), and TART were described only in the first group [76]. Three Scottish siblings were considered to have FGD for years; raised renin activity and sequencing corrected the diagnosis (section 6) [95]. The reports collected in OMIM delimit the extremes of the spectrum. In the severe form, a 31-week 46,XY newborn with female external genitalia, bronzed skin, severe salt wasting, undetectable urinary steroids and absence of gonads, adrenal tissue and uterus on imaging was homozygous for a single-nucleotide deletion; a 46,XY child of consanguineous Syrian parents, with a female phenotype, severe AI at 21 months and complete agenesis of the corpus callosum, had a homozygous missense variant with about 11% residual activity; and a 46,XX child with hyperpigmentation at 7 months, raised ACTH and normal cortisol was compound heterozygous, with one variant inherited from the mother and another de novo [33]. In the mild form, a 46,XY boy with mid-penile hypospadias, bilateral cryptorchidism and bilateral club foot had no signs of AI until 9 years, and his twin with a female phenotype had died at 2.5 years of an unexplained illness; two siblings, one 46,XY with underdeveloped genitalia and one 46,XX, had small calcified adrenals [33]. In none of the six patients collected up to 2008 was the massive adrenal enlargement of STAR lipoid hyperplasia described, and an equivalent phenotype exists in the rabbit with deletions of the gene [33].

3.9. SPLIS (SGPL1)

SPLIS combines, variably, steroid-resistant nephrotic syndrome (SRNS; 80%), PAI (65%), hypothyroidism (35%), testicular failure (33% of boys), immunodeficiency (36%), developmental delay (31%), ichthyosis or acanthosis (31%), cranial nerve deficits (22%) and sensorineural hearing loss (19%) [46]. All patients with PAI have glucocorticoid deficiency and some also mineralocorticoid deficiency; most become symptomatic in the first decade, with the latest onset at 42 years, and adrenal calcifications or enlargement, sometimes visible in the prenatal period, are a probable risk factor [46]. AI may precede the nephropathy [3]. The median time from proteinuria to kidney failure was 30 months (<1 to 60) and biopsy shows focal segmental glomerulosclerosis with podocyte effacement, sometimes collapsing, or diffuse mesangial sclerosis; 14 patients were transplanted between 3 and 22 years [46]. Immunodeficiency (T lymphopenia, sometimes low B and NK cells, hypogammaglobulinaemia, opportunistic infections) was found in 93% of those assessed, and seven patients had abnormal T cell receptor excision circles (TREC) on newborn screening [46]. In 15 pregnancies there were hydrops, adrenal calcifications, increased nuchal translucency and four fetal deaths [46].

3.10. Other manifestations and treated disease

Thyroid function abnormalities are frequent in genetic PAI: in the Turkish cohort, 26% of patients had subclinical hypothyroidism, two primary hypothyroidism, one transient hypothyroidism and two thyroglossal duct cysts [37]. In the French cohort of 59 children with rare causes of PAI (64% monogenic), followed for a median of 7.6 years, there was adrenal crisis in 45%, mainly due to poor adherence, overweight in 27%, normal puberty in 72%, precocious in 17% and delayed in 14% (37 patients with data), and final height of −1.1 standard deviations in males and −0.4 in females (28 patients) [96]. These numbers describe treated patients; the natural history without treatment corresponds to the mortality from hypoglycaemia and infection described in section 3.1.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

The Endocrine Society recommends testing to exclude PAI in acutely ill patients with unexplained symptoms or signs of volume depletion, hypotension, hyponatraemia, hyperkalaemia, fever, abdominal pain, hyperpigmentation or, especially in children, hypoglycaemia (strong recommendation, moderate-quality evidence) [1]. NICE advises suspecting AI in the presence of unexplained hyperpigmentation or at least one persistent symptom without another explanation, including anorexia, postural dizziness, muscle weakness, hypoglycaemia, poor growth, hypotensive crisis and prolonged neonatal jaundice in children; in black or brown skin hyperpigmentation may not be evident, so it should be asked about and the buccal mucosa and scars examined [97]. AI should be considered in babies and children with DSD, such as ambiguous genitalia or bilateral cryptorchidism [97].

In FGD, the absence of salt wasting means that the picture does not look like Addison's disease: there is no hyperkalaemia or hypotensive crisis in the typical form and the presentation is hypoglycaemia, often ketotic and with seizures, triggered by an intercurrent illness [6]. The clues by age described in the British cohort are prolonged neonatal jaundice or hypoglycaemic seizures in glucocorticoid insufficiency, salt wasting in the first two months in boys with X-linked AHC, neonatal onset in MRAP, onset between 6 months and 4 years in NNT, onset in mid-childhood in triple A and ketotic hypoglycaemia in childhood in the partial forms of STAR and CYP11A1 [35]. The combination of seizures and hyperpigmentation should prompt investigation for AI, even in a child already being followed for epilepsy [65].

4.2. Emergency signs

Adrenal crisis manifests as vomiting, dehydration, hypotension or shock, hypoglycaemia and altered consciousness, and in the young child may be difficult to recognise [47]. In paediatric classic congenital adrenal hyperplasia, the median time between the first symptoms and the crisis was one day [1]. In any acutely ill patient with suspected severe AI or crisis, intravenous (IV) hydrocortisone at a stress dose is given immediately, before the results are known (strong recommendation) [1]. The family in section 10 shows the possible course when hypoglycaemia is not recognised: status epilepticus, cardiac arrest and a blood glucose of 5.4 mg/dL in a child in the second year of life, already hyperpigmented [62].

4.3. Newborn screening

There is no specific newborn screening for FGD. CAH screening by 17-OHP in dried blood spots detects accumulation of the precursor in 21-hydroxylase deficiency and does not detect CYP11A1 deficiency or FGD [11]. A newborn with FGD2 and normal CAH screening showed that this result does not exclude PAI [78]. In SPLIS, seven patients had abnormal TREC on newborn immunodeficiency screening, an indirect sign of the disease [46].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criterion for FGD

There are no formal diagnostic criteria for FGD published by a society. The criterion used in the Irish and British series is the combination of raised ACTH with low cortisol, normal renin and aldosterone and exclusion of the other causes of adrenal failure [34, 36]. The Endocrine Society notes that, in FGD and mild forms of CAH, mineralocorticoid production may be preserved, so normal renin and aldosterone do not exclude PAI [1]. Attribution to a gene requires biallelic pathogenic variants (or, in CYP11A1, careful demonstration of a dominant form); no biochemical test is gene-specific [4, 6].

5.2. Confirmation of primary adrenal insufficiency

The corticotropin stimulation test confirms PAI when conditions allow (strong recommendation, high-quality evidence) [1]. The standard IV dose, with sampling at 30 or 60 minutes, is 250 µg in adults and children aged 2 years or more, 125 µg in children under 2 years and 15 µg/kg in infants; a peak cortisol below 500 nmol/L (18 µg/dL), assay-dependent, indicates AI [1]. The sensitivity of the 250 µg test in PAI was 92% (95% CI 81–97%) in five studies; there are no studies of the 1 µg test in PAI, which is reserved for drug shortages [1]. The lower limit of normal for cortisol at 30 minutes ranges between 418 and 574 nmol/L (15.2–20.8 µg/dL) depending on the immunoassay, so the cut-off should be based on assay-specific normative data; oral oestrogens increase cortisol-binding globulin (CBG), and nephrotic syndrome, liver disease, the postoperative period and intensive care reduce CBG and albumin [1]. This last point matters in SPLIS, in which nephrotic syndrome lowers total cortisol.

The FDA label for Cortrosyn® (cosyntropin) indicates 0.25 mg IV or IM in adults and from 2 to 17 years and 0.125 mg from birth to 2 years, with baseline, 30 and 60 minute samples, regarding a stimulated cortisol below 18 µg/dL as suggestive of AI, and instructs that glucocorticoids and spironolactone be withheld on the day of the test and oestrogens 4–6 weeks before; the label does not provide for the guideline dose of 15 µg/kg in infants [98]. In Portugal, Synacthen Depot® 1 mg/mL (tetracosactide adsorbed on zinc phosphate) has an SmPC approved by INFARMED, with the 5-hour test (1 mg IM and cortisol at baseline and at 0.5, 1, 2, 3, 4 and 5 hours) reserved for inconclusive results of the 30-minute test with Synacthen® 0.25 mg/mL, or to assess the functional reserve of the cortex; it contains benzyl alcohol, is contraindicated in preterm infants and newborns and is not recommended below 3 years [99]. Tetracosactide diluted to 1 µg/mL in normal saline remains stable at 2–8 °C for up to 60 days [1].

