X-Linked Congenital Adrenal Hypoplasia (NR0B1) and Xp21 Contiguous Gene Deletion Syndrome

Orphanet class of adrenal hypoplasia congenita (ORPHA:595337): X-linked hypoplasia due to NR0B1 (DAX-1), Xp21 contiguous deletion (NR0B1, GK, ± DMD, ± IL1RAPL1), isolated glycerol kinase deficiency, Xp21 duplication of the DSS locus and class differentials (NR5A1/SF-1, IMAGe, IMAGe-I, MIRAGE and autosomal recessive forms)

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

Adrenal hypoplasia congenita (AHC) designates a group of disorders in which the adrenal cortex fails to develop or to be maintained, with primary adrenal insufficiency (PAI) usually beginning in the neonatal period or in childhood. The acronym AHC is used throughout this article, as GeneReviews recommends, to avoid confusion with congenital adrenal hyperplasia, which shares the English acronym “CAH” [1]. The principal entity is X-linked AHC due to variants in NR0B1 (a gene historically designated DAX1), which combines PAI with hypogonadotropic hypogonadism (HH). The remaining entities are grouped because they share the Xp21 locus (contiguous deletion, glycerol kinase deficiency and duplication of the dosage-sensitive sex reversal locus, DSS) or because they constitute the class differentials with adrenal hypoplasia [1–4]. OMIM stands for the Online Mendelian Inheritance in Man catalogue; the OMIM entries cited were read in the catalogue itself [5–7].

1. Introduction

1.1. Founding description and historical development

The first description attributed to AHC is that of Sikl, in 1948, of a newborn with intense skin hyperpigmentation, “coal black” in colour, sparing the palms and soles, who died at 33 days of life of Addison disease due to congenital hypoplasia of the adrenal glands [1, 38]. In the following decades, the observation of families with several affected boys in the maternal line led to the recognition of an X-linked form. In the late 1980s and early 1990s, reports focused on boys with Xp21 deletions that combined adrenal insufficiency with glycerol kinase deficiency and Duchenne muscular dystrophy, and mapping of these deletions allowed the locus order Xpter–AHC–GKD–DMD–centromere to be deduced [1, 39].

1.2. Molecular identification

In 1994, two groups simultaneously published the cloning of the gene in Nature. Zanaria and colleagues isolated the DAX-1 gene, deleted or mutated in patients with X-linked AHC, and showed that it encodes an atypical member of the nuclear receptor superfamily, lacking the classic deoxyribonucleic acid (DNA)-binding domain, which acts as a negative regulator of transcription [40]. Muscatelli and colleagues found the gene deleted in 14 patients and carrying point variants in the coding region in 12 unrelated individuals; all patients older than 14 years with a point variant had HH, which showed that the same gene causes both the adrenal insufficiency and the hypogonadism [39]. The name DAX-1 derives from “DSS-AHC critical region on the X chromosome, gene 1”, because the gene lies in the overlap between the AHC critical region (200–500 kb) and the 160 kb region whose duplication causes dosage-sensitive sex reversal (DSS) in 46,XY individuals, described by Bardoni and colleagues in the same year [39, 41]. NR0B1 is now the standard gene name, and DAX1 (sometimes Ahch) is the historical designation [1]. More than 200 patients with single-nucleotide variants and deletions of NR0B1 had been published by 2018, and a Brazilian series from 2026 reports more than 250 pathogenic variants recorded in the Human Gene Mutation Database (HGMD), half of them deletions [1, 42].

1.3. Expansion of the class

Steroidogenic factor 1 (SF-1), encoded by NR5A1, was linked to human disease in 1999, in a 46,XY individual with complete sex reversal and adrenal insufficiency carrying the historical heterozygous variant G35E; in 2002 a recessive form was described, due to homozygosity for R92Q [43, 44]. Vilain and colleagues described in 1999 the IMAGe association (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) in three boys without DAX1 or SF1 variants [45]. The association became a syndrome in 2012, when Arboleda and colleagues identified gain-of-function variants in the imprinted gene CDKN1C, active only when inherited from the mother [46, 47]. In 2016, Narumi and colleagues defined MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) due to gain-of-function variants in SAMD9 [48]. In 2018, Logan and colleagues described an IMAGe-like recessive form with immunodeficiency due to biallelic POLE variants (IMAGe-I) [49].

1.4. Nomenclature and scope definitions

GeneReviews discourages the expression “congenital adrenal hypoplasia”, because its English acronym “CAH” coincides with that of congenital adrenal hyperplasia, and prefers “adrenal hypoplasia congenita” (AHC); the former designation “complex glycerol kinase deficiency” now corresponds to the Xp21 contiguous gene deletion syndrome [1]. In this article, X-linked AHC designates disease due to a hemizygous pathogenic variant of NR0B1 or to a deletion that includes NR0B1; Xp21 deletion syndrome designates non-recurrent deletions that include NR0B1 and at least GK, with or without DMD (proximal extension) and IL1RAPL1 (distal extension); isolated glycerol kinase deficiency designates intragenic GK variants without adrenal involvement; and DSS duplication designates the gain in NR0B1 dosage that causes 46,XY gonadal dysgenesis, an allelic dosage form [1, 24, 28]. Orphanet groups these entities, together with IMAGe, MIRAGE and the autosomal recessive forms, in the clinical group ORPHA:595337, and also links NR0B1 to complete and partial 46,XY gonadal dysgenesis and to 46,XX testicular DSD [2, 8]. The article follows the class rule: it describes the common syndrome, the classifications, all types and genes in a table (section 6), and examines the Xp21 entities in depth. The differential diagnosis includes congenital adrenal hyperplasia, familial glucocorticoid deficiency and ACTH resistance, X-linked adrenoleukodystrophy, dystrophinopathy, congenital HH, congenital combined pituitary hormone deficiency, differences of sex development and 46,XY gonadal dysgenesis, including NR5A1 and the DSS duplication, genetic hypoglycaemia, and the Silver-Russell and Beckwith-Wiedemann syndromes, which are allelic to CDKN1C.

2. Molecular Genetics and Pathophysiology

2.1. The NR0B1 gene and the DAX-1 protein

NR0B1 lies at Xp21.2 and has two exons; in the NM_000475.4 sequence used by GeneReviews, the reading frame runs from the ATG (nucleotide 1) to the TAA codon (nucleotide 1410), with an intron of about 3 kb between nucleotides 1167 and 1168, and encodes a protein of 470 amino acids (NP_000466.2) [1]. The current MANE Select transcript is NM_000475.5, with the same c. numbering for the variants tested in VariantValidator; variants in this article are written in that version [9]. The protein is an orphan nuclear receptor: the carboxy-terminal region resembles the ligand-binding domain of nuclear receptors, and the amino-terminal region has repeated motifs instead of the zinc-finger DNA-binding domain. Crystallographic studies have shown that DAX-1 binds directly to NR5A2 (LRH-1), in a complex with two DAX-1 molecules [1]. The gene is expressed during development and after birth in the adrenal cortex, hypothalamus, pituitary, testes and ovaries, and in embryonic stem cells [1, 50]. Each of the three complete amino-terminal repeats contains LxxLL motifs for interaction with nuclear receptors, and the carboxy-terminal region contains a transcriptional silencing domain and an AF-2 domain [6]. An alternative exon located between exons 1 and 2 gives rise to an isoform (DAX1-α or DAX1A) of 400–401 amino acids, identical to DAX-1 in the first 389 amino acids but lacking the carboxy-terminal repression domain; in vitro, this isoform attenuates the repression exerted by DAX-1 on SF-1-mediated transactivation [6]. In the pubertal and adult human testis, the protein is located mainly in the nuclei of Sertoli cells, with expression increasing during testicular development, and its expression is reduced in testes with maturation arrest or Sertoli cell-only syndrome [6].

2.2. Adrenal mechanism

Most studies describe DAX-1 as a negative regulator of nuclear receptor pathways, including SF-1-mediated transactivation; other studies show transcriptional activation effects [1]. A 2026 review presents DAX-1 as a component of dynamic transcriptional networks with SF-1, SOX9 and other nuclear receptors, with emerging roles in ribonucleic acid (RNA)-associated regulation and a dosage-sensitive influence on gonadal fate [51]. In the adrenal gland, loss of function prevents the transition from the fetal zone to the definitive (permanent) zone of the cortex, which explains the combined glucocorticoid and mineralocorticoid deficiency [33, 50]. In functional studies, DAX-1 binds to hairpin DNA structures in the STAR promoter and represses its transcription, with a silencing activity that depends on the cooperation of two domains in helices H3 and H12; part of the protein associates with polyribosomes and polyadenylated RNA, through the amino-terminal repeats and the ligand-binding-like domain [6]. One hypothesis proposes that DAX-1 acts as a repressor that controls the pace of differentiation of cortical stem cells: without it, premature differentiation, without prior expansion, would lead to transient hyperactivity followed by hypoplasia through depletion of the cell reservoir. A mouse model with deletion of exon 2 of Nr0b1 develops adrenal failure with ageing, which is consistent with this hypothesis [1]. Transient hyperactivity provides a possible explanation for the neonatal macrophallus and the ACTH-dependent precocious puberty described in some boys [1, 52].

2.3. Gonadal and pituitary mechanism

The HH of X-linked AHC has a mixed hypothalamic and pituitary origin. Habiby and colleagues studied two families with LH sampling every 10 minutes for 24 hours and pulsatile gonadotropin-releasing hormone (GnRH) administration (25 ng/kg every 2 hours for 7 days): one patient did not respond and the other responded only to the first pulse, without the priming effect seen in Kallmann syndrome, which demonstrated a combined defect of GnRH secretion and gonadotropic response [53]. There is also a primary testicular defect: exogenous gonadotropins rarely induce spermatogenesis, testicular biopsy shows maturation arrest and hypospermatogenesis, and a man with normal puberty and an intact hypothalamic-pituitary-gonadal axis had progressive oligospermia [50, 54–56]. In 2026, a Brazilian man with normal puberty, normal testosterone and azoospermia illustrated the gonadotropin- and androgen-independent Sertoli cell dysfunction proposed by animal models [57]. In sex determination, NR0B1 lies in the DSS locus, a 160 kb region whose duplication causes sex reversal in 46,XY individuals, and the current hypothesis is that of an SRY antagonist, with a dosage-sensitive influence on the SRY–SOX9 axis; deletion of the locus in 46,XY boys does not prevent testicular differentiation, which shows that the locus is not required for testicular development but is sensitive to excess dosage [1, 41, 51].

The designation “anti-testis gene” arose from sex reversal due to duplication, but mouse models show that DAX-1 also participates in testis formation. In the Nr0b1-deleted mouse, the XY gonad develops normally until day 12.5 post coitum; from day 13.5 onwards, the testis cords become disorganised and incomplete, with fewer peritubular myoid cells (with reduced proliferation), a discontinuous basal lamina and Leydig cells confined to the coelomic surface, and in the adult the rete testis is obstructed by Sertoli cells, the seminiferous tubules dilate and the germ cells degenerate [58]. Crossing these mice onto other genetic backgrounds disturbed testicular development [59, 60]. In the C57BL/6J strain, XY mice lacking DAX-1 have complete gonadal sex reversal: the gonads begin to develop as ovaries and the pre-Sertoli cells do not upregulate Sox9, even though Sry is expressed at the right time and level; in the DBA/2J and hybrid strains testes form, the reversal behaves as a complex trait that includes the Tda1 gene on chromosome 4, and overexpression of Sry corrects testicular development [61]. The variability depends on the strain-specific abundance of Sry transcripts, and some phenotypically female XY C57BL/6J mice lacking DAX-1 had live offspring [62]. These data underpin the model of a “window” of DAX-1 activity outside which, through deficiency or excess, the testis does not form; in human AHC the testes form, but the disorganisation of the cords and the HH that gonadotropins or androgens do not fully correct are consistent with a pro-testis role [63]. In excess dosage, transgenic XY mice overexpressing Dax1 have lower Sox9 expression in the fetal testis and, when they are also heterozygous for Sox9 (a situation in which the testis forms normally), develop ovotestes; the ovarian portion expresses FOXL2 and loses SOX9, anti-Müllerian hormone (AMH) and CYP17A1, although it retains SRY and SF-1 [64]. DAX-1 reduces activation of TES, the testis-specific enhancer of Sox9, because it decreases SF-1 binding to this element and antagonises activation mediated by SF-1, SF-1/SRY and SF-1/SOX9, which constitutes the probable mechanism of dosage-sensitive sex reversal [64]. The 2026 review by Bardoni and Lalli re-examines the anti-testis hypothesis in the light of these genetic, developmental, molecular and biochemical data [51].