When the test is not possible, a morning cortisol below 140 nmol/L (5 µg/dL) with raised ACTH serves as a preliminary test (weak recommendation, very low-quality evidence); morning cortisol values to exclude AI are controversial (from >285 to >480 nmol/L) and random cortisol cannot be used to exclude it [1]. NICE uses serum cortisol between 08:00 and 09:00 from 1 year of age, with modern immunoassays: below 150 nmol/L AI is probable and warrants urgent referral; between 150 and 300 nmol/L the result is uncertain and is repeated; above 300 nmol/L AI is very unlikely; below 1 year, cortisol is collected at any time and interpreted by the specialist [97]. Oral oestrogen should be stopped 6 weeks before measurement and, after an IM or intra-articular glucocorticoid injection, 4 weeks should elapse [97].

Plasma ACTH is always measured: with confirmed cortisol deficiency, an ACTH more than twice the upper reference limit is compatible with PAI (strong recommendation) [1]. A raised ACTH with normal cortisol may be the first sign of early PAI; an ACTH above 300 ng/L (66 pmol/L) produces maximal stimulation, and in some patients ACTH only exceeds the reference range without reaching double [1]. Renin and aldosterone are measured simultaneously to determine mineralocorticoid deficiency (strong recommendation) [1]. In a new paediatric presentation, renal function, cortisol, renin, aldosterone, ACTH in an EDTA tube, glucose, 17-OHP and the urinary steroid profile are collected before hydrocortisone, without delaying treatment [100].

The 2025 European review on paediatric PAI stresses that the classic threshold of 500 nmol/L (18 µg/dL) derives from older immunoassays with cross-reactivity with other steroids: with LC-MS/MS, thresholds of 422 nmol/L at 30 minutes and 485 nmol/L at 60 minutes of the standard test have been proposed, and with new-generation immunoassays thresholds of 386–414 nmol/L (14–15 µg/dL), depending on the assay; age-specific reference ranges are lacking, and the diagnosis should integrate clinical and biochemical findings rather than depend on a single value [67]. Salivary cortisol and cortisone reflect the free fraction and are non-invasive, but the lack of standardisation and of validated paediatric thresholds prevents routine use; the rise in renin may precede changes in electrolytes, ACTH and cortisol in the early stages [67]. In the same review, next-generation sequencing gives a definitive diagnosis in up to 70–80% of children with a suspected genetic cause, with the exome reserved for cases that remain unexplained [67].

5.3. Aetiological diagnosis

The guideline recommends determining the aetiology in all patients [1]. In the algorithm, adults are tested for anti-21-hydroxylase antibodies; children have basal 17-OHP (above 1000 ng/dL is diagnostic of 21-hydroxylase deficiency); antibody-negative men and preadolescent boys have very long-chain fatty acids (VLCFA) to exclude X-linked adrenoleukodystrophy (X-ALD); once these causes have been ruled out, adrenal computed tomography (CT) is performed; the clinical picture and family history may make steps redundant or point to specific genetic syndromes [1]. In children with autoimmune PAI, autoimmune polyendocrinopathy type 1 (APS-1) is considered, with anti-interferon ω and α antibodies, and about 30% of patients with positive anti-CYP21A2 antibodies progress to PAI within 5 years [1]. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows profiles of 15 or more steroids in a single analysis and broadens the identification of causes [1].

Raised renin with global steroid deficiency and low 17-OHP suggests CYP11A1 or STAR, and was the clue that corrected the diagnosis in the Scottish siblings referred as FGD [11, 95]. Adrenal size on imaging helps: enlarged, lipid-laden glands in classic STAR, small in CYP11A1 and in AHC; imaging may, however, not discriminate and non-classic STAR is biochemically indistinguishable from MC2R or MRAP FGD [3, 10]. Lymphocyte immunophenotyping by flow cytometry with NK subpopulations (reduced total NK, loss of CD56dim, relatively preserved CD56bright), the study of spontaneous chromosomal breaks and growth and head circumference charts point to MCM4 [8]. The Schirmer test documents alacrima and high-resolution oesophageal manometry establishes achalasia and its subtype by the Chicago classification, complemented by endoscopy and barium oesophagogram (dilated oesophagus with "bird's beak" narrowing) [92, 101]. Proteinuria, thyroid function, immunity and adrenal imaging (calcifications) point to SPLIS, which can be confirmed by sphingolipid measurement in a specialised laboratory [46]. The urinary steroid metabolome by gas chromatography-mass spectrometry (GC-MS) was normal in a presymptomatic NNT infant who already had raised ACTH, and the transhydrogenase activity assay is for research only [6, 62].

5.4. Genetic testing

Experts now recommend genetic investigation in all children with PAI after excluding the common CAH, metabolic and autoimmune causes, with next-generation sequencing (NGS) by a targeted panel of more than 20 genes or by exome as the most cost-effective approach [102]. In the United Kingdom, clinical panel testing has already been introduced; in resource-limited settings a more focused analysis may be justified [35]. The panel should include at least MC2R, MRAP, STAR, NNT, TXNRD2, MCM4, AAAS, CYP11A1, SGPL1, NR0B1, NR5A1, ABCD1, CDKN1C, SAMD9, POLE and the CAH genes, because the Korean case diagnosed at 18 years had undergone a targeted panel without NNT [35, 64]. The Turkish HaloPlex panel covered 160 known and candidate genes, with all coding exons and 100 base pairs of intronic flank [37]. In populations with a founder effect, targeted testing has a good yield: Sanger sequencing of the three recurrent variants of MC2R, CYP11A1 and MRAP would have diagnosed 22 of the 85 Turkish families (26%) [37].

These values are diagnostic yields in selected cohorts referred for research, not the clinical sensitivity of a panel [35]. In Tunisia, NGS increased the yield by 11% compared with the candidate gene approach [69]; in the United Kingdom, 47 patients (30.3%) remained without a diagnosis, 29 of them after NGS [35].

The limitations of the test should appear in the report and in counselling. Exon sequencing does not detect deep intronic variants, which may be a more frequent cause than previously thought [35]. Complete deletions of the MC2R locus and deletions of NNT exons 2–3 require copy number variant (CNV) analysis [37]. The phase of the variants has to be established by parental testing or by long-read sequencing, as in the Austrian triple A case and the Canadian CYP11A1 case [74, 92]. Reanalysis of previous sequencing data identified the diagnosis in CYP11A1 and NNT cases, and genome sequencing resolved a panel-negative case [64, 65, 74]. A negative result does not exclude a genetic cause.

The report should state the gene, the transcript with version (MANE Select), the nucleotide and protein HGVS description, zygosity, the classification according to the rules of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and the phase when there are two variants. VUS neither establish nor exclude the diagnosis and require segregation studies: MRAP p.(Lys30del) is likely pathogenic under the 2015 ACMG rules but a VUS according to the ClinGen variant interpretation group [78], NNT p.(Thr356Ile) was classified as a VUS [63] and, in IMAGe, a VUS in CDKN1C neither establishes nor excludes the diagnosis [56]. The proportion of variants detectable by a method also has to be distinguished from clinical sensitivity: in NR0B1, sequencing detects about 75% of variants and targeted deletion and duplication analysis about 25% [3].

5.5. Practical algorithm

5.6. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible in all monogenic forms of the class. In X-linked AHC, fetal sex is determined first and only a 46,XY fetus is tested [3]. In SPLIS, prenatal ultrasound may show hydrops, adrenal calcifications and increased nuchal translucency [46]. When the proband's molecular diagnosis has not been confirmed, storing DNA is recommended [3].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differentials

The decisive distinction in the newborn and infant is between FGD and the causes with salt wasting. 21-hydroxylase CAH is the most common cause of PAI in childhood, accounting for 85% of 803 Italian children and 113 of 172 French children with PAI, and is distinguished by raised 17-OHP [82, 96]. X-linked AHC is the most frequent genetic differential in a boy: in Turkey it explained 12 of 95 children and in the United Kingdom 7.7% of the research cohort, in addition to 51 boys diagnosed by clinical testing [35, 37]. Presentation is bimodal, in the first month or after 18 months, with salt wasting in all Turkish patients with NR0B1, and rarely boys have predominant cortisol insufficiency with normal salt balance, with mineralocorticoid deficiency appearing later [3, 37]. In boys with salt-wasting PAI, without a family history and without another cause, the yield of NR0B1 analysis is 20–40% according to GeneReviews and 50–70% in isolated cases according to the Oxford Desk Reference, a difference that reflects different reference populations [3, 106]. Normal or low 17-OHP in a child with salt wasting strongly suggests AHC, and creatine kinase should be measured because of the possibility of an Xp21 deletion [106].