2.4. Spectrum of NR0B1 variants

The combined data of Lin and colleagues (2006) indicate that about 75% of boys with X-linked AHC have a variant detectable by sequencing and about 25% a deletion of NR0B1; in about one third of the latter, the deletion extends to neighbouring genes [1, 65]. Inactivating variants (deletions, nonsense and frameshift) give rise to an absent or truncated protein; missense variants cluster in key regions of the ligand-binding-like domain and alter conformation, repressor function or nuclear localisation [1, 60, 66]. In the Brazilian series of 12 families, large and small deletions accounted for almost half of the cases, and no hotspot was identified [42]. In a 1998 compilation of 48 families and 42 variants, 23 were frameshift, 12 nonsense, 6 missense and one a single-codon deletion; all amino acid substitutions lay in the carboxy-terminal half, in the conserved hydrophobic core of the ligand-binding-like domain, and one family had gonadal mosaicism [5, 6]. AHC mutant proteins relocate from the nucleus to the cytoplasm even with the amino-terminal nuclear localisation signal intact, and several missense variants produce a misfolded protein; cytoplasmic retention accompanies loss of repressor function [6]. The following table brings together the variants cited in the article, normalised in VariantValidator (GRCh38, NC_000023.11), with the published nomenclature where it differs.

2.5. Genotype-phenotype correlations and modifiers

There is no clear correlation between the type or location of the variant and the phenotype, with two exceptions: missense variants in the ligand-binding-like domain (p.Tyr380Asp, p.Ile439Ser) and those close to the repression helix (p.Ser259Pro, p.Pro279Leu) are associated with late onset and partial loss of function; and very amino-terminal nonsense variants (stop codons at positions 37 or 39) are also associated with late onset, because translation reinitiates at the methionine of codon 83 and produces a truncated protein with partially preserved function [1, 71]. Intrafamilial variability is the rule: in a Japanese family, four hemizygous carriers of the same variant had a crisis at 16 days, a crisis at 3 years, purely biochemical insufficiency at 4 years and diagnosis at 14 years through pigmentation and family history; in the Korean family with c.94_113del, two boys had a neonatal crisis with HH and two had late-onset PAI with normal puberty [69, 72]. The same c.1292del variant presented in the 1st month in a Brazilian boy and in adolescence in a boy followed in Coimbra [42, 67]. GeneReviews notes that, among siblings, the younger tends to be diagnosed earlier owing to greater clinical suspicion, which introduces a bias into comparisons of age at onset [1]. The p.Trp105Cys variant, located in the amino-terminal domain and associated with a form with predominant hypoaldosteronism, causes only a mild loss of repression and activation functions in vitro, was found in three asymptomatic male relatives and is classified in OMIM as a variant of uncertain significance; an association with isolated mineralocorticoid deficiency should not, therefore, be based on it [5, 6]. In one family, the maternal grandfather of two affected boys was hemizygous for a nonsense variant and had no apparent disease, which the authors interpreted as non-penetrance [6]. Two brothers with p.Leu381His illustrate variability within the same genotype: the elder presented in the 1st year of life, and the younger, asymptomatic and without hyperpigmentation at 8 months, had normal basal steroids but reduced adrenal reserve on dynamic testing [6, 73]. A man with a complex rearrangement that removed the whole of exon 2 had PAI at 6 weeks, transient recovery of adrenal function for a few months in infancy and, later, HH of pituitary origin [5, 6].

2.6. The Xp21 region and contiguous gene deletion

The gene order, from telomere to centromere, is IL1RAPL1, NR0B1, GK and DMD [1, 39, 74]. Deletions extending proximally include GK and then the 3′ end of DMD, or the whole gene; those extending distally (telomeric to NR0B1) include IL1RAPL1, whose loss is associated with X-linked intellectual disability (XLID21, OMIM #300143) and sometimes with autism spectrum disorder [1, 74–76]. The cognitive spectrum of XLID21 ranges from moderate intellectual disability to autism without intellectual disability; males are as a rule the most affected, and some female carriers have mild deficits, which have also been observed in carriers of Xp21 deletions that included the region telomeric to NR0B1 [12, 76]. Loss of the 3′ terminal exons of DMD causes Duchenne dystrophy and can escape screening directed at the hotspots of exons 3–8 and 44–60 [32, 77]. Other genes close to DMD at Xp21.1 that may form part of larger contiguous deletions are XK (McLeod syndrome), CYBB (X-linked chronic granulomatous disease), RPGR (retinitis pigmentosa) and OTC (ornithine transcarbamylase deficiency) [29]. Xp21 deletions are not recurrent: within a family, affected members as a rule share the same deletion and a similar phenotype, but some families have NR0B1, GK and DMD deleted and others only NR0B1 and GK [1]. The Japanese series of Gau and colleagues described a complex duplication–deletion–duplication rearrangement, and family 1 of the Brazilian series a deletion–insertion–inversion–deletion rearrangement, which shows that not all deletions are simple events [30, 42]. An Xp21 deletion may also spare NR0B1: a Portuguese boy with a deletion of about 6.08 Mb that includes the whole of DMD and the terminal exons of GK has dystrophinopathy and glycerol kinase deficiency with normal adrenal function [78].

2.7. Glycerol kinase

Glycerol kinase phosphorylates glycerol to glycerol-3-phosphate, an essential step for the use of glycerol as a gluconeogenic precursor and for the re-esterification of free fatty acids [31]. The GK gene spans more than 50 kb at Xp21.2, has 21 exons and is expressed in several tissues, with the highest expression in the liver; the other members of the gene family (at 1q41, Xq23 and two loci on chromosome 4) are pseudogenes or processed genes expressed in the testis [10]. Fibroblast activity in patients with complete deficiency is below 1–5% of the reference [31]. In a study with infusion of ¹³C₃-labelled glycerol, the affected men of an American family with GK c.373_374del did not convert glycerol into glucose or triglycerides, a conversion preserved in the female carrier [79]. There is no apparent genotype-phenotype correlation among the numerous GK alterations [31]. Walker and colleagues showed that the same absence of activity can be silent or associated with psychomotor delay, seizures and bone dysplasia, even among brothers with the same exon 17 deletion, and attributed the variation to ascertainment bias, metabolic stress or modifiers [80]. In a study of missense variants, enzyme activity in cell lines was similar in symptomatic and asymptomatic patients and the variants of both groups lay close to the active-site cleft, which led to glycerol kinase deficiency being considered a complex trait modulated by independent genetic factors [10]. The Gk knockout mouse dies at 3–4 days with hyperglycerolaemia, raised free fatty acids and autonomous glucocorticoid synthesis, and heterozygous females are normal [10].

2.8. Xp21 duplication and NR0B1 dosage

Gain of an active copy of NR0B1 in 46,XY individuals causes gonadal dysgenesis (46,XY sex reversal type 2, OMIM #300018) [1, 15, 41]. The genes included in the duplications described are MAGEB, NR0B1, CXorf21, GK and part of MAP3K7IP3; NR0B1 is presumed responsible without definitive proof [28]. Barbaro and colleagues described two 46,XY sisters with an interstitial Xp21.2 duplication containing DAX1 and, later, multigenerational transmission through fertile 46,XX carriers [81, 82]. A systematic review of 47 patients showed large duplications in 61.7% and submicroscopic duplications in 38.3%, maternal inheritance in 63.3% and a relationship between size and presentation, which was earlier and more syndromic with large duplications [83]. A 7.79 Mb duplication with 30 genes, including NR0B1 and DMD, caused gonadal dysgenesis, growth delay, hypotonia and raised muscle and liver enzymes in a 46,XY infant [84]. A 257 kb submicroscopic deletion whose distal breakpoint lay 11.3 kb upstream of NR0B1, without including the gene, caused gonadal dysgenesis without adrenal insufficiency in a 21-year-old 46,XY woman with primary amenorrhoea; the carrier mother had a history of ovarian cysts, and the authors proposed increased NR0B1 expression through a position effect [15]. In the mouse, additional copies of Dax1 delay testicular development and only cause complete sex reversal with weak Sry alleles, which supports the action of DAX-1 as an SRY antagonist [6, 15].

The study of three-dimensional chromatin architecture proposes a common mechanism for Xp21.2 rearrangements. In a German study with genome sequencing and chromosome conformation capture (Hi-C), NR0B1 lies in a topologically associating domain (TAD) with IL1RAPL1 and MAGEB1-4, followed by a second TAD with TASL (CXorf21), GK and TAB3 [85]. A 46,XY adolescent with primary amenorrhoea, a uterus, dysgerminoma on one side and gonadoblastoma with focal transition to dysgerminoma on the other had a complex rearrangement upstream of NR0B1, without gain of the gene itself: a 447 kb duplication with TASL, GK and the 3′ part of TAB3, inserted in inverted orientation next to NR0B1, a 389 kb duplication with MAGEB1-4 and part of IL1RAPL1, and two small deletions; a second 46,XY child, with female genitalia, a small uterus, muscular hypotonia and gonadoblastoma, had a 1.24 Mb triplication with MAGEB1-4, NR0B1, TASL, GK, TAB3 and part of IL1RAPL1, and the mother carried a tandem duplication of the same segment [85]. The authors propose that deletions, duplications or inversions of the locus cause partial or complete gonadal dysgenesis by disrupting the boundary of the TAD neighbouring NR0B1, with formation of a new domain (neo-TAD), ectopic capture of enhancers (enhancer hijacking) and ectopic expression of NR0B1 [85]. In Campinas (Brazil), a 46,XY child with atypical genitalia (external masculinisation score of 4), an absent left gonad and a dysgenetic right testis, diagnosed with partial gonadal dysgenesis, had a 297 kb tandem duplication upstream of NR0B1, with TASL, GK and part of TAB3, inherited from the mother; this was the first description of a duplication upstream of NR0B1, without the gene, associated with 46,XY partial gonadal dysgenesis [86]. In practice, a copy-number gain at Xp21.2 that does not include NR0B1 does not exclude the DSS mechanism, and the orientation and insertion site of the duplicated segments can only be defined by genome sequencing [85, 86].

2.9. NR5A1 (SF-1): two inheritance patterns

DAX-1 represses transactivation mediated by SF-1, a nuclear receptor with which it shares its tissues of expression (adrenal, gonads, hypothalamus and pituitary), which provides the mechanistic basis for the phenotypic proximity of the two disorders [1, 60]. Two inheritance patterns are documented: dominant, through haploinsufficiency or a dominant effect, as with the historical heterozygous variant G35E in the P box of the DNA-binding domain, which caused complete 46,XY sex reversal and adrenal insufficiency; and recessive, as with the R92Q variant in the A box, with partial loss of DNA binding, which caused PAI only in the homozygous state, with normal heterozygous parents and sister [43, 44]. The designations G35E and R92Q are historical protein nomenclature: R92Q corresponds to NM_004959.5:c.275G>A p.(Arg92Gln), confirmed in VariantValidator, and G35E (p.Gly35Glu) remains as the published designation, without DNA-level mapping [9, 44]. In practice, heterozygous NR5A1 variants account for 10–15% of non-syndromic 46,XY DSD, with sex-limited autosomal dominant inheritance, and PAI is a rare finding [28, 87]. A 2025 case report described isolated normosmic HH and short stature in a 16-year-old boy homozygous for an NR5A1 variant [88].

The gene lies at 9q33.3, has seven exons, the first of which is non-coding, and encodes a 461-amino-acid protein with two zinc-finger DNA-binding motifs, an FTZ-F1 box (the A box, an accessory DNA-binding region), a hinge region, a ligand-binding domain and a C-terminal AF2 transactivation domain [7]. OMIM links five phenotypes of dominant inheritance to the gene in its table, distributed across four entries: 46,XY sex reversal type 3 (#612965), adrenal insufficiency (NR5A1-related PAI) and premature ovarian insufficiency 7, which share the same entry (#612964), 46,XX sex reversal type 4, of testicular or ovotesticular type (#617480), and spermatogenic failure 8 (#613957) [7, 19, 89, 90]. The table of entry #612964 classifies PAI as dominant, whereas the text of the same entry attributes it to homozygosity and also describes a heterozygous case; this inconsistency reflects the dual inheritance already documented and should not be read as proof of a single pattern [19]. The rarity of PAI in this gene was measured in a series of 117 children and adults with PAI of unknown cause (CAH, adrenoleukodystrophy and autoimmunity excluded), in which NR5A1 variants causing PAI appeared in only two individuals, both 46,XY with gonadal dysgenesis; by contrast, heterozygous variants were found in 4 of 30 46,XY individuals with DSD in a British and international series and in 5 of 27 (18.5%) German 46,XY individuals with severe undervirilisation without PAI [7, 20]. The gonad is thus more sensitive to SF-1 dosage than the adrenal cortex: complete loss-of-function variants in a single allele, such as the premature stop p.Cys16Ter or a single-nucleotide deletion that shifts the frame from codon 6, caused 46,XY gonadal dysgenesis with normal adrenal function, and an 8 bp deletion with a dominant-negative effect in vitro also spared the adrenal gland [7]. As for the G35E variant, the original study detected no dominant-negative effect on a generic reporter, but a later study with the anti-Müllerian hormone promoter showed that the mutant blocks the synergy between normal SF-1 and GATA4; the two observations coexist because they depend on the promoter and cofactor tested [7]. The heterozygous p.Arg255Leu variant in the hinge region was described in a 46,XX girl with PAI at 14 months and normal ovaries on magnetic resonance imaging, with no published post-pubertal follow-up of ovarian function [19]. The same position 92 of the A box illustrates the variability: R92Q (NM_004959.5:c.275G>A p.(Arg92Gln)) caused PAI in the homozygous state in a 46,XY infant with complete reversal and in a 46,XX girl, but, in the heterozygous state inherited from an unaffected father, was found in a 46,XX person with bilateral ovotestes; R92W (NM_004959.5:c.274C>T p.(Arg92Trp)), which is recurrent, causes variable testicular development in 46,XX individuals from several families, with healthy female carriers indicating incomplete penetrance, and in one of these families caused partial testicular dysgenesis in a 46,XY brother [7]. A 0.232 Mb microdeletion at 9q33.3 including NR5A1 and four further genes, which arose de novo in a woman with premature ovarian insufficiency, was transmitted to a 46,XY son with partial gonadal dysgenesis; MLPA screening of 67 additional individuals with 46,XY DSD, proximal hypospadias or premature ovarian insufficiency found no other copy-number variations [19, 20]. In the mouse, absence of Ftzf1 (Nr5a1) causes adrenal and gonadal agenesis, female internal genitalia in both sexes and death by day 8 of life from adrenal insufficiency; heterozygotes maintain almost normal basal adrenal function through cellular hypertrophy and increased StAR expression, but reveal a deficit under stress [7, 20]. By extrapolation from the animal model, without clinical confirmation, a human carrier of a heterozygous NR5A1 variant may have reduced adrenal reserve only under stress; the sources consulted do not convert this hypothesis into a screening recommendation [7].

2.10. CDKN1C, POLE and SAMD9

CDKN1C (11p15.4) encodes p57KIP2, an inhibitor of cyclin-dependent kinases in G1 phase, with an N-terminal kinase-binding domain, a central PAPA domain of proline-alanine repeats and a C-terminal domain that binds PCNA (proliferating cell nuclear antigen); the maternal allele is preferentially expressed [3]. IMAGe variants are missense variants in an eight-amino-acid region of the PCNA domain; they disturb the PCNA binding required for ubiquitin-mediated degradation, make the protein more stable and block entry into S phase (gain of function); there are no causal deletions or duplications, as expected of a gain of function [3, 46]. The five variants of the original description clustered within a six-residue interval close to the PCNA-binding domain, and their targeted expression in Drosophila restricted eye and wing growth, which supported the gain-of-function mechanism; the locus had been mapped through a 17.2 Mb region identical by descent shared by seven affected members of the Argentinian family (LOD 5.4), without contiguous gene deletion or duplication [21]. Loss-of-function variants of the same gene cause Beckwith-Wiedemann syndrome, and some variants at residue 279 (NM_000076.2 nomenclature) cause Silver-Russell syndrome without adrenal insufficiency [3, 91]. GeneReviews uses NM_000076.2, which is not the MANE transcript; MANE numbering (NM_001122630.2) differs by 33 nucleotides and 11 amino acids [9].

POLE encodes the catalytic subunit of polymerase ε. In IMAGe-I, the 15 patients from 12 families described all had the common intronic variant NM_006231.4:c.1686+32C>G, which alters splicing, in trans with a loss-of-function variant [9, 49]. SAMD9 (7q21) is a single-exon gene with mild antiproliferative activity; MIRAGE variants are gain-of-function missense variants that exaggerate this activity and restrict cell growth [4, 48]. The recurrent variants in GeneReviews, in NM_017654.4 (MANE), are c.1376G>A p.(Arg459Gln), c.2920G>A p.(Glu974Lys), c.2944C>T p.(Arg982Cys) and c.3878G>A p.(Arg1293Gln) [4, 9]. In a registry of 243 published and 62 unpublished patients with SAMD9 or SAMD9L variants, more than 90% had germline gain-of-function missense variants, and at least two thirds had somatic genetic rescue: transient or progressive monosomy 7, compensatory somatic variants or uniparental disomy 7q [93]. Biallelic loss-of-function variants of SAMD9 cause a non-overlapping disorder, normophosphataemic familial tumoral calcinosis [4].

3. Clinical Spectrum and Manifestations by System

3.1. X-linked AHC: adrenal insufficiency

Presentation has a bimodal distribution: about 60% of affected boys have acute PAI in infancy, at a mean age of 3 weeks, and about 40% in childhood, between 1 and 9 years [1, 94–96]. Rarely, PAI appears in young adulthood [1]. The typical presentation in the infant is a salt-wasting crisis with vomiting, feeding difficulty, dehydration and shock; there may be hypoglycaemia, often with seizures, and some patients present first with isolated mineralocorticoid deficiency. In older children, the crisis is triggered by intercurrent illness or other stress [1]. Without glucocorticoids and mineralocorticoids, PAI is rapidly lethal through hyperkalaemia, acidosis, hypoglycaemia and shock, and, when it is not recognised, may leave neurological sequelae and developmental delay [1]. Hyperpigmentation, of variable degree, results from increased pituitary production of pro-opiomelanocortin and regresses with treatment [1]. The disease may begin with salt wasting alone and cortisol deficiency develop over time; rarely, cortisol deficiency predominates and salt balance is normal [1]. In an Israeli series of 12 patients from 5 families (1984–2007), 10 had neonatal PAI, aldosterone deficiency usually preceded cortisol deficiency, cortisol in the first weeks ranged from very low to high (up to 1776 nmol/L), and the initial diagnosis was wrong in 4 [97]. An 18-day-old newborn presented with severe hyponatraemia, hyperkalaemia and hypochloraemia, renin above the measurable limit, low aldosterone and normal cortisol, was first treated as primary hypoaldosteronism and only later developed low cortisol with raised ACTH [98]. In a five-generation Greenlandic pedigree, 11 boys died of adrenal insufficiency in the first 3 weeks of life; in the three treated boys who survived, the adrenal glands could not be identified on computed tomography, and the two who reached puberty had HH. The p.Asn440Ile variant was later identified in the affected boys, and testing of 33 at-risk female relatives identified 10 carriers and excluded 23 [5, 6]. In a Hispanic boy, hyperpigmentation was intense from birth and regressed over the first 6 months of treatment, whereas it usually develops gradually over months or years [5].

3.2. Late-onset form and presentation in adulthood

PAI with onset in young adulthood is explained by residual glucocorticoid and mineralocorticoid activity and may be limited to compensated insufficiency (raised ACTH) or progress to clinical insufficiency [1, 71, 100]. By 2017 only eight patients or families with adult presentation had been published [55]. Kyriakakis and colleagues described two British men: one with PAI at 19 years and HH at 38, with a brother with PAI at a similar age; another with PAI at 30 years and, at 37, HH and azoospermia that did not respond to gonadotropins, with maturation arrest and hypospermatogenesis on biopsy [55]. Tabarin and colleagues described a man with apparently isolated PAI at 28 years, partial pubertal development, undiagnosed incomplete HH and marked oligospermia that gonadotropins did not correct [54]. The late form may present through the reproductive phenotype (infertility) before PAI, and Guclu and colleagues reported sudden death in a young man with undiagnosed AHC in the context of puberty and stress [1, 100, 101]. In Portugal, a 13-year-old boy followed in Coimbra, with a previous diagnosis of “CAH”, reached adolescence prepubertal, with short stature and without crises, and had the c.1292del variant, previously described only in early-onset disease (section 10) [67].

3.3. Reproductive axis

HH typically manifests as delayed puberty (onset after 14 years) or as pubertal arrest: some boys enter puberty and progress to Tanner stage 3, or a testicular volume of 6–8 mL, and then stop. Without testosterone, they are unlikely to achieve complete secondary sexual characteristics [1]. The “minipuberty” of infancy is normal, which indicates that loss of axis function occurs after infancy [1]. Cryptorchidism has been described but is not characteristic [1]. Macrophallus at birth and precocious puberty in childhood are increasingly reported: Domenice and colleagues described ACTH-dependent precocious puberty of testicular origin; in the Israeli series, 5 of the 12 boys had penile and testicular enlargement in childhood; and a boy with central precocious puberty and normal adrenal function had a frameshift variant [52, 97, 102]. In the Chinese series, of the 13 patients older than 14 years, 3 had spontaneous puberty and 10 delayed puberty due to HH [99]. In the classic form, azoospermia is the rule despite exogenous gonadotropins or pulsatile GnRH; some men have oligospermia with progressive decline of spermatogenesis, and a man with normal puberty and an intact axis had deteriorating oligospermia [1, 56, 103]. Normal puberty with normal testosterone and azoospermia, described in Belo Horizonte, shows that the testicular defect can exist without HH [57]. Older records show that dehydroepiandrosterone sulfate for 1 year did not induce puberty in a 19-year-old and that low-dose pulsatile GnRH did not induce it in an 18-year-old patient either [5]. In two British families, the p.Tyr399Ter variant was associated with loss of the Leydig cell response to human chorionic gonadotropin (hCG), and p.Leu297Pro preserved this response [6].

3.4. Other manifestations

One patient with tall stature and renal ectopia, and two patients with progressive high-frequency sensorineural hearing loss from 14 years of age, without known NR0B1 status, have been described; the absence of further cases makes it unlikely that deafness is an associated feature [1]. A sudden rise in ACTH on treatment revealed a pituitary corticotroph adenoma in one patient [1, 104]. In family 12 of the Brazilian series, severe hypoglycaemia with seizures from 2 years of age, psychomotor delay and alacrima suggested Allgrove syndrome, but AAAS had no variants and the diagnosis was an NR0B1 c.970dup variant [42].