The partial forms of CYP11A1 and STAR are the most frequent phenocopies of FGD. In the United Kingdom, CYP11A1 explained 12 of 155 cases and non-classic STAR forms 5 cases [35]. Three non-consanguineous Scottish siblings were followed for years with a clinical diagnosis of FGD; a 2002 linkage analysis suggested X-linked inheritance, and NR0B1 and ABCD1 were negative, until raised renin in the youngest sibling and NGS in 2016 identified c.940G>A p.(Glu314Lys) in compound heterozygosity with NM_000781.3:c.790_802del p.(Lys264LeufsTer5) [95]. Raised renin is therefore a sign against classic FGD, but does not exclude NNT, which has initial mineralocorticoid deficiency in 5 of 18 patients and in 14 of 18 over follow-up [29, 40]. In MCM4 deficiency, growth restriction may lead to an initial suspicion of Silver-Russell syndrome and chromosomal fragility to one of Fanconi anaemia, and it is hyperpigmentation and raised ACTH that point to PAI [31].

X-ALD should be excluded in all boys and men with PAI and negative antibodies, because the "Addison-only" form may precede neurological disease; two boys in the Turkish cohort with ABCD1 and one with AAAS had only an adrenal phenotype and were diagnosed only by genetic testing [1, 37]. MIRAGE shares adrenal insufficiency, achalasia and hypolacrimia with triple A, but is distinguished by cytopenias, infections, growth restriction, atypical genitalia and diarrhoea [81]. The alacrima, achalasia and intellectual disability syndrome due to GMPPA (AAMR) mimics triple A with normal adrenal function [23, 24]. In the original description, 13 patients from 9 families, mostly consanguineous, from Pakistan, Turkey, Palestine and Morocco, had alacrima, feeding difficulties due to achalasia and psychomotor delay from birth or the first years, with frequent hypotonia and, variably, gait abnormalities, spasticity, nasal speech, visual and hearing deficits, hypohidrosis, postural hypotension and anisocoria; none had signs of adrenal insufficiency and all were negative for AAAS, and GMPPA was then sequenced in 63 families with alacrima and achalasia without AAAS variants [24]. In a review of 26 patients (9 months to 47 years), all presented with gastrointestinal symptoms due to achalasia and all had alacrima and developmental delay; there was intellectual disability in the 22 with data, growth deficit in 11 of 12, hypotonia in 10 of 21, gait abnormalities in 7 of 17, hypohidrosis in 8 of 24, deafness in 6 of 17, postural hypotension in 5 of 17 and seizures in 2, and oral N-acetylglucosamine improved ocular symptoms in 3 patients, an uncontrolled report [24]. Patients' cells have increased GDP-mannose without changes in the N-glycosylation profiles of transferrin, immunoglobulin G and apolipoprotein C-III, so normal transferrin isoelectric focusing does not exclude the diagnosis; in the Gmppa-null mouse, a mannose-free diet corrected the myopathy but not the brain developmental abnormalities [24]. ACTH deficiency of pituitary origin is distinguished by low ACTH and the absence of hyperpigmentation [3]. Glycerol kinase deficiency, isolated or as part of the Xp21 deletion, is diagnosed by urinary glycerol; fasting tests, a ketogenic diet and exercise are dangerous and IV solutions with glycerol or lipids should be avoided [105]. SPLIS, Wolman disease and Smith-Lemli-Opitz syndrome are metabolic causes to consider when there are adrenal calcifications, hepatosplenomegaly, ichthyosis or malformations [77, 109, 110].

7. Treatments and Risk Management Strategies

7.1. General principles

The treatment of FGD and the entities of the class is lifelong glucocorticoid replacement, complemented by mineralocorticoid only when deficiency has been demonstrated, by prevention and treatment of adrenal crisis and by management of the extra-adrenal manifestations of each gene [1, 47]. There is no intervention trial specific to FGD1–5, MCM4 deficiency or triple A on ClinicalTrials.gov, and management is extrapolated from the guidelines for PAI in general (Endocrine Society 2016, NICE NG243 of 2024, the 2023 consensus of the British Society for Paediatric Endocrinology and Diabetes — BSPED — and the 2021 Endo-ERN statement) [1, 47, 97, 100, 112]. ACTH products, including injectable corticotropin and tetracosactide, have no therapeutic role, because ACTH resistance is the disease itself and endogenous levels are already raised; cosyntropin has FDA labelling only as a diagnostic agent [4, 98]. In Portugal, the Synacthen Depot® SmPC includes neurological, rheumatological, cutaneous, gastrointestinal and oncological therapeutic indications that do not apply to PAI [99].

The reference dose is that of the guideline; the label dose (European Medicines Agency — EMA — and INFARMED SmPCs, Food and Drug Administration — FDA — labels) is given for comparison, with the difference explained. All uses of hydrocortisone and fludrocortisone in genetic PAI fall within the labels' indication of "primary adrenocortical insufficiency", which is defined by indication and not by gene.

7.2. Glucocorticoid replacement

The Endocrine Society recommends glucocorticoid in all patients with confirmed PAI (strong recommendation, high-quality evidence) [1]. Daily cortisol production is 5–8 mg/m², which corresponds to 15–25 mg/day of oral hydrocortisone, tending towards the lower limit; the half-life of hydrocortisone is about 90 minutes, the last dose is taken 4–6 hours before bedtime and a typical adult regimen is 10 mg on waking, 5 mg at lunch and 5 mg in the late afternoon [1]. A morning dose adjusted to body surface area (5.5 mg/m²) or weight (0.12 mg/kg) gives more physiological curves than a fixed dose of 10 mg [1]. In a systematic review of 15 observational studies there was no difference in quality of life between ≥30 and <30 mg/day of hydrocortisone, and the evidence in favour of prolonged- or dual-release formulations is very low [1].

Paediatric formulations solved a practical problem: until recently the paediatric dose required crushing tablets (10 mg in Europe, 5 mg in the USA) or using compounded capsules, and up to 25% of compounded capsules fail the European Pharmacopoeia criteria for uniformity of mass or content [47]. Alkindi® (granules in capsules for opening of 0.5, 1, 2 and 5 mg) is given with the granules unchewed, not added to liquids, or within 5 minutes if mixed with soft food, and is not administered via nasogastric tube because of the risk of obstruction [116]. When switching from crushed or compounded tablets to Alkindi®, the total dose is maintained, but the previous imprecision may cause exposure to fall and precipitate a crisis; a missed dose is taken immediately and the next one at the usual time [116]. The Portuguese SmPC for Hidrocortisona Roussel® indicates, below 6 years, crushing the tablets and mixing them with food [114]. Khindivi® (oral solution 1 mg/mL) may be given via gastric tube, but is not approved for stress doses or below 5 years, because it contains polyethylene glycol 400, propylene glycol and glycerin, with a risk of hyperosmolality, metabolic acidosis, hypoglycaemia, hepatorenal injury and central nervous system toxicity in young children [118]. NICE advises against the subcutaneous (SC) pump and the IM or IV route for routine daily replacement [97].

Glucocorticoid monitoring is clinical (weight, postural blood pressure, energy, signs of excess) and the guideline recommends against hormonal monitoring: ACTH is usually above normal in treated children and guiding the dose by ACTH leads to over-replacement [1]. This point is specific to ACTH resistance: the tendency to try to suppress ACTH leads to glucocorticoid overtreatment, and the genetic diagnosis helps to avoid it [35]. Signs of excess are weight gain, insomnia and peripheral oedema; those of deficiency are nausea, anorexia, weight loss, lethargy and hyperpigmentation [1]. In CAH, doses above 20 mg/m²/day in infants and 15–17 mg/m²/day in adolescents are associated with loss of final height, and doses above 8 mg/m²/day may exceed physiological levels [1].

Some entities need doses above the guidelines. In the three Slovenian siblings with NNT, the mean hydrocortisone dose was 16.6 mg/m²/day in the two elder siblings and 13.0 mg/m²/day in the youngest (minimum 9.3, maximum 24.5), above the usual paediatric range of 7–12 mg/m²/day, which the authors interpret as very reduced endogenous production; another NNT patient cited started on 18 mg/m²/day and was maintained on 15 mg/m²/day [62]. In the Korean lipoid hyperplasia cohort (mostly classic), the dose was 21.7 mg/m²/day (IQR 14.9–26.5) at diagnosis and 17.3 mg/m²/day (13.9–22.7) at last follow-up, at a median of 11.6 years [84]. These doses are observational and do not constitute a recommendation; with residual endogenous production a lower dose may suffice [116].

Adverse effects of over-replacement include a cushingoid appearance, weight gain, arterial hypertension, diabetes, fragility fractures and, in children, growth deceleration; they are managed by reducing the dose to the minimum effective dose with clinical monitoring [1, 97]. Dexamethasone is not recommended (cushingoid effects and difficult titration) [1].

7.3. Mineralocorticoid and salt

Confirmed mineralocorticoid deficiency is treated with fludrocortisone and without salt restriction (strong recommendation, high-quality evidence) [1]. Fludrocortisone is not routine in typical FGD: several MC2R patients started mineralocorticoid before diagnosis and stopped it afterwards, maintaining salt and fluids in heat and during exertion [35]. It is required, or should be reassessed, in the subgroups with demonstrated deficiency: NNT (5 of 18 in France; 2 of 7 in Turkey), triple A (12.5% in the review; 16% in Morocco; 7 of 23 in Turkey), partial CYP11A1 (about half in the United Kingdom; 20 of 22 in the Turkish p.Arg451Trp series), non-classic STAR (most in the United Kingdom) and transient FGD2 [35, 37, 40, 44, 45, 71, 78, 87].

Monitoring is clinical (salt craving, postural hypotension, oedema) and by electrolytes, with renin at the upper limit of normal as a marker of an adequate dose [1]. In hot climates or with heavy sweating, temporary increases of 50–100% in the dose or more salt may be needed [1]. If hypertension develops on fludrocortisone, the dose is reduced; if blood pressure remains uncontrolled, an angiotensin II receptor antagonist or an angiotensin-converting enzyme inhibitor is started, followed by a dihydropyridine, while maintaining fludrocortisone, and diuretics are avoided; spironolactone and eplerenone are contraindicated [1]. As 40 mg of hydrocortisone is equivalent to about 100 µg of fludrocortisone in mineralocorticoid effect, mineralocorticoid is not needed with hydrocortisone above 50 mg/24 h [1]. Fludrocortisone is not adjusted on sick days or during a crisis and is restarted when the patient tolerates the oral route [100]. Overdose produces hypertension, oedema, weight gain and hypokalaemia, so potassium should be checked frequently [122]. Mineralocorticoid excess in the infant manifests as hypertension and suppressed renin, and blood pressure should be monitored in the first year, when mineralocorticoid sensitivity increases [1].

7.4. Sick days and stress doses

Education on dose adjustments during intercurrent illness, fever and stress is recommended for all patients, and the dose should be adjusted to the severity of the illness [1]. The guidelines differ in form:

The Alkindi® SmPC indicates doubling or tripling the total daily dose in situations of minor stress and switching to the parenteral route in severe situations, which coincides with the Endocrine Society [116]. The Plenadren® SmPC indicates, in mild intercurrent illness, taking the maintenance dose 2 or 3 times a day at intervals of 8 ± 2 hours, instead of increasing the morning dose, a regimen documented in more than 300 episodes in the trial programme [119]. The Hidrocortisona Generis® SmPC indicates increasing the dose 2 to 4 times under stress [115]. In the BSPED guidance, patients on background prednisolone preferably switch to sick-day hydrocortisone or, if impractical, to prednisolone 7.5 mg/m²/day in 2 doses; patients on Efmody® switch to immediate-release hydrocortisone in 4 doses or add immediate-release hydrocortisone up to a total of 30 mg/m²/day [100]. The Endocrine Society notes that 20 minutes of intense exercise did not require extra hydrocortisone in CAH and that 5–10 mg extra for prolonged training is under discussion, without a general recommendation [1].

7.5. Adrenal crisis

The frequency of crises in adult PAI was 6.6 per 100 patient-years in a retrospective series of 444 patients (gastrointestinal triggers 32.6%, other infections 24.3%) and 8.3 per 100 patient-years in a prospective study of 768 patient-years, with crisis mortality of 0.5 per 100 patient-years; in paediatric classic CAH (122 patients) it was 5.8 per 100 patient-years [1]. Endo-ERN estimates 5–10 crises per 100 patient-years [47]. In the Italian paediatric PAI cohort, the rate was 2.7 per 100 patient-years [82]. In the paediatric studies reviewed in 2025, the incidence of crises in PAI ranged between 3.4 and 10.9 per 100 person-years, with frequent infections and young age as risk factors, and the risk was higher in PAI than in secondary or tertiary AI [67]. Paediatric risk factors include young age at diagnosis, PAI, the need for mineralocorticoid and recurrent admissions; diarrhoea and vomiting may make the crisis refractory to oral doses [100].

The guideline recommends, when hydrocortisone is not available, using prednisolone, with dexamethasone the least preferred option, only when there is no alternative [1]. Life-threatening hyperkalaemia is treated with IV calcium gluconate, nebulised salbutamol, insulin with glucose, bicarbonate and resins [100]. Cardiac monitoring is recommended during a crisis [1]. BSPED and the Endocrine Society differ in the volume of the initial fluid bolus in children (10 versus 20 mL/kg) and in the maintenance hydrocortisone dose (by weight versus by body surface area) [1, 100].

The parenteral dose in the labels is broader and serves only for comparison. The FDA label for Solu-Cortef® (hydrocortisone sodium succinate, 100, 250, 500 mg and 1 g) indicates 100–500 mg IV or IM, repeatable every 2, 4 or 6 hours, and in paediatrics 0.56–8 mg/kg/day in 3 or 4 doses (20–240 mg/m²/day), with a risk of hypernatraemia after 48–72 hours; the label defines no maximum dose and allows, in acute life-threatening situations, doses above the usual ones [123]. The Portuguese SmPC for Solu-Cortef® 100 mg/2 mL indicates 100–500 mg or more, depending on severity, repeatable every 2, 4 or 6 hours, with the IV route preferred in emergencies and a paediatric dose never below 25 mg/day [124]; that for Hidrocortisona Generis® 100 mg powder for solution for injection gives the same paediatric minimum [125]. The guideline dose (100 mg followed by 200 mg/24 h in adults) lies within the label range.

7.6. Perioperative care and procedures

Cortisol secretion is about 75–100 mg/day in major surgery and about 50 mg/day in minor surgery, rarely above 200 mg in the first 24 hours, and critically ill patients have cortisol clearance reduced by more than 50% [1]. SC and IM hydrocortisone have similar pharmacokinetics [1]. For adults, NICE refers perioperative management to the tables of Woodcock and colleagues (Association of Anaesthetists, 2020), which are not among the sources consulted, and for those under 16 years refers to BSPED [97].

7.7. Education, identification and emergency kits

All patients should have a steroid emergency card and medical alert identification, and an emergency glucocorticoid injection kit with training (good practice) [1]. The action points are to identify the problem (updated card; bracelet or necklace "Adrenal insufficiency – needs steroids!"), to educate the patient, partner or parents in the two sick-day rules (double the oral dose with fever, illness requiring bed rest, need for antibiotics or before a minor procedure; inject 100 mg of hydrocortisone IM or IV in severe illness, trauma, persistent vomiting, fasting for a procedure or surgery), to provide a reserve supply of hydrocortisone and fludrocortisone and a kit with 100 mg vials of hydrocortisone sodium succinate, and to reinforce education at each visit [1]. Real competence is low: 46% of patients did not have sufficient competence in stress management, about one third of emergencies occurred away from home, only 12% of those who had a crisis self-injected and, among 60 caregivers of children with CAH in the USA, 70% had written instructions and half had injection training [1]. The English national incident reporting system (September 2019 to August 2022) identified 83 risk reports in children with AI, including glucocorticoid not given perioperatively and delayed or omitted doses [100].