3.5. Heterozygous women

Very occasionally, heterozygous women have PAI or HH, possibly owing to skewed X inactivation; one heterozygote had extreme pubertal delay [1, 103]. In one family, a woman homozygous for an NR0B1 variant had isolated HH [105]. In that family, the authors attributed the homozygosity to gene conversion, and the maternal grandfather of the affected boys was hemizygous without apparent disease [6]. A woman with an Xp21 deletion had mild PAI and dystrophinopathy owing to extremely skewed inactivation, with preferential expression of the abnormal allele [106]. Two girls with a deletion including DMD, GK, NR0B1 and IL1RAPL1 had developmental delay and myopathy without adrenal dysfunction [107]. In the 2026 Japanese series, the 2-year-old sister of the index case had mild delay, a waddling gait, Gowers sign and raised CK, and the mother had raised CK, both with the same deletion [30]. In two families with Xp21 deletion, Duchenne dystrophy, glycerol kinase deficiency and AHC in the boys, there were female carriers with intellectual disability, one of them with a cytogenetically visible deletion distal to the OTC and RPGR genes [76].

3.6. Xp21 deletion syndrome

The phenotype depends on the extent of the deletion. To the AHC findings are added glycerol kinase deficiency (metabolic acidosis, hypoglycaemia, metabolic crises on fasting), dystrophinopathy when DMD is included, and developmental delay, seizures and strabismus [1]. In the early descriptions, two brothers aged 2 and 5 years had raised urinary glycerol, growth delay, intellectual disability, non-paralytic esotropia, spasticity, myopathy and osteoporosis with pathological fractures; the younger died at 30 months on the first day of a febrile illness, and autopsy showed small adrenal glands [13]. Darras and Francke found, in all patients with myopathy, deletions spanning the 3′ end of DMD, with severity and progression of the myopathy proportional to the extent of the deletion, and no DMD deletion in patients without myopathy [13]. Agenesis of the corpus callosum has also been described in a 10-year-old boy with a deletion of at least 3 Mb and, with a larger deletion extending to Xp11.2, death at 36 hours of a newborn with AHC, glyceroluria and hepatic ornithine transcarbamylase deficiency, with hypoglycaemia, hyperammonaemia and orotic aciduria [13]. A 2000 review counted about 100 patients from 78 families with complex glycerol kinase deficiency [14]. In Saudubray, complex glycerol kinase deficiency appears in infants; the first and most severe symptoms are those of adrenal hypoplasia, the symptoms of glycerol kinase deficiency may be masked by the mineralocorticoid deficiency, dystrophinopathy appears in childhood and is always symptomatic, and intellectual disability is frequent [31]. In the review by Gau and colleagues, 79% (11/14) of patients with an Xp21 deletion including IL1RAPL1 had acute PAI with onset in infancy, and 89% (8/9) of patients with a deletion of NR0B1 and IL1RAPL1 without GK or DMD had global developmental delay [30]. Contiguous deletions represent about 5–7% of X-linked AHC in the large cohorts from the United Kingdom, China and Japan, a figure cited by Gau and colleagues by indirect attribution [30]. Cases from 2025–2026 add clinical detail: sensorineural deafness and exogenous Cushing syndrome due to high glucocorticoid doses for dystrophinopathy in an infant; markedly raised cardiac biomarkers without structural anomaly, nystagmus and pale optic discs in an infant from Poland; sudden death at 7 months in a Serbian infant with late diagnosis; and immunodeficiency, hypotonia and splenic abscesses with a 6.9 Mb deletion (Xp21.2–Xp11.4) in a patient from the series of Kara and colleagues [108–111]. Dystrophinopathy contributes progressive muscle weakness, almost universal cardiomyopathy and mild non-progressive learning difficulty in about 30% of boys with Duchenne dystrophy [77]. The 2018 GeneReviews states that men with a deletion including DMD do not reproduce and typically die in adolescence or young adulthood; with specialist care and nocturnal ventilation, the mean age at death in Duchenne dystrophy is about 30 years, and the 2026 GeneReviews on dystrophinopathies reports increased longevity with current therapies [1, 29, 77].

3.7. Isolated glycerol kinase deficiency

Saudubray describes three clinical forms in the early descriptions: infantile, with severe developmental delay; juvenile, frequently symptomatic, with episodic vomiting, metabolic acidosis, stupor and coma; and adult, asymptomatic, detected incidentally through pseudohypertriglyceridaemia [31]. The same 2000 review brought together 38 patients from 24 families with isolated deficiency, at least 7 of whom had a metabolic crisis during a catabolic state; in a Dutch series of 8 boys from 3 families, 4 were asymptomatic, 3 had gastrointestinal symptoms with ketoacidosis, hypoglycaemia or both, and 1 had recurrent seizures with no apparent relation to catabolism [14]. In the juvenile form, two boys with episodic vomiting, acidosis, stupor and coma from 4 years of age, and another patient with isolated deficiency, improved on a low-fat diet [14]. Orphanet considers the infantile form obsolete and retains the juvenile (ORPHA:284411) and adult (ORPHA:284414) forms [24]. In isolated deficiency there is a risk of hypoglycaemia and hyperketonaemia, with ketoacidotic crises with or without hypoglycaemia [31]. The adult form is the one most frequently recognised today: in a systematic review of 39 individuals in 15 articles, patients had a history of raised triglycerides resistant to lipid-lowering drugs and, compared with 584 men with triglycerides above 300 mg/dL without the deficiency, had lower body mass index, total cholesterol, non-HDL cholesterol and gamma-glutamyltransferase, higher HDL cholesterol and less diabetes [112]. In the American family studied by Shah and colleagues, the five affected men had lower total cholesterol (3.72 ± 0.70 vs. 4.77 ± 0.85 mmol/L; p = 0.024) and lipase-measured triglycerides of 5.28 ± 1.38 mmol/L against 0.81 ± 0.32 mmol/L by nuclear magnetic resonance [79]. In Spain, a 78-year-old man was treated for 5 years with lipid-lowering drugs for triglycerides of 844–1864 mg/dL with a negative lipaemic index; free glycerol was 12,600 µmol/L and a maternal nephew was affected [113]. In Canada, a 65-year-old man enrolled in the SHASTA-2 trial of plozasiran appeared not to respond to the drug, until free glycerol of 4.37 mmol/L (reference 0.03–0.13) was measured; after correction, the true triglycerides had fallen by up to 71% [114]. In French-Canadian families of the Saguenay–Lac-Saint-Jean region, measurement of fasting plasma glycerol in a cohort of 1056 adults identified 18 men from 5 families with severe hyperglycerolaemia (above 2.0 mmol/L), all with the p.Asn288Asp variant on a common haplotype; the affected men had no apparent disease, but glycerolaemia correlated with alterations of glucose metabolism and body fat distribution [10, 14]. In the United Kingdom, an adult was diagnosed incidentally, during an admission for hyponatraemia and acute kidney injury, through the discrepancy between triglycerides and the lipaemic index [115]. After puberty, most patients do not need a diet, the frequency of decompensations decreases and there is an increased risk of glucose intolerance [31].

3.8. Xp21 duplication (DSS locus)

In the systematic review of 47 46,XY individuals with NR0B1 duplication, the median age at presentation was 1.0 year (from birth to 38 years); 66% had complete gonadal dysgenesis, 27.7% partial and 6.4% typical male genitalia; gonadoblastoma occurred in 17% (median age 11 years) and germ cell tumour in 2.1% (at 15 years); one paternity was described; large duplications presented earlier (0.7 vs. 15 years; p = 0.008) and with more syndromic features (96.6% vs. 22.2%) [83]. A small supernumerary Xp marker chromosome with NR0B1 and MAGEB caused partial gonadal dysgenesis and gonadoblastoma [28]. The Oxford Desk Reference states that about 80% of 46,XY women with gonadal dysgenesis have no identified aetiology and that a uterus and streak gonads are frequently found [116].

3.9. IMAGe syndrome

GeneReviews brings together 31 individuals from 19 families with a clinical diagnosis and 19 from 11 families with molecular confirmation [3]. All newborns had intrauterine growth restriction (IUGR), with weight of −2 to −4 standard deviations (SD) and length of −1.8 to −4.5 SD; short stature persists (−2.7 to −6.5 SD), with variable growth hormone (GH) deficiency [3]. Adrenal insufficiency appears universal, with possible ascertainment bias: in one family, all 7 carriers with a maternally inherited variant were affected; the crisis appears in the 1st month, typically in the 1st week, with ACTH frequently above 1000 pg/mL (normal 10–60 pg/mL) and intense hyperpigmentation; some patients have mild PAI or hypoaldosteronism without glucocorticoid deficiency [3, 46]. All have some skeletal anomaly, mainly delayed bone age; metaphyseal and epiphyseal dysplasia develops in early childhood and is often absent in the neonatal period, so early diagnosis rests on clinical and endocrine findings [3, 47]. Genital anomalies (cryptorchidism, usually bilateral, micropenis, hypospadias) are almost universal in boys and have not been described in girls [3]. Development was normal in 15 of 16 individuals with information; there is variable hypercalcaemia in 8 of 16, hypercalciuria and nephrocalcinosis; and one case of rhabdomyosarcoma has been reported [3]. Two women with IMAGe have had children; no offspring of affected men is known [3]. In the original description, the three boys also had HH, epiphyseal dysplasia in two, and hypercalciuria or hypercalcaemia with nephrocalcinosis in one and prenatal hepatic and splenic calcifications in another; CK was normal and there was no glycerol kinase deficiency, which distinguished them from Xp21 deletion [21]. In the five-generation Argentinian family, in addition to the four patients studied, ten relatives who died in the neonatal period with IUGR or hyperpigmentation were considered presumably affected [21]. A 2010 review, prompted by a 4-year-old boy with bilateral sensorineural deafness, proposed that epiphyseal dysplasia, constant in the published cases, serve as a criterion when the metaphyseal dysplasia is mild or limited to the short tubular bones; craniosynostosis, cleft palate and scoliosis have also been described [21].

3.10. IMAGe-I (POLE)

IMAGe-I shares IUGR, metaphyseal dysplasia, AHC and genital anomalies, but is distinguished by variable immunodeficiency with lymphocyte deficiency, microcephaly, characteristic facial features (long thin nose, small, low-set and posteriorly rotated ears, crowded teeth, micrognathia) and a short broad neck [3, 49]. In the 15 patients from 12 families of the series by Logan and colleagues, identified from cohorts with microcephalic primordial dwarfism and patients with IMAGe without a CDKN1C variant, postnatal short stature ranged from −5.5 to −11.27 SD and head circumference from −2.7 to −8.03 SD (relative macrocephaly); 12 had PAI, 11 immunodeficiency (lymphocyte subset deficiency and/or IgM hypogammaglobulinaemia, and NK cell deficiency in 3), all boys had bilateral cryptorchidism and/or hypospadias, and there were three deaths from respiratory infection [117]. In an Australian boy, PAI only became manifest at 4.5 years, through hyperpigmentation and fatigue, and hand radiographs showed cupped metaphyses and dense “ivory” epiphyses in the distal interphalangeal joints [117].