NICE recommends giving 2 or 3 emergency kits to each patient, with premixed hydrocortisone sodium phosphate 100 mg/1 mL or hydrocortisone sodium succinate 100 mg powder with 5 or 10 mL of water for injections, written instructions with pictures, an emergency card, glucose gel below 16 years and an orange needle with a 1 mL syringe below 1 year [97]. BSPED adds kits for home, nursery or school and other residences, open access to the paediatric ward, registration with the ambulance service, a clinical alert in the record and review of doses using updated measurements at each visit [100]. Endo-ERN has harmonised a European emergency card for children and adults, in the national language and in English, recommends a reserve medication supply of at least 3 months with a sick-day pack and cites as European emergency injections Solu-Cortef®, Hydrocortisone 100-Rotexmedica®, Hydrocortisone Panpharma 100® and Actocortina 100 mg®; the SC route is an off-label alternative to IM in adults [47].

7.8. Entity-specific treatment

Triple A. AI is the potentially fatal and fully treatable component and is treated as in the other forms, with hydrocortisone in all patients and fludrocortisone in the subgroup with mineralocorticoid deficiency [9, 87, 93]. Achalasia follows the 2020 American College of Gastroenterology (ACG) guideline, written for adults and without a paediatric section or reference to Allgrove syndrome, so its application to triple A is an extrapolation [101]:

Drugs are less effective than definitive treatments: nifedipine 10–30 mg sublingually before meals or isosorbide dinitrate 5 mg sublingually before meals, adult doses; the sources give no paediatric doses for triple A [101]. Published experience in triple A includes POEM in 7 Chinese patients, with a fall in the Eckardt score from 5.3 to 0.8 and a median follow-up of 5.8 years without relevant complications [90], paediatric POEM in three cases [126], Heller myotomy with fundoplication in 4 of 12 Moroccan children with good results [87] and Heller myotomy with repeated dilations in an Austrian adult [92]. Alacrima is treated with artificial tears (ocular lubricants), without a dose defined in the sources [90]. The neuropathy and pyramidal signs have no specific treatment in the sources consulted.

MCM4 deficiency. Glucocorticoid replacement is lifelong; immunity is managed by early recognition and treatment of viral infections, especially herpesvirus infections, and growth and nutrition are monitored; no intervention corrects the replication defect and there is no ClinGen actionability assertion [8].

SPLIS. The GeneReviews treatment table proposes vitamin B6 (pyridoxine) 10 mg/kg/day divided into two doses, up to 200 mg/day, on the basis of the authors' experience and without a trial, with possibly greater efficacy in p.(Arg222Gln) homozygotes; excess pyridoxine is neurotoxic, with distal sensory and motor neuropathy overlapping that of the disease, so baseline and periodic nerve conduction studies are performed [46]. PAI is managed by paediatric endocrinology with glucocorticoid, mineralocorticoid when necessary and sodium, sick-day rules and emergency and perioperative management; hypothyroidism is treated with levothyroxine, micropenis and puberty with testosterone, and sperm banking is proposed [46]. Steroid-resistant nephrotic syndrome frequently progresses to kidney failure and transplantation, with difficult vascular anatomy in some patients [46]. A natural history study (UCSF, 28 patients, started in 2025) and an international registry (120 patients), both observational, are ongoing [127, 128].

Forms with gonadal involvement (NNT, STAR, CYP11A1, TXNRD2). In the partial forms of STAR and CYP11A1 there is a risk of sex steroid insufficiency and subfertility, and sperm cryopreservation should be considered [35]. In the p.Arg451Trp series, two patients required sex steroids for later hypergonadotrophic hypogonadism [45]. In TART, histological review with CD56 avoided interpreting the lesion as a neoplasm in a patient who underwent orchidectomy at 25 years [95]. Fertility preservation was discussed in a case of NNT with testicular involvement [6]. In 46,XX women with STAR, ovulation induction with clomifene and in vitro fertilisation resulted in deliveries [10].

Entities in the differential. In X-linked AHC, hypogonadotrophic hypogonadism is treated with testosterone at increasing doses from about 12 years, with gradual increases over 2–3 years up to adult doses, and treatment is lifelong; fertility was achieved in one man by testicular sperm extraction with intracytoplasmic injection [3]. In IMAGe, growth hormone deficiency is assessed and urological surgery, testosterone and orthopaedics are managed [56]. In MIRAGE, management includes transfusions, antibiotic prophylaxis, haematopoietic stem cell transplantation in severe neutropenia or myelodysplasia with monosomy 7, IV immunoglobulin, elemental nutrition and artificial tears [81].

Dehydroepiandrosterone. The Endocrine Society suggests a trial of dehydroepiandrosterone (DHEA) 25–50 mg as a single oral morning dose for 6 months in women with PAI and low libido, depressive symptoms or low energy despite optimised replacement, stopping it if there is no benefit, and monitoring by morning serum DHEAS before the dose (target in the middle of the normal range); the meta-analysis of controlled trials showed no substantial clinical benefit, but DHEA restores pubarche in adolescents [1]. DHEA has no marketing authorisation as a medicinal product for this indication in the sources consulted.

7.9. Agents to avoid and interactions

Hydrocortisone is metabolised by CYP3A4: inducers (phenytoin, carbamazepine, oxcarbazepine, rifampicin, rifabutin, barbiturates, efavirenz, nevirapine, St John's wort) require a dose increase and inhibitors (itraconazole, posaconazole, voriconazole, erythromycin, clarithromycin, ritonavir, grapefruit juice, liquorice) may require a reduction [120]. Levothyroxine, carbamazepine, mitotane and St John's wort increase cortisol clearance, and phenytoin increases the metabolism of fludrocortisone; liquorice and grapefruit juice should be avoided with fludrocortisone [1]. NICE advises increasing the dose with enzyme inducers such as antiretrovirals [97]. Spironolactone and eplerenone are contraindicated with fludrocortisone and diuretics should be avoided [1]. Dexamethasone and long-acting synthetic glucocorticoids are avoided in children [1]. In SPLIS, nephrotoxic drugs, renally excreted drugs in kidney failure, live vaccines, exposure to infectious agents and non-irradiated blood products are avoided [46]. In the glycerol kinase deficiency of the Xp21 deletion, IV solutions with glycerol or lipids, including some anaesthetics, are avoided [105]. Khindivi® should not be used below 5 years because of its excipients [118].

7.10. Pregnancy, lactation and transition

In pregnancy, the guideline recommends monitoring for signs of over- and under-replacement (weight gain, fatigue, postural hypotension or hypertension, hyperglycaemia) with at least one review per trimester, increasing hydrocortisone according to the course, especially in the third trimester, preferring hydrocortisone to cortisone acetate, prednisolone or prednisone (weak recommendation) and not using dexamethasone, which is not inactivated in the placenta (strong recommendation) [1]. Total cortisol rises 2–3-fold because of CBG and free cortisol rises from week 22; it is usual to increase hydrocortisone by 20–40% from the 24th week, the diagnostic cut-offs suggested in pregnancy are 700, 800 and 900 nmol/L (25, 29 and 32 µg/dL) in the three trimesters and renin is not useful for monitoring [1]. In the active phase of labour (dilatation >4 cm or contractions every 5 minutes in the last hour), hydrocortisone 100 mg IV is given followed by 200 mg/24 h, as for major surgery (strong recommendation), with rapid tapering to the previous dose after delivery [1]. NICE recommends preconception counselling, maintaining glucocorticoid and, in PAI, mineralocorticoid, a multidisciplinary team, an extra 20 mg of hydrocortisone immediately in fever, infection, trauma or brief vomiting, 100 mg IM immediately and admission in hyperemesis gravidarum, a sick-day dose for 48 hours after delivery and gradual reduction if the dose was increased in the third trimester [97]. The SmPCs for Alkindi® and Plenadren® indicate that replacement hydrocortisone may be used in pregnancy, because it is metabolised by placental 11β-hydroxysteroid dehydrogenase type 2 into inactive cortisone, and during breastfeeding, because replacement doses probably have no clinical impact on the child [116, 119]. The Inocort® SmPC allows replacement fludrocortisone in pregnancy and breastfeeding, with observation of the newborn for adrenal suppression if the mother received substantial doses [122]. In IMAGe, affected pregnant women have an increased risk of AI and of cephalopelvic disproportion [56].

Transition to adult services is a period of risk: NICE recommends more frequent appointments at diagnosis, during rapid growth, at puberty, during transition and with poor adherence, and refers to its transition guideline; between 16 and 18 years, young people in adult services follow the Society for Endocrinology guideline [97, 100]. In the French cohort of rare causes, poor adherence was the main cause of crises [96]. At the end of life glucocorticoid is maintained, with once-daily, SC or IM formulations [97].

7.11. Comparative regulatory status

The absence of a product from the ANVISA open data file, which does not state the pharmaceutical form, does not prove the absence of access in Brazil through exceptional importation or compounding [129].

7.12. Clinical trials

None of these studies specifically included patients with FGD. The Infacort® trial measures a pharmacokinetic endpoint and the Efmody®–Plenadren® trial compares morning exposures with formulations whose pharmacokinetics differ by design, which is not equivalent to clinical superiority; the CAH trial cannot be transposed to FGD, and indirect comparisons between trials are not valid. Clinically relevant outcomes (crises, mortality, growth, quality of life) were not primary endpoints. A ClinicalTrials.gov search for "familial glucocorticoid deficiency", "ACTH resistance", "triple A/Allgrove", "MC2R" and "NNT adrenal" found no intervention trials, which does not prove their absence from other registries [135]. The MC2R antagonists in development for CAH (atumelnant, phase 2, NCT05907291 and extension NCT06712823; OMS1620, phase 1 in volunteers, NCT07811089) [135] have the opposite mechanism to FGD1, which serves as a human model of loss of receptor function, and have no application in FGD.

7.13. Developments in the last 12 months (October 2025 to October 2026)

7.14. Divergences between guidelines

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

The Endocrine Society recommends genetic counselling in all PAI of monogenic cause [1]. FGD1–5, MCM4 deficiency, triple A, SPLIS and most CYP11A1 deficiencies are autosomal recessive: the parents of a patient are as a rule asymptomatic heterozygotes, as in the MC2R, NNT and TXNRD2 families in which segregation was studied [42, 49, 62]. In each pregnancy of a carrier couple, the risk of an affected child is 25%, that of an asymptomatic carrier child 50% and that of a non-carrier child 25%; an unaffected sibling of a patient has a two-thirds probability of being a carrier. The children of a patient are affected only if the other parent is a carrier, which is more likely in consanguineous unions and in populations with a founder variant. Consanguinity was present in 74% of Turkish families (81% in the recessive forms) [37]. In populations with a founder variant, the risk of the spouse being a carrier is known: 1 in 25 in the Irish Traveller community (1 in 13 in the 4 to 15 years age group) [34], about 2% for TXNRD2 p.(Tyr447Ter) in British people of Pakistani origin [42] and 6.67% for SGPL1 p.(Tyr416Cys) in the Dariusleut Hutterite colony [46].

In CYP11A1 deficiency there are two patterns. The recessive form (homozygosity or compound heterozygosity, such as homozygous p.Arg451Trp or p.Glu314Lys with a severe variant) follows the risks above [27, 35]. The dominant form has been described in a patient with a de novo variant and in a family with three heterozygous carriers of p.(Val79Ile) in two generations; in this situation, the transmission risk is 50% per pregnancy, but the sources do not estimate penetrance, and before counselling on the basis of a single variant a second intronic or structural variant on the other allele should be excluded [26, 75]. The dominant allelic disorder of NNT (sebaceous hyperplasia due to gain of function) confers no risk of FGD on offspring and heterozygous loss-of-function carriers do not develop this hyperplasia [80].

Among the entities in the differential, X-linked AHC has different risks: the father of an affected boy is neither affected nor a carrier; the mother is an obligate carrier if there is more than one affected individual, with possible germline mosaicism (<1%); if the mother is a carrier, each son has a 50% risk of being affected and each daughter 50% of being a carrier; the daughters of an affected man (conceived by medically assisted reproduction) are all carriers and no son inherits the variant; in the Xp21 deletion, most mothers are carriers and maternal chromosomal microarray is performed [3]. Heterozygous females are rarely affected, owing to skewed X inactivation [3]. IMAGe syndrome is dominant with imprinting: only maternal transmission causes disease, the children of an affected woman have a 50% risk and those of a male carrier 50% of being unaffected carriers; patients' mothers are often unaffected because they inherited the variant from their father [56]. MIRAGE usually results from a de novo gain-of-function variant in SAMD9, with adaptive somatic loss of the mutated allele [81].

8.2. Cascade testing and presymptomatic diagnosis

Cascade testing of siblings is the family intervention with the greatest direct benefit. In the Slovenian NNT family, the third sibling was diagnosed at 4.5 months, asymptomatic, by familial genetic testing, and only the ACTH test confirmed the insufficiency; the authors advise genetic testing of siblings in the first months of life and assessment of adrenal function, especially if hyperpigmentation appears [62]. Presymptomatic diagnosis was also achieved in families with NR0B1, MC2R and TXNRD2 [35]; in the TXNRD2 kindred, the proband's children were screened from birth and diagnosed between 0.1 and 6.9 years [42]. Biochemistry alone is not enough to rule out the disease in a sibling: the Irish children with FGD had normal initial cortisol and ACTH, a homozygous TXNRD2 child had normal biochemistry at 7.4 years and the urinary metabolome was normal in the presymptomatic NNT sibling [34, 42, 62]. An asymptomatic homozygous child in the TXNRD2 kindred remained under clinical and biochemical surveillance before any replacement [42]. In SPLIS, clarifying the genetic status of asymptomatic siblings is recommended [46]. In X-linked AHC, a male newborn at risk without known genetic status has biochemistry in the first days (electrolytes and basal cortisol may initially be normal and change; basal ACTH is useful) and asymptomatic maternal male relatives undergo molecular testing, because about 40% manifest only in childhood or later [3]. In IMAGe, newborn siblings undergo molecular testing or, without a known variant, electrolytes, ACTH and skeletal assessment [56].

In minors, testing a sibling at risk of disease is justified by the direct benefit, which is avoiding the first crisis [62]. Determining carrier status in unaffected siblings has no clinical consequence in childhood, and the sources consulted make no specific recommendation on the timing of such testing.

8.3. Prenatal diagnosis, preimplantation testing and other options

With the familial variants identified, couples at risk may opt for prenatal diagnosis, PGT or other reproductive options (gamete donation, adoption). In X-linked AHC, prenatal diagnosis or PGT begins with determination of fetal sex and only 46,XY fetuses are tested [3]. In SPLIS, prenatal ultrasound may detect hydrops, adrenal calcifications and increased nuchal translucency, with fetal deaths described [46]. The occurrence of multiple stillbirths in three Turkish families with severe MC2R variants suggests that the most severe forms may cause fetal loss, which should be discussed in counselling [37]. When it has not been possible to confirm the molecular diagnosis in a proband, storing DNA is recommended [3].

8.4. Content of counselling

Counselling covers the inheritance pattern of the familial form, the risk for siblings and offspring, intrafamilial heterogeneity (relatives with the same NNT genotype may differ) [40], the progressive nature of the loss of adrenal function in the redox forms [62], the risk of crisis and preventive measures for homozygous siblings not yet on replacement, and fertility in the forms with gonadal involvement (sperm cryopreservation in the partial forms of STAR and CYP11A1; azoospermia in some NNT patients; testicular failure in SPLIS) [35, 40, 46]. In 46,XX women with STAR, fertility may be achieved spontaneously or with ovulation induction in the non-classic form and by in vitro fertilisation in the classic form [10].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

No source consulted provides a validated population prevalence of FGD outside Ireland, and the available numbers measure different things:

The Irish prevalence is a minimum and should not be presented as a European prevalence; the authors themselves note that the true prevalence is unknown [34]. The 9 Irish Traveller patients (5 female) were negative for MC2R and MRAP, and diagnosis was delayed because the initial assessment showed cortisol of 422–575 nmol/L and ACTH <34 ng/L; only later biochemistry assumed the typical pattern of FGD type 1 or 2 [19, 34]. The proportions by gene in the research cohorts (section 5.4) are yields in referred populations and not population frequencies [35].