3.11. MIRAGE syndrome

In the 44 patients brought together by GeneReviews, the frequencies were: growth restriction 43/44, recurrent infections 40/44, myelodysplasia 37/44, gastrointestinal complications 36/44, adrenal hypoplasia 34/44 and atypical genitalia in 33/34 46,XY individuals [4]. PAI, in about 80%, presents at birth with diffuse hyperpigmentation, severe dehydration and hypotension, and the adrenal glands are aplastic or hypoplastic on ultrasound [4]. Severe cytopenias appear between birth and 2 years in about 60% and later in childhood in about 40%; progression to myelodysplastic syndrome (MDS) is defined by acquisition of monosomy 7 or del(7q) with multilineage dysplasia, whereas other somatic alterations (uniparental disomy 7, SAMD9 variants on the same allele) may improve haematopoiesis [4]. Chronic diarrhoea affects about 80%, one third have oesophageal dysfunction with aspiration pneumonia, most have moderate to severe delay, and 5 of 17 patients who lived more than 3 years had renal dysfunction [4]. In 2026 there were descriptions of a 22-year-old survivor with three acquired somatic reversions who received a living-donor kidney transplant at 21 years, and of three children with hypotonia, seizures, cerebral and cerebellar hypoplasia and early non-infectious death, one with malignant hyperthermia [118, 119]. In the founding series of Narumi and colleagues (11 Japanese patients), all had thrombocytopenia and/or anaemia requiring transfusions in early childhood, with spontaneous resolution, and severe invasive infections (sepsis, meningitis, fungal infections); 6 died before 2 years, mainly from infection, 9 had chronic diarrhoea with colonic dilatation, and two with mosaic monosomy 7 developed MDS and died of this complication; at autopsy in two female patients, the adrenal glands were very small and disorganised, and the ovaries and thymus hypoplastic [120]. Heterozygous SAMD9 variants also cause monosomy 7 myelodysplasia and leukaemia syndrome type 2 (OMIM #619041), with overlapping features [120, 121].

3.12. NR5A1 and autosomal recessive forms

In a systematic review of 312 46,XY individuals with DSD due to NR5A1, 85% had atypical and 15% female genitalia, 54% were raised as female, 82% had spontaneous puberty (95% CI 45–96), and PAI occurred in only 1.6% [122]. In a French cohort of 34 carriers of heterozygous variants, 61.7% had functional hyposplenism (severe in 47%), 44.1% morphological anomalies of the spleen and 11.7% asplenia [123]. In 46,XX women, the variants are associated with premature ovarian insufficiency and, rarely, with testicular or ovotesticular DSD [28]. The first human case, a phenotypically female child with PAI in the first two weeks of life and a 46,XY karyotype, initially received a presumptive diagnosis of lipoid adrenal hyperplasia; at 10 years, before pubertal induction, gonadotropins responded to GnRH but testosterone did not respond to hCG, and laparotomy revealed a uterus and streak gonads; the uterus distinguishes this complete gonadal dysgenesis from defects of steroidogenesis, in which there are no Müllerian derivatives, and transdermal oestradiol followed by cyclical progestogen induced breast development and regular menstruation [20]. In the 46,XX girl homozygous for R92Q, PAI became manifest at 2 weeks with hyperpigmentation, salt-wasting crisis, prolonged jaundice, hypoglycaemia and vomiting, with glucocorticoid and mineralocorticoid deficiency and a hypoplastic right adrenal gland on magnetic resonance imaging [19]. In four families with 46,XY DSD and 46,XX ovarian insufficiency, the same variant was present in both phenotypes, for example in a mother with ovarian insufficiency diagnosed at 35 years and in her 46,XY daughter with complete gonadal dysgenesis; none of the carriers had signs of PAI [7, 19]. Autosomal recessive “miniature adult” type AHC (%240200) has a cortex formed by a small amount of permanent adult cortex, with no known molecular basis, and AHC with absent pituitary LH (202150) has been described in three patients [1, 18, 27]. OMIM entry %240200 is heterogeneous: it brings together familial cases of hypoadrenocorticism described between 1952 and 1968, the sporadic or recessive “miniature adult” form, and genetic susceptibility to autoimmune Addison disease [17]. Histology separates the two classic forms: in the X-linked form, the cortex is disorganised, without differentiated zones, and retains only clusters of large eosinophilic cells (cytomegalic type); in the “miniature adult” form the fetal cortex and almost all of the permanent cortex are missing [16, 17]. The latter is frequently associated with brain and pituitary anomalies, such as anencephaly, or with isolated pituitary anomalies, which points to hypoplasia secondary to lack of ACTH stimulation [17]. The cytomegalic type is not exclusive to the X-linked form: two sisters born to the same parents had PAI; the first, small for gestational age, died at 7 weeks with cytomegalic histology, and the second had no identifiable adrenal glands on computed tomography at 1 year; entry 202155, created for this 1993 report, has no assigned molecular basis [16]. Those three siblings (a boy and two girls, described by Burke and colleagues in 1988) died in the neonatal period; the adrenal glands were of the “miniature adult” type, the boy had micropenis and undescended testes with Leydig cell deficiency, immunohistochemistry showed selective absence of LH in the pituitary cells of all three, without structural anomaly of the brain or pituitary, and glycerol kinase activity was reduced by a mechanism that the authors considered distinct from Xp21 deletion [18].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age

In the male newborn and infant, suspicion arises with a salt-wasting crisis in the first month or first months of life, with vomiting, poor weight gain, dehydration, hyponatraemia, hyperkalaemia and acidosis, especially with typical male genitalia; the Oxford Desk Reference stresses that the presentation may be similar to that of salt-wasting CAH [1, 32]. In Saudubray’s algorithm for dehydration with salt wasting, atypical genitalia at the end of the 1st week point to CAH, typical genitalia in the same period to hypoaldosteronism, and onset between infancy and early childhood to adrenal hypoplasia congenita [124]. The authors of the Brazilian series recommend considering X-linked AHC in all boys with an adrenal crisis in the first months or in early childhood, especially if there is a family history of early death of boys, after excluding CAH [42]. In the child between 1 and 9 years, the signs are a crisis triggered by infection or stress, hypoglycaemia, hyperpigmentation and tiredness [1]. In the adolescent and young adult, the combination of PAI with absent or arrested puberty, or of PAI with infertility, should lead to NR0B1 testing; Kyriakakis and colleagues recommend testing all adults with PAI and HH or impaired fertility without an established cause [1, 55].

4.2. Red flags for contiguous deletion or a syndromic entity

Persistently raised CK, hypertriglyceridaemia (especially with non-lipaemic serum), increased urinary glycerol, developmental delay or a family history of intellectual disability in a boy with AHC point to an Xp21 deletion and justify CMA [30, 32]. Gau and colleagues recommend not attributing developmental delay prematurely to adrenal crises or perinatal events and asking about mild delay in female relatives [30]. IUGR with genital anomalies and, later, metaphyseal dysplasia suggests IMAGe; the association of neonatal PAI with cytopenias, infections and chronic diarrhoea suggests MIRAGE; and atypical or female genitalia in a 46,XY individual with PAI suggest NR5A1 or disorders of steroidogenesis [3, 4, 28]. In an adult with very high triglycerides, no response to lipid-lowering drugs and a negative lipaemic index, glycerol kinase deficiency should be considered [113, 125].

4.3. Emergency signs

Adrenal crisis is an emergency: hypotension or shock, persistent vomiting, drowsiness or unresponsiveness, hypoglycaemia and seizures require immediate parenteral hydrocortisone, without waiting for results [34, 126]. The Society for Endocrinology points out that diagnostic measures must never delay treatment and that giving high doses of glucocorticoids for a short period is never harmful, whereas failure to treat may be fatal [127]. In patients already diagnosed, death from a crisis can still occur if replacement is not adjusted under stress or in the face of fluid imbalance, as in severe gastroenteritis [1].

4.4. Newborn screening and presymptomatic diagnosis

There is no specific newborn screening for X-linked AHC. Newborn screening for CAH by 17-OHP does not detect it, because 17-OHP is normal or low [32, 33]. The strategy for early detection is familial: in at-risk boys in the maternal line, molecular testing for the familial variant and biochemical surveillance from the first days allow replacement to be started before a crisis, which Achermann and colleagues demonstrated in 2000; about 40% of affected boys only become manifest in childhood or later, so an asymptomatic boy is not safe [1, 73]. In a Japanese family in 2025, targeted evaluation identified a 4-year-old brother with a low cortisol response to the short Synacthen test without symptoms [72]. In the pregnancy of a carrier of an Xp21 deletion, fetal ultrasound showed the two-layered structure of the adrenal gland in the healthy fetus and did not confirm it in the affected fetus; the authors suggest that the finding may anticipate the need for steroids immediately after birth, but the observation is based on two fetuses and is not validated [128].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal clinical criteria for X-linked AHC. The diagnosis is established in a male proband by identification of a hemizygous pathogenic NR0B1 variant or of a non-recurrent Xp21 deletion that includes NR0B1 [1]. For IMAGe and MIRAGE, also without formal criteria, the diagnosis rests on the suggestive findings and on a heterozygous pathogenic variant of CDKN1C (PCNA domain, maternal allele) or a gain-of-function variant of SAMD9; to define its series, the MIRAGE GeneReviews uses at least four core features in 46,XY individuals and at least three in 46,XX individuals. A VUS in these genes neither establishes nor excludes the diagnosis [3, 4].

5.2. Confirmation of primary adrenal insufficiency

The 2016 Endocrine Society guideline recommends testing acutely ill patients with unexplained signs of PAI (volume depletion, hypotension, hyponatraemia, hyperkalaemia, fever, abdominal pain, hyperpigmentation or, especially in children, hypoglycaemia) and confirming with the corticotropin stimulation test when the patient’s condition allows [34]. The standard test uses 250 µg of intravenous corticotropin in adults and children aged 2 years or more, 125 µg in children under 2 years and 15 µg/kg in infants, with samples at 30 or 60 minutes; a peak cortisol below 500 nmol/L (18 µg/dL), assay-dependent, indicates adrenal insufficiency [34]. If the test is not possible, a morning cortisol below 140 nmol/L (5 µg/dL) with raised ACTH is a preliminary indicator; an ACTH above twice the upper limit of the reference range, with confirmed cortisol deficiency, is consistent with PAI; and renin and aldosterone should be measured simultaneously to characterise the mineralocorticoid deficiency [34]. In Brazil, the Ministry of Health PCDT (Portaria Conjunta n.º 20, of 24 November 2020) uses thresholds of basal cortisol sampled between 6 and 9 a.m.: cortisol below 5 µg/dL with ACTH above 100 pg/mL is highly suggestive of PAI, cortisol above 15 µg/dL makes the diagnosis unlikely, and values between 5 and 15 µg/dL require a stimulation test; as corticotropin (cosyntropin) is not registered with ANVISA, the indicated alternative is the insulin tolerance test (insulin 0.05–0.1 IU/kg, target blood glucose 40 mg/dL, cortisol at 0, 30, 60 and 90 minutes), contraindicated in children under 20 kg and in patients with seizures, heart disease or cerebrovascular disease, and a cortisol of 18 µg/dL or more at any time point excludes insufficiency [129]. The contraindication below 20 kg excludes precisely infants, the typical age of presentation of AHC, in whom the diagnosis rests on basal cortisol and ACTH, renin and aldosterone [34, 129]. GeneReviews adds that isolated basal cortisol is not reliable, because a “normal” value in a sick child is inappropriately low [1]. In the Chinese series, ACTH was raised in 100% of the 42 patients and cortisol low in 88% [99]. In the first weeks, cortisol may be normal or even high and aldosterone deficiency may precede cortisol deficiency, so the evaluation should be repeated [97, 98]. In the Brazilian series, some ACTH and cortisol values appeared normal owing to assay limitations or to glucocorticoids already started [42]. With a crisis under way, the guideline recommends starting hydrocortisone before any result and considers it essential to take a basal sample for ACTH and cortisol before the first dose, provided this does not delay treatment [34, 127].

5.3. Biochemical and imaging aetiological discrimination

Normal or low serum 17-OHP in a child with a salt-wasting crisis strongly suggests X-linked AHC; in CAH due to 21-hydroxylase deficiency, a 17-OHP value above 1000 ng/dL is diagnostic [32, 34]. In the Portuguese case from Coimbra, 17-OHP, dehydroepiandrosterone sulfate (DHEA-S) and androstenedione remained suppressed despite raised ACTH, a clue that distinguishes AHC from 21-hydroxylase deficiency; the initially low ACTH reflected suppression by prednisolone [67]. The Endocrine Society algorithm for PAI includes basal 17-OHP, anti-21-hydroxylase antibodies and, in preadolescent boys, very-long-chain fatty acids for adrenoleukodystrophy; the guideline’s list of differential diagnoses includes AHC due to NR0B1, Xp21 deletion with Duchenne dystrophy, SF-1 variants and IMAGe [34]. Serum CK should be measured in all boys with AHC to detect a deletion that includes DMD [32]. Computed tomography, magnetic resonance imaging or ultrasound may show small adrenal glands; ultrasound is less specific but avoids radiation and sedation in a sick child, and apparent absence of the adrenal glands may rarely be due to ectopia of normal-sized glands [1]. In the syndromic forms, the adrenal glands are small or of normal size in IMAGe, unlike the enlarged glands of CAH and lipoid hyperplasia [1, 3].

5.4. Evaluation of the gonadal axis

HH is characterised by low or normal basal LH and follicle-stimulating hormone (FSH) with low testosterone in the context of absent or arrested puberty, a reduced LH and FSH response to the luteinising hormone-releasing hormone (LHRH) test and low inhibin B [1]. GeneReviews writes “primary hypogonadism” in this passage; the data described (low gonadotropins, reduced response to LHRH) correspond to central hypogonadism, and the associated primary testicular defect is expressed mainly in spermatogenesis [1, 50]. Raised endogenous FSH indicates primary testicular failure and predicts lack of response to corifollitropin with hCG, according to the summary of product characteristics of Elonva® [130].

5.5. Glycerol kinase deficiency

Glycerol kinase deficiency is suspected in the laboratory from raised urinary glycerol excretion on organic acid analysis by gas chromatography-mass spectrometry and from falsely raised triglycerides, because enzymatic methods measure free glycerol as if it were triglyceride glycerol [1, 31]. The discrepancy between very high triglycerides and non-lipaemic serum or a negative lipaemic index is the most useful laboratory clue, and Fernández-Prendes and colleagues propose a laboratory algorithm based on it [111, 113]. Urinary glycerol is quick and simple; cases of hyperglycerolaemia without the deficiency are rare and, in case of doubt, the GK variant is sought, which also allows female carriers and asymptomatic men to be identified [31]. Fibroblast activity assays detect complete deficiency (activity below 1–5%) [31]. Provocation tests with a ketogenic diet, fasting or exercise are useless and dangerous [31]. In a boy with newly diagnosed glycerol kinase deficiency, the presence or absence of a contiguous deletion must be established: an isolated GK finding on a sequencing panel does not exclude it, copy-number analysis is required, and PAI must be actively excluded before the deficiency is called “isolated” [125].

5.6. Genetic testing: strategy and yield

GeneReviews proposes three approaches: NR0B1 sequencing first when the clinical picture is of X-linked AHC, followed by targeted deletion and duplication analysis or CMA if negative; CMA first when the clinical picture suggests an Xp21 deletion; or a multigene panel with NR0B1 and the genes of the differential, which should include deletion and duplication analysis [1]. In the Brazilian series, the strategy was Sanger sequencing of NR0B1 and, when there was no amplification, multiplex ligation-dependent probe amplification (MLPA, SALSA P185 Intersex), with classification according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [42]. In a boy with suspected CAH, testing of CYP21A2, POR and targeted NR0B1 copy-number analysis were negative, and only exome sequencing with CNV analysis identified a deletion of about 4.44 Mb at Xp21.3–p21.1; the authors recommend studying Xp21 copy number in boys with suspected CAH and negative routine tests [131]. In Japan, array-CGH has been covered by insurance since 2021 [30]. A 2025 review in the European Journal of Endocrinology advocates a stepwise and personalised diagnostic approach to paediatric PAI, in which CAH is the most frequent cause and several non-CAH causes have recently been identified [132]. On NR0B1 sequencing in 106 patients with idiopathic HH or constitutional delay of puberty, sporadic or familial, no pathogenic variants were found, which makes an NR0B1 cause unlikely in HH without a personal or family history of adrenal insufficiency [6].

The proportion of variants detectable by a method is not the clinical sensitivity of the test. Yield depends on selection: GeneReviews estimates 20–40% for an NR0B1 variant in boys with salt-wasting PAI, without a family history or other features, after exclusion of CAH and other causes, whereas the Oxford Desk Reference gives 50–70% in isolated cases without a family history [1, 32]. In the cohorts, Lin and colleagues found DAX1 variants in 58% (37/64) of 46,XY boys referred for adrenal hypoplasia and in 8/8 boys with HH and a suggestive family history [65]. GeneGuidance stresses that the 20–40% yield is not a prevalence [33].

The figure of about 40% of NR0B1 variants in paediatric PAI cited by the Brazilian series does not correspond to the denominator of the British study it cites, where the proportion was 7.7% in the research cohort [42, 133].

5.7. Report content and variants of uncertain significance

The report should state the gene, the transcript with version (NM_000475.5), the variant in HGVS, the zygosity (hemizygous in a male, heterozygous in a female), the ACMG/AMP class and, for deletions, the genomic coordinates with the reference genome version and the list of genes included [9, 42]. Coordinates published in GRCh37 and GRCh38 are not interchangeable, and the Brazilian series uses different systems between families [30, 42]. In the Brazilian series, the c.497G>A p.(Arg166Gln) variant was classified as a VUS (PM2 and BS2) despite a severe clinical picture; segregation in affected and unaffected relatives and functional studies are the routes to reclassification [42]. In MIRAGE, somatic loss of heterozygosity in haematopoietic tissue (monosomy 7, del(7q), uniparental disomy 7), with preferential loss of the chromosome carrying the variant, may give false negatives in DNA from leucocytes or bone marrow; fibroblasts or hair roots are preferred and, if suspicion persists, SNP array and deep sequencing (more than 1000 reads per position) [4]. In MIRAGE, a karyotype is mandatory even with female external genitalia [4].

5.8. Prenatal and preimplantation diagnosis

Once the familial variant or deletion has been identified, prenatal testing and preimplantation genetic testing (PGT) are possible; as a rule fetal sex is determined first and testing is done only if the karyotype is 46,XY [1]. In Xp21 duplication and in IMAGe, prenatal testing and PGT are possible when the variant of the carrier parent is known; in MIRAGE also, with the caveat of false-negative parental results due to somatic loss of chromosome 7 [3, 4, 28]. Before molecular testing, prenatal diagnosis of a male fetus with Xp21 deletion was made from very high glycerol in amniotic fluid and very low glycerol kinase activity in cultured amniocytes, later confirmed with DNA probes [13].

5.9. Practical algorithm

6. Differential Diagnosis

6.1. Table of types and class differentials

The table brings together the entities of the AHC class and the main differentials of neonatal- and childhood-onset PAI in a boy, with the feature that distinguishes them and the test that discriminates them.

6.2. X-linked AHC and congenital adrenal hyperplasia

Salt-wasting CAH due to 21-hydroxylase deficiency is the most common differential and the first to exclude [1]. Both present with a salt-wasting crisis in the first month, but in AHC the boy’s genitalia are typical (or with macrophallus), 17-OHP is normal or low, adrenal androgens are suppressed despite raised ACTH and the adrenal glands are small [1, 32, 67]. The reverse error is frequent: in the Israeli series, the initial diagnosis was wrong in 4 of 12 patients, and the Portuguese boy, the eldest brother of a sibship from Georgia and a boy with a 4.44 Mb Xp21 deletion were first considered to have CAH [67, 97, 131, 140].

6.3. AHC and familial glucocorticoid deficiency

Familial glucocorticoid deficiency due to MC2R, MRAP or NNT usually spares the zona glomerulosa, so renin and aldosterone are normal and hyponatraemia, when present, is transient and confined to severe cases [1, 96]. AHC affects both lines, although mineralocorticoid deficiency may precede glucocorticoid deficiency or vice versa [1, 97].

6.4. AHC and X-linked adrenoleukodystrophy

In a boy with PAI between 2 years of age and adolescence, adrenoleukodystrophy, also X-linked, must be excluded by very-long-chain fatty acids; the childhood cerebral form appears mainly between 4 and 8 years, and adrenomyeloneuropathy at the end of the third decade, with paraparesis, sphincter dysfunction and frequently PAI [1, 34]. In a series of 8 boys with childhood-onset Addison disease, 5 had raised plasma hexacosanoic acid and all of these had cerebral involvement on magnetic resonance imaging; review of the family histories found other undiagnosed cases [5]. AHC affects mineralocorticoids early and is associated with HH; adrenoleukodystrophy is not [1].

6.5. Syndromic forms: IMAGe, IMAGe-I and MIRAGE

In the neonatal period, a boy with PAI, small adrenal glands and cryptorchidism may have X-linked AHC or IMAGe; the IUGR, metaphyseal dysplasia and facial features of IMAGe do not belong to X-linked AHC [3]. MIRAGE may initially be indistinguishable from IMAGe; recurrent infections, chronic diarrhoea and haematological abnormalities appear with age [4, 47]. IMAGe-I adds immunodeficiency to the IMAGe picture and has recessive inheritance [49]. IMAGe and Beckwith-Wiedemann syndrome due to CDKN1C have opposite management plans, which makes correct interpretation of the functional effect of the variant critical [91]. Silver-Russell syndrome shares IUGR and frontal bossing, but has asymmetry, clinodactyly and different postnatal growth, and the CDKN1C variants that cause it do not produce PAI [3].

6.6. Other causes and pitfalls

Other syndromes and anomalies with adrenal hypoplasia or a similar picture include Pena-Shokeir type 1 fetal akinesia sequence, alobar holoprosencephaly, Meckel syndrome, SeRKAL syndrome (46,XX sex reversal with dysgenesis of kidneys, adrenals and lungs, due to biallelic WNT4), triploidy, tetraploidy, trisomies 19 and 21, 5p duplication and 11q− syndrome [1]. Metabolic causes include Wolman disease, mitochondrial disorders and Smith-Lemli-Opitz syndrome; autoimmune causes include autoimmune polyendocrinopathy type 1 (AIRE); and there are also extrinsic, infectious and drug-induced causes [1]. Older familial reports of PAI with preserved aldosterone may correspond, in current terms, to ACTH resistance (familial glucocorticoid deficiency, section 6.3), as OMIM itself acknowledges [17]. Autoimmune Addison disease is, in most cases, a component of an autoimmune polyendocrine syndrome; anti-21-hydroxylase antibodies are the sensitive and specific marker, and susceptibility is polygenic, with association with the MICA5.1 microsatellite allele and the HLA-DR3/DQ2 haplotype in an Italian series (28 patients, 75 controls) and with the T allele of PTPN22 (rs2476601) in a meta-analysis of 563 European patients (OR 1.36), which has no individual diagnostic value [17]. Undiagnosed congenital hypoadrenocorticism may be mistaken for sudden infant death, which justifies including adrenal histology and genetic testing in the post-mortem investigation of infants with unexplained death and affected siblings [17]. Pseudohypoaldosteronism mimics neonatal salt-wasting CAH, but glucose, 17-OHP and testosterone are normal and the patient needs salt and not hydrocortisone [32]. In the adult, glycerol kinase deficiency must be distinguished from true hypertriglyceridaemia, and lack of response to lipid-lowering drugs is a clue [31, 112]. In prenatal diagnosis through low maternal oestriol, the Oxford Desk Reference does not include X-linked AHC among the causes listed, and extrapolation is not justified [141].

7. Treatments and Risk Management Strategies

7.1. Principles and reference guidelines

There is no cause-directed therapy for X-linked AHC and no specific clinical trials; treatment consists of hormone replacement for PAI and hypogonadism, prevention of crises and, in Xp21 deletion, management of dystrophinopathy, glycerol kinase deficiency and neurodevelopment [1, 142]. Reference doses come from the 2016 Endocrine Society guideline for PAI in adults and children, the 2023 British Society for Paediatric Endocrinology and Diabetes (BSPED) consensus for paediatric emergency and perioperative care, the 2022 Endo-ERN guideline for pubertal induction and the 2026 OPTIMIZE DMD consortium recommendations for the interface with corticosteroid therapy for dystrophinopathy [34, 35, 126, 143, 144]. When the label dose differs from the guideline dose, the guideline dose is the reference and the label dose is given for comparison.

7.2. Maintenance glucocorticoid replacement

In children, the guideline suggests hydrocortisone in three or four daily doses, with an initial total dose of about 8 mg/m² of body surface area, adjusted to individual need, and advises against long-acting synthetic glucocorticoids (prednisolone, dexamethasone) [34]. Hydrocortisone is preferred because it has a short half-life and is easier to titrate; doses above 8 mg/m²/day may exceed the physiological range, and in CAH doses above 20 mg/m²/day in infants and 15–17 mg/m²/day in adolescents reduced final height, so growth and weight are the main guides to adjustment [34]. The guideline notes that plasma ACTH typically remains above the reference range and is not useful for routine monitoring; insufficient weight gain, fatigue, anorexia and hyperpigmentation indicate the need for an increase, and excessive weight gain with reduced growth velocity indicates excess [34]. The BSPED consensus considers about 8 mg/m²/day physiological replacement and reserves 10–15 mg/m²/day for CAH [126]. The Endocrine Society guideline does not define a maximum maintenance dose, and the BSPED consensus notes that there is no suggested maximum daily dose in children, unlike adults (200 mg/24 h), a maximum it aligns with older adolescents [34, 126]. In adults, the guideline suggests hydrocortisone 15–25 mg/day or cortisone acetate 20–35 mg/day in two or three doses, the largest on waking; prednisolone 3–5 mg/day is an alternative in patients with reduced adherence, and dexamethasone should be avoided; monitoring is clinical (weight, postural blood pressure, energy, signs of excess) and not by hormone measurements [34]. CYP3A4 inducers (carbamazepine, mitotane, St John’s wort) increase cortisol clearance and require a higher dose, and starting levothyroxine may precipitate a crisis [34]. In the Coimbra case, switching from prednisolone to hydrocortisone 10 mg/m²/day required adjustment to 13 and 12.5 mg/m²/day because of persistently raised ACTH and low cortisol [67].

7.3. Mineralocorticoid replacement and sodium chloride

All children with confirmed aldosterone deficiency should receive fludrocortisone, with an initial dose of 100 µg/day; this dose is not adjusted to body surface area and is often maintained throughout life [34]. Infants need sodium chloride supplements from the neonatal period until 12 months; in the first 6 months, the guideline indicates 1–2 g/day (17–34 mmol/day), divided between feeds, owing to mineralocorticoid resistance of the immature kidney and the low sodium content of breast milk and formula [34]. Sensitivity to mineralocorticoids increases in the first months of life, and blood pressure should be monitored especially in the first year [34]. In adults, the initial dose is 50–100 µg/day, without salt restriction; the guideline does not define a maximum fludrocortisone dose, and the Brazilian PCDT gives ranges of 0.05–0.3 mg/day in children and 0.05–0.4 mg/day in adults [34, 129]; if hypertension develops, fludrocortisone is reduced first and, if it persists, an antihypertensive is added without stopping fludrocortisone [34]. Signs of deficiency are insufficient weight gain, salt craving, dehydration, hyponatraemia with hyperkalaemia and raised renin; those of excess are hypertension and suppressed renin, and renin should lie at the upper limit of the reference range or slightly above [34]. By traditional equivalence, 40 mg of hydrocortisone corresponds to 100 µg of fludrocortisone, and mineralocorticoid replacement is not needed when hydrocortisone exceeds 50 mg/24 h [34]. The Portuguese SmPC of Inocort® indicates, in the paediatric population, half to one tablet (0.05–0.1 mg) per day, adjusted to age, weight and severity, and the FDA label for fludrocortisone indicates the usual adult dose of 0.1 mg/day (from 0.1 mg three times a week to 0.2 mg/day) and states that paediatric safety and efficacy have not been established; the paediatric reference dose is that of the guideline, and the US label does not cover it [34, 150, 151].

7.4. Stress doses and sick days

The Endocrine Society guideline recommends, in febrile illness at home, doubling (fever above 38 °C) or tripling (above 39 °C) the oral hydrocortisone dose until recovery, usually 2–3 days, with increased intake of fluids containing electrolytes; if the patient cannot tolerate oral intake, hydrocortisone IM or subcutaneously 100 mg in adults and 50 mg/m² IM in children (or, by estimate, 25 mg in infants, 50 mg at school age and 100 mg in adolescents) [34]. The 2023 BSPED consensus adopts a different scheme for children: in moderate or severe illness (fever, influenza, infection, illness that prevents school attendance, vomiting or diarrhoea with the dose retained for at least 30 minutes), oral hydrocortisone about 30 mg/m²/day in four equal doses for the duration of the illness, with no maximum dose defined in the source for children; in mild illness (cold without fever, minor injuries), no change; in the case of a dose not tolerated, drowsiness, unresponsiveness, major trauma or shock, IM hydrocortisone and an emergency call [126]. The European SmPC of Alkindi® indicates doubling or tripling the usual dose in less severe situations (mild infection, moderate fever, minor surgery) and the parenteral route in hospital in severe situations (gastroenteritis with vomiting or diarrhoea, high fever, trauma, surgery under general anaesthesia) [152]. The BSPED also suggests considering one or two sick-day doses after vaccinations and, on long flights, repeating the usual morning dose every 6–8 hours [126]. Intense exercise for 20 minutes did not require additional hydrocortisone in patients with CAH, and there is no evidence for a general recommendation of supplementation during prolonged training [34].

7.5. Adrenal crisis

Crisis doses are empirical: there are no systematic dose-response studies, and the guidelines give more weight to preventing underdosing than to the effects of brief overdosing [34]. The sources diverge on fluids (20 mL/kg in the US guideline, 10 mL/kg repeatable in the British consensus) and on how to calculate the paediatric dose (body surface area, age or weight); in practice, the local protocol should adopt a single written scheme [34, 126]. The BSPED consensus adopts the adult maximum of 200 mg/24 h of hydrocortisone in older adolescents and defines no daily maximum in children, whose surgical stress doses are 50–100 mg/m²/day [126]. The BSPED consensus recommends using the neonatal doses in infants who are very small for gestational age or growth-restricted [126]. The labels for hydrocortisone sodium succinate (Solu-Cortef® in the USA; Hidrocortisona Generis 100 mg powder for solution for injection in Portugal) indicate initial adult doses of 100–500 mg, repeatable every 2, 4 or 6 hours, and the Portuguese SmPC states that, in the paediatric population, the dose should not be less than 25 mg/day; the FDA label warns of hypernatraemia and the Portuguese SmPC of hyponatraemia with high doses maintained for more than 48–72 hours [153, 154]. The reference crisis dose is that of the guideline.

7.6. Perioperative care

For minor to moderate surgery, the guideline suggests hydrocortisone 25–75 mg/24 h in adults, usually for 1–2 days, and in children 50 mg/m² IM or double or triple the usual dose; for major surgery under general anaesthesia, trauma, delivery or illness requiring intensive care, 100 mg IV followed by 200 mg/24 h by continuous infusion (or 50 mg every 6 h), and in children 50 mg/m² IV followed by 50–100 mg/m²/day every 6 h, with IV fluids containing 5% glucose and 0.2 or 0.45% NaCl adjusted to weight and rapid tapering with transfer to the oral route according to progress [34]. The BSPED recommends, for minor surgery, the sick-day dose before the procedure and a return to the usual dose afterwards (up to 24 h if there is pain or malaise); for major surgery (more than 90 minutes), 2 mg/kg IV at induction (max. 100 mg; newborns and preterm infants 4 mg/kg), 2 mg/kg every 6 h intraoperatively and 1 mg/kg (max. 50 mg) every 6 h postoperatively, or a continuous infusion [126].

7.7. Education, card and emergency kit

The guideline recommends that all patients have a steroid emergency card, medical identification and a hydrocortisone injection kit, with training in self-administration [34]. The document summarises two “sick-day rules”: double the oral dose with fever or illness requiring bed rest, with infection requiring antibiotics or before a minor outpatient procedure; and inject glucocorticoid IM or IV in severe illness, trauma, persistent vomiting, fasting for a procedure or surgery [34]. The reasons are quantitative: in an analysis of 444 patients, the frequency of crises in adult PAI was 6.6 per 100 patient-years; in a prospective study, 8.3 per 100 patient-years, with crisis mortality of 0.5 per 100 patient-years, which means that about 1 in 12 patients will have a potentially fatal crisis in the following year; and, in an international survey, only 12% of patients with a crisis in the previous year self-injected [34]. In a Japanese prospective cohort of 349 patients with PAI diagnosed up to 15 years of age (961 person-years), the incidence of crisis was 4.27 per 100 person-years (95% CI 3.15–5.75), with greater risk at younger age and with a greater number of infections [155]. GeneReviews recommends an emergency plan from the local hospital, clear admission criteria, rapid access to medical advice and a medical alert bracelet [1]. Between September 2019 and August 2022, NHS England recorded 83 incident reports in patients with PAI, mainly glucocorticoids not given perioperatively or as prescribed [126].

7.8. Hydrocortisone formulations

Alkindi® (hydrocortisone granules in capsules for opening, 0.5, 1, 2 and 5 mg) has held European marketing authorisation since 9 February 2018 for replacement therapy of adrenal insufficiency from birth to 18 years, with a recommended dose of 8–10 mg/m²/day in isolated PAI (10–15 mg/m²/day in CAH), in three or four doses [152]. In the USA, Alkindi Sprinkle® was approved on 29 September 2020 for paediatric patients with adrenocortical insufficiency, with an initial dose of 8–10 mg/m²/day in three doses (two in older children), rounded to 0.5 or 1 mg [156]. The granules must not be chewed, the capsule must not be swallowed, and the US label prohibits administration by nasogastric or gastric tube because of the risk of obstruction; the European SmPC warns that switching from compounded or crushed hydrocortisone to Alkindi® may lower relative exposure and cause symptoms of PAI, despite an identical total dose [152, 156]. The paediatric pharmacokinetic and safety data of the US label come from 24 patients [156]. In Portugal, Hidrocortisona Generis 10 mg tablets has an SmPC indication in CAH from 12 years and refers younger patients to other hydrocortisone-containing medicines; use in X-linked AHC is outside the literal indication of that SmPC, and the reference replacement dose is that of the guideline [34, 157]. Plenadren® (modified release) has been authorised in the EU since 3 November 2011 for adult PAI, and Efmody® (modified release, 2021) only for CAH from 12 years [158].

7.9. Pubertal induction

GeneReviews recommends testosterone in increasing doses to induce puberty, started near or shortly after the expected age (12 years in boys), with gradual increases over 2–3 years up to adult doses and lifelong replacement, which is also needed for growth and bone mineralisation; if puberty has not started by 14 years and tests indicate probable HH, induction may be brought forward to keep pace with peers [1]. The 2022 Endo-ERN guideline recommends that, in boys with a diagnosis carrying a high risk of hypogonadism, induction should begin at 12 years if there are no pubertal signs (R3.4, very low quality of evidence) and that it should use testosterone (R3.5) [35]. The guideline’s systematic review found only four studies in boys with HH and did not allow a conclusion as to the optimal treatment [35]. In Xp21 deletion with intellectual disability, the guideline recommends careful induction, with mental health follow-up and adapted sex education [35]. The dystrophinopathy Care Considerations indicate referral to endocrinology if puberty has not occurred by 14 years and allow testosterone to be considered from 12 years in boys on glucocorticoids without pubertal development [146].

The guideline advises against adding DHEA-S, recommends structured assessment at baseline and every 3–6 months (pubertal stage, bone maturation, growth velocity, local reactions, gynaecomastia, priapism, haematocrit, liver function and behaviour) and, with late diagnosis in young adults, allows higher initial doses (enantate 200–250 mg/month, then every 2–3 weeks) [35]. Gynaecomastia occurs in up to one third of boys treated with gonadotropins or testosterone [35]. Induction with 25–50 mg/month of enantate is use outside the conditions of the Portuguese SmPC of Testoviron Depot®, supported by the guideline [35, 161]. In the Coimbra case, IM testosterone 25 mg/month at 15 years led to Tanner stage II in 6 months (testes of 5–6 mL), and the dose was raised to 50 mg/month [67]. The FDA testosterone label stresses that, in HH, adrenal and thyroid replacement remains necessary and is of primary importance [159]. The abstract of a case published in 2025 gives a testosterone dose of “100–240 mg/day”, an implausible value that is not reproduced as a dose [70].

7.10. Fertility

X-linked AHC combines HH with a primary testicular defect, and the rule in the classic form is azoospermia despite gonadotropins or pulsatile GnRH [1, 50]. Frapsauce and colleagues described the first paternity: a man with c.1210C>T p.(Gln404Ter), testosterone 1.2 nmol/L, FSH 2.1 IU/L and LH 0.1 IU/L, treated with menotropin 150 IU three times a week and human chorionic gonadotropin (hCG) 1500 IU twice a week, remained azoospermic at 20 months; multiple bilateral testicular biopsies showed severe hypospermatogenesis with rare spermatozoa in one fragment, intracytoplasmic sperm injection (ICSI) produced four embryos, and transfer of one cryopreserved embryo resulted in the birth of a healthy boy [36]. GeneReviews notes that it is not known whether the result is generalisable, and recommends, when the diagnosis is made after the age of puberty with adequate testosterone production, discussing semen analysis and sperm cryopreservation, given the progressive decline of spermatogenesis [1, 56]. Clinical genetics texts summarise the general rule for HH (pubertal induction and testosterone replacement; fertility through exogenous gonadotropins or pulsatile GnRH), in which DAX-1 and SF-1 appear among the orphan nuclear receptors involved [164, 165]. In the Chinese series, six patients treated with hCG had a slight increase in testicular volume and testosterone, and the authors propose pulsatile GnRH when the response to hCG is unsatisfactory [99].

The Endo-ERN guideline (R4.1) recommends discussing two options in secondary hypogonadism: testosterone, which does not stimulate testicular growth or spermatogenesis, or gonadotropins; the combination of recombinant FSH and hCG is more effective than hCG alone, and FSH pretreatment may optimise Sertoli cell maturation [35]. The examples in Table 5 of the guideline are recombinant FSH 1.5 U/kg three times a week, or 75–150 IU three times a week with hCG 250–500 IU twice a week, with six-monthly increases up to a maximum of 2500 IU three times a week, or hCG 1500 IU twice a week SC; after induction with gonadotropins, transfer to testosterone is considered after semen analysis, with cryopreservation if spermatozoa are present (R4.2) [35]. These results come from congenital HH in general: in a meta-analysis of 103 studies and 5328 patients, spermatogenesis was achieved in 86% (95% CI 82–91) with hCG and FSH against 40% (95% CI 25–56) with hCG alone; in a London cohort of 35 young people treated with recombinant FSH and hCG, 15 of 18 with semen analysis had spermatogenesis [166, 167]. These figures do not apply to X-linked AHC, in which the testicular defect limits the response; the use of gonadotropins in this disease is an extrapolation [36, 50]. The FDA label for Gonal-f® (follitropin alfa) indicates induction of spermatogenesis in HH when infertility is not due to primary testicular failure: pretreatment with hCG 1000–2250 IU two to three times a week until testosterone is normal (3–6 months) and then follitropin alfa 150 IU SC three times a week with hCG; the trials included 76–78 men aged 16–48 years [168]. The FDA label for hCG (Novarel®) indicates, in male HH, 500–1000 IU three times a week for three weeks and then twice a week for three weeks, or 4000 IU three times a week for 6–9 months followed by 2000 IU three times a week for a further 3 months [169]. In the EU, Elonva® (corifollitropin alfa) has an extension to male adolescents from 14 years with HH, with hCG: 100 µg SC every 2 weeks for 12 weeks if ≤60 kg (150 µg if >60 kg), followed by Elonva® every 2 weeks with hCG twice a week (500–5000 IU), with no data beyond 52 weeks or beyond 17 years, and not recommended in those who have already received GnRH, gonadotropins or testosterone [130]. The 2026 joint Brazilian position statement (SBEM/SBU/ABEMSS) provides fertility preservation strategies in adult male hypogonadism, with hCG, selective oestrogen receptor modulators or aromatase inhibitors when indicated [149].

7.11. Xp21 deletion with dystrophinopathy: interface between corticosteroid therapy and replacement

Boys with a deletion that includes DMD receive glucocorticoids in pharmacological doses for dystrophinopathy: prednisone or prednisolone 0.75 mg/kg/day (max. 30–40 mg), deflazacort 0.9 mg/kg/day (max. 36 mg) or vamorolone 6 mg/kg/day (max. 300 mg in the USA; 240 mg in the EU, United Kingdom, China and Canada) [143]. In Xp21 deletion, these patients also have permanent primary PAI, with their own mineralocorticoid deficiency; there is no “axis recovery” to test, and physiological replacement and the stress plan are maintained for life [1, 148]. Vamorolone is a mineralocorticoid receptor antagonist, may cause hyponatraemia and hyperkalaemia (especially with spironolactone or eplerenone) and is not suitable for stress cover; the European SmPC requires temporary supplementation with systemic hydrocortisone in stress situations [143, 144, 170]. The sources on dystrophinopathy do not deal specifically with the patient with Xp21 deletion and primary PAI; by deduction from the mechanism, vamorolone adds mineralocorticoid antagonism in a patient who already depends on fludrocortisone, which makes monitoring of sodium, potassium and renin more important if this drug is chosen. For moderate stress on corticosteroid therapy for dystrophinopathy, Table 4 of Weber and colleagues indicates hydrocortisone 30–50 mg/m²/day in doses every 6–8 h (or prednisone/prednisolone 9–12 mg/m²/day every 12 h), added to the usual dose on deflazacort or vamorolone, started with symptoms and continued for 24 h after resolution; for severe stress, hydrocortisone IM or IV 100 mg/m² (max. 100 mg; some protocols 200 mg) and IV maintenance of 50–100 mg/m²/day (typical max. 100 mg/day) [144]. The 2018 Care Considerations recommend prescribing emergency IM hydrocortisone to all patients on daily glucocorticoids (50 mg below 2 years; 100 mg from 2 years) and hydrocortisone 50–100 mg/m²/day in severe illness, major trauma or surgery with prednisone or deflazacort above 12 mg/m²/day [146]. The emergency IM dose diverges between sources (by age in BSPED and the Care Considerations; 100 mg/m² up to 100 mg in Weber and colleagues) [126, 144, 146]. Deflazacort has minimal mineralocorticoid activity and a half-life of 1.1–1.9 h, and there are no data to recommend its use as stress cover [143, 144]. In the Portuguese case of Xp21 deletion without NR0B1, deflazacort 0.9 mg/kg/day was started at 5 years and 11 months after PAI had been excluded [78]. In an infant with complete Xp21 deletion, higher doses of glucocorticoids for dystrophinopathy caused exogenous Cushing syndrome and complications [108]. Statins may worsen weakness and cause rhabdomyolysis, and suxamethonium may trigger malignant hyperthermia [29]. Therapies directed at dystrophinopathy include givinostat, antisense oligonucleotides and gene therapy [29].

7.12. Glycerol kinase deficiency

Treatment is symptomatic and preventive: avoid fasting and catabolism, ensure fluids, calories and glucose during intercurrent illness and, in acute decompensation, give IV glucose in sufficient quantity to block lipolysis, avoiding lipids and glycerol-containing solutions (including some anaesthetics) [31]. In young children, frequent meals with complex carbohydrates, extra food or glucose during infections and before intense physical activity, and home testing for ketonuria as an early sign are recommended [31]. A low-fat diet has been reported as useful, and alcohol should be avoided [31, 78]. The most important intervention in isolated deficiency is to recognise pseudohypertriglyceridaemia and stop lipid-lowering drugs, which have no effect; patients have been treated for years (in one case 13 years), and in the published series stopping them had no adverse consequences [111, 113, 125]. In complex deficiency, the priority is to recognise and treat PAI [31].

7.13. IMAGe and IMAGe-I

PAI is treated as in other causes, with glucocorticoid, mineralocorticoid, oral sodium chloride and stress doses [3]. Hypercalcaemia and nephrocalcinosis may be secondary to sodium chloride supplementation, which justifies monitoring calcium [3]. The response to GH is variable: one child had a poor GH response to glucagon and others, with normal GH, responded to treatment; cryptorchidism and hypospadias are treated surgically; male HH with testosterone in increasing doses; and scoliosis and hip dysplasia by orthopaedics [3]. In IMAGe-I, the sources consulted do not describe specific management beyond that of PAI; the variable immunodeficiency with lymphocyte deficiency is part of the described phenotype and should be characterised [49].

7.14. MIRAGE

Management includes transfusions, antibiotic prophylaxis in severe neutropenia, prophylactic IV immunoglobulin if immunoglobulins are low, hydrocortisone and fludrocortisone, an elemental diet for diarrhoea, duodenal feeding for recurrent aspiration pneumonia, artificial tears, control of ambient temperature and nephrological follow-up; removal of dysgenetic gonads and genital surgery are decided with an interdisciplinary team [4]. Haematopoietic stem cell transplantation (HSCT) is curative for myelodysplasia, severe chronic neutropenia or transfusion dependence, but adrenal hypoplasia complicates it: of the 8 patients with MIRAGE transplanted in the two available reports, all had severe complications (adrenal crisis with blood pressure and electrolyte instability, systemic infections, hepatic veno-occlusive disease, respiratory failure) and 3 died; non-curative supportive care is sometimes preferable [4]. The 22-year-old survivor described in 2026 received prophylactic IV immunoglobulin and a living-donor kidney transplant at 21 years [118].

7.15. NR5A1 and DSS duplication

In carriers of NR5A1 variants, management is that of 46,XY DSD, by an interdisciplinary team, with the 2019 diagnostic algorithm and the Endocrine Reviews review of lifelong management [171–173]. 46,XY individuals with a heterozygous NR5A1 variant may need management of PAI, and dysgenetic gonads carry an increased risk of gonadoblastoma [28, 174]. In the systematic review of 312 individuals, 10% (95% CI 5–21) changed gender, always from female to male [122]. The authors of the French cohort consider evaluation of splenic function mandatory, given hyposplenism in 61.7% [123]. In DSS duplication, gonadoblastoma in 17% (median age 11 years) underpins evaluation of the dysgenetic gonads within the DSD team [83, 172].

7.16. Comparative regulatory status

The Brazilian date for givinostat is the “process finalisation date” in the ANVISA open-data set, which does not necessarily correspond to the approval date published in the Diário Oficial [163]. The Brazilian package inserts were not read. The Brazilian clinical protocol and therapeutic guidelines (PCDT) are described in section 7.22.

7.17. Clinical trials and treatment studies

None of these studies included patients identified as having X-linked AHC, and the proportions achieving spermatogenesis cannot be transposed to a disease with a primary testicular defect [50, 166]. The adrenal suppression in VISION-DMD describes the axis of boys with isolated dystrophinopathy and does not apply to the patient with Xp21 deletion and primary PAI, who already has permanent insufficiency; its relevance lies in the authors’ recommendation to use hydrocortisone as the stress dose in patients on vamorolone [177]. No indirect comparisons are made between the studies in the table. A search of ClinicalTrials.gov (NR0B1, DAX1, adrenal hypoplasia congenita, glycerol kinase deficiency, Xp21 deletion, MIRAGE and IMAGe) identified no therapeutic trials directed at these entities, which does not prove that none exist [142].

7.18. Developments in the last 6–12 months

Between October 2025 and October 2026, clinical publications were series and case reports (level of evidence