9.2. Geography, ancestry and founder effect

The distribution of genes varies with the population. In the USA, the sources consulted contain no population-based FGD series; the available North American data refer to the education of caregivers of children with CAH and to medicine labels [1]. In Europe, the British cohort (155 patients) had MC2R as the main cause, with a p.Ser74Ile founder effect in Irish and Scottish families, CYP11A1 p.Glu314Lys in British families (also described in France, Spain, the USA, Canada and Australia) and no case of MCM4 or SGPL1 [35]. In Ireland, the Irish Traveller community concentrates the MCM4 variant NM_182746.3:c.71-2A>G (historical designation c.71-1insG) [34, 53, 68]. In Turkey, with high consanguinity, there are three founder variants with regional distribution (MC2R c.560del, CYP11A1 p.Arg451Trp in the east and MRAP c.106+1del in the west) [37]. In France, a cohort of 59 children with rare causes of PAI showed that monogenic causes accounted for 64% and that the phenotype varied with the genotype [96]; in the French NNT cohort, p.Arg129Ter was recurrent in Algerian patients [40]. In Slovenia, the NNT family was not consanguineous [62]. In Austria and Greece, patients with compound heterozygous triple A have been described, and AAAS p.Ser263Pro has a Slavic origin in 69.4% of carriers (25 of 36) [43, 91, 92]. In Italy, FGD was rare (0.6%) in a cohort dominated by 21-hydroxylase deficiency (85%) [82].

Outside Europe, Tunisia has 45 patients with triple A due to the Maghrebi AAAS variant c.1331+1G>A among 74 patients with congenital PAI [69]; the same variant was found in the homozygous state in Colombia, where 30 patients cluster in the "Paisa" region with a possible founder effect [70]. TXNRD2 p.Tyr447Ter has an allele frequency of 1.04% in British people of Pakistani origin [42] and NNT p.Arg71Ter has been described in children of Pakistani ancestry [35]. In Korea, classic lipoid hyperplasia is almost always due to p.Gln258Ter (27 of 29 homozygous patients) [84]. In China, the series of 111 patients with non-21-hydroxylase PAI had NR0B1 (39) and STAR (33) as the main causes and only 3 patients with MC2R or MRAP [137]. SPLIS has a higher estimated frequency in East Asian, Finnish, Turkish and Iranian ancestry and a Hutterite founder variant [46]. In the Palestinian families, NNT p.Gly200Ser rests on a shared haplotype and there was one carrier among 200 controls of the same origin [29]; in triple A, the haplotypes of the North African families point to an ancient founder effect, which the authors placed in an Arab origin predating the migrations to North Africa, and linkage to 12q13 was also demonstrated in Puerto Rican families [32].

In the British cohort there was an excess of boys (102 of 155; 65.8%; p <0.001), which persisted after excluding NR0B1 and was greater among the undiagnosed, which led the authors to propose an as yet unknown X-linked phenomenon or a sex difference in neonatal adrenal function; in Turkey there was no difference between sexes [35]. The observation echoes that of Franks and Nance, who in 1970 had already noted an excess of boys in the published families and suggested an X-linked form [19].

9.3. Portugal and Brazil

In the sources consulted, the only Portuguese patient identified is a woman with triple A syndrome and progressive bulbospinal amyotrophy at 33 years, homozygous for an AAAS nonsense variant (section 3.7), described by Goizet and colleagues in 2002 [32]; this allele (OMIM 605378.0002) corresponds to NM_015665.6:c.1432C>T p.(Arg478Ter), the same variant that was among the most frequent in Turkey [60, 71]; there are no data on Portuguese patients with FGD1–5 or with the other entities of the class. From Brazil there is a commentary by Almeida (São Paulo) on the British study, which recommends genetic investigation by NGS in all children with PAI after excluding the common causes and which presents no data on Brazilian patients [102]. The lack of data in these sources does not demonstrate the absence of patients or publications. As regards access to medicines, Portugal has oral hydrocortisone, injectable hydrocortisone and fludrocortisone on the market, and the paediatric and modified-release formulations have centralised authorisation without identified marketing; in Brazil, the ANVISA open data file shows fludrocortisone and hydrocortisone sodium succinate with active registration and shows no identifiable oral hydrocortisone (section 7.11) [114, 122, 129].

9.4. Special populations

In people with black or brown skin, hyperpigmentation may go unnoticed and should be looked for in the buccal mucosa and scars [97]. Infants have lower mineralocorticoid sensitivity and need supplementary salt and appointments every 3–4 months [1]. Critically ill patients have reduced cortisol clearance [1]. In pregnancy, requirements increase in the third trimester and diagnostic cut-offs change (section 7.10) [1]. Physically active young people may need higher doses of fludrocortisone, and hot climates increase salt and mineralocorticoid requirements [1, 97]. In countries where hydrocortisone is not available, such as Italy and Norway according to Endo-ERN, cortisone acetate is used [47].

9.5. Reference networks and patient associations

Endo-ERN, with thematic group 1 (adrenal), is the European reference network for these diseases and maintains a list of adrenal guidelines and consensus statements (https://endo-ern.eu/specific-expertise/adrenal/) [47]. The European emergency card and stress instructions are available at https://adrenals.eu/emergency-card/ and https://adrenals.eu/stress-instructions/ [47]. The patient associations cited by BSPED are the Addison's Disease Self-Help Group (https://www.addisonsdisease.org.uk/), Living with CAH (https://www.livingwithcah.com/) and the Pituitary Foundation (https://www.pituitary.org.uk/) [100]; in the USA, the National Adrenal Diseases Foundation (https://www.nadf.us/) [3]. The Orphanet page for FGD (https://www.orpha.net/en/disease/detail/361) and that for triple A (https://www.orpha.net/en/disease/detail/869) list additional resources [13, 22]. The sources consulted identify no associations specific to FGD or triple A in Portugal or Brazil.

10. Illustrative Clinical Case

Krasovec and colleagues described three Slovenian siblings with FGD4, followed up to the ages of 21.6, 20.2 and 4.2 years [62]. The parents reported no consanguinity, but both families came from the same region of central Slovenia; a paternal uncle of the father died at 1 year of an unidentified cause, which the authors suggest may have been an Addisonian crisis without being able to confirm it; the pedigree is in Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC9140979/figure/genes-13-00717-f001/) [62]. All three were born with normal weight and length, with no signs of AI in the neonatal period and no hypoglycaemia, and all had neonatal indirect hyperbilirubinaemia treated with phototherapy [62].

Patient 1, already markedly hyperpigmented, arrived at the emergency department in the second year of life in status epilepticus, which yielded only to drug treatment and was followed by cardiac arrest; after resuscitation, investigation showed pneumonia, blood glucose of 5.4 mg/dL (reference 65–110), cortisol of 6 nmol/L (140–690) and ACTH of 678 pmol/L (<10.2), and the diagnosis of PAI was made at 1.4 years [62]. Patient 2, with increasing pigmentation of the scrotum, knees and neck, presented at 1.1 years febrile and prostrate, with cortisol of 53 nmol/L and ACTH of 905 pmol/L [62]. These presentations led to testing of the third sibling, diagnosed at 4.5 months in the asymptomatic phase: basal cortisol was normal (276 nmol/L) with raised ACTH (54.4 pmol/L), and the ACTH test showed a peak cortisol below 500 nmol/L [62]. At 6 months, without treatment, the urinary steroid metabolome by GC-MS showed normal excretion of cortisol, corticosterone and DHEA metabolites, despite the already raised ACTH, which the authors interpret as gradual loss of steroidogenic cells; deficiencies of STAR, P450scc, 3β-hydroxysteroid dehydrogenase, 21-, 11- and 17-hydroxylase and Smith-Lemli-Opitz syndrome were excluded [62].

All three were homozygous for the variant NM_182977.3:c.1575dup p.(Pro526ThrfsTer65) in exon 11 of NNT, which creates a premature stop codon, and the parents were healthy heterozygotes [17, 62]. They started oral hydrocortisone at diagnosis, with a marked fall in ACTH; the mean dose was 16.6 mg/m²/day in patients 1 and 2 and 13.0 mg/m²/day in patient 3, between 9.3 and 24.5 mg/m²/day, above the usual paediatric range, and the course of the dose and of morning ACTH is shown in Figure 4 (https://pmc.ncbi.nlm.nih.gov/articles/PMC9140979/figure/genes-13-00717-f004/) [62]. The deficiency was isolated glucocorticoid deficiency, without the need for mineralocorticoid. In patient 2, ACTH was optimal between 7 and 15 years and then rose, with several values above 500 pmol/L despite dose increases and, according to the patient, without lapses in adherence; the authors discuss the pituitary hyperplasia or autonomous ACTH-secreting tissue described after decades of replacement and propose surveillance by MRI [62].

Hyperpigmentation disappeared in patient 1 and persisted in patient 2, mainly on the elbows (Figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC9140979/figure/genes-13-00717-f002/, consulted) [62]. Stature followed genetic potential, but the body mass index of patient 1 fell from the 25th centile to below the 5th centile after 15 years (Figure 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC9140979/figure/genes-13-00717-f003/) [62]. Patient 2 had an inguinal testis corrected at 8.9 years; puberty began at 11–12 years, but testicular volume progressed slowly (15 mL at 17.5 years in patient 2; 10–12 mL at 17.9 years in patient 1) and at the last visit both had 15 mL, testosterone of 25–30 nmol/L, inhibin B of 200 ng/L and normal basal and post-GnRH LH and FSH; both had treated varicocele [62]. Densitometry at 13.6 and 14.4 years showed osteopenia; at the last visit Z-scores were −2.4 (whole body) and −2.5 (L1–L4) in patient 1 and −1.8 and −1.0 in patient 2, who had had a forearm fracture from high-energy trauma at 12 years; with low 25-hydroxyvitamin D (33 and 35 nmol/L), they started vitamin D and calcium [62]. The authors attribute the low bone mineral density to hydrocortisone, low body mass index or oxidative stress, without having excluded other genetic causes, and the association with NNT is not established [62]. Echocardiography was normal in all three (left ventricular ejection fraction of 69–70%, without hypertrabeculation) [62].

The case illustrates three points. Hyperpigmentation preceded the crisis by months in the two elder siblings and severe hypoglycaemia was the mode of presentation. Genetic testing of the youngest sibling prevented a crisis and showed that biochemistry may be almost normal in the initial phase of a progressive adrenal loss. Hydrocortisone doses were above those recommended by the guidelines (about 8 mg/m²/day in the Endocrine Society guideline; 8–10 mg/m²/day in NICE), which is an observation of this report and not a recommendation; ACTH was used here as a follow-up parameter, whereas the guideline recommends adjusting the dose by the clinical picture and not by ACTH [1, 97].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis of treated FGD depends mainly on the prevention of crises and on the sequelae of hypoglycaemia before diagnosis. Deaths in NNT families were due to adrenal crisis, usually triggered by intercurrent infection [6], and untreated hypoglycaemic seizures may leave permanent neurological injury, such as cerebral palsy in an undiagnosed sibling in an MRAP family [38]. In adult PAI, crisis mortality is about 0.5 per 100 patient-years and one in every 200 patients dies of a crisis, even with a known diagnosis [1, 100]. PAI is associated with increased overall and cardiovascular mortality [102]. Adults with PAI have about twice the risk of death; in non-CAH forms with onset in childhood, a recent study showed final height within the normal range but below parental target height [67]. In the French cohort of 59 children with rare causes of PAI, mortality was 10% (6 of 59) over a median of 7.6 years, and 45% had an adrenal crisis, mainly due to poor adherence [96]; in the Italian cohort of 803 children, there were 3 deaths from the underlying disease and adult height was −0.70 ± 1.20 standard deviations (70 patients) [82]. In the Korean lipoid hyperplasia cohort, adult height was normal (Z 0.1 in 8 patients) [84]. In 5 of 155 British children the AI resolved without a genetic cause, in one boy 13 years after onset [35].

Prognosis varies by entity. In triple A, AI is treatable and the progressive neurological involvement determines adult morbidity [9, 89]. In NNT, gonadal (TART, Leydig cell adenoma, azoospermia), thyroid and cardiac (hypertrophic cardiomyopathy) complications appear during follow-up [40]. In partial CYP11A1, gonadal function may fail after puberty and TART may be mistaken for neoplasia [45, 95]. In MCM4 deficiency, viral infections and the theoretical neoplastic risk shape the prognosis [8, 53]. In SPLIS, survival depends on genotype and kidney transplantation (28% without transplantation with biallelic loss of function; 77% with p.Arg222Gln; 66.7% with p.Tyr416Cys) [46]. In MIRAGE, the median age at death was 3 years, with about 60% of deaths due to infection, and the oldest living patient was 20 years old [81]. In X-linked AHC, death from crisis may occur in known patients with inadequate replacement during stress, and a sudden rise in ACTH revealed a pituitary adenoma in one patient [3].

11.2. Surveillance

The Endocrine Society recommends review by an endocrinologist at least annually in adults and children and at least every 3–4 months in infants, with annual assessment for signs of over- and under-replacement and reinforcement of education at each visit [1]. NICE recommends, below 16 years, an appointment at least every 6 months and a face-to-face appointment at least annually, more frequently at diagnosis, during rapid growth, at puberty, during transition and with poor adherence [97]. The screening for associated autoimmunity recommended in PAI of unexplained origin does not apply when the genetic cause has been established [1].

The sources do not define surveillance intervals for the extra-adrenal manifestations of NNT, TXNRD2 and triple A; the authors recommend monitoring mineralocorticoids, gonads, heart and thyroid throughout follow-up, not just once [40]. The surveillance model for X-linked AHC (electrolytes, aldosterone and renin every 4 months in the first two years and then annually, when mineralocorticoids are initially sufficient) is an example of surveillance of residual function, but has not been validated in FGD [3]. The guideline recommends against hormonal monitoring of glucocorticoid, and routine cortisol day curves are not indicated; serum or salivary cortisol curves are useful only when malabsorption is suspected [1, 97].

12. Summary and Final Considerations

Familial glucocorticoid deficiency is a class of autosomal recessive primary adrenal insufficiencies in which cortisol failure, with markedly raised ACTH, dominates the picture and the renin-aldosterone axis usually remains functional. The genes of the class are grouped by mechanism: ACTH resistance due to a defect of the receptor (MC2R, FGD1) or of its trafficking (MRAP, FGD2); deficient cholesterol transport or cleavage with residual activity (non-classic STAR, FGD3, and partial CYP11A1); oxidative injury of the zona fasciculata (NNT, FGD4, and TXNRD2, FGD5); replicative stress (MCM4); nuclear pore dysfunction (AAAS, triple A); and sphingolipid metabolism (SGPL1). CYP11A1 also has rare dominant forms, and NNT has a dominant cutaneous allelic disorder due to gain of function.

The typical presentation is hypoglycaemia with seizures, hyperpigmentation and prolonged neonatal jaundice in the newborn or early childhood, without salt wasting, which steers the diagnosis away from Addison's disease and delays recognition. The clues by gene are neonatal onset in MRAP, tall stature in MC2R, early hyperpigmentation and gonadal, thyroid and cardiac lesions in NNT, growth restriction with NK cell deficiency in MCM4, alacrima from birth and neuropathy in triple A, raised renin with typical male genitalia or hypospadias in CYP11A1, and steroid-resistant nephrotic syndrome in SPLIS. Initial biochemistry may be normal in an affected sibling and normal renin does not exclude PAI.

The diagnosis is confirmed by the corticotropin test and by ACTH, and the aetiology is established, after CAH, autoimmunity and X-ALD have been excluded, by a multigene PAI panel with copy number analysis, or by exome or genome, with yields of 66.5% to 86% in selected paediatric cohorts. A panel that omits genes of the class, deep intronic variants and the absence of phase studies are causes of falsely negative results.

Hydrocortisone replacement follows the guideline doses (about 8–10 mg/m²/day in 3–4 doses in children and 15–25 mg/day in adults), without guiding the dose by ACTH, which remains raised in ACTH resistance. Some patients with NNT and with lipoid hyperplasia received higher doses in the published series. Fludrocortisone is reserved for demonstrated mineralocorticoid deficiency, which should be sought throughout follow-up in NNT, MRAP, triple A, STAR and CYP11A1. Sick-day education, the emergency card and the injectable hydrocortisone kit are the main measures for reducing mortality. The paediatric granule formulations and the extension of modified-release hydrocortisone to AI in the EU in 2026 changed the replacement options, but no trial has specifically studied FGD. Cascade testing of siblings allows diagnosis before the first crisis, and long-term follow-up includes the gonads, thyroid, heart, bone, nervous system and kidney according to the gene.

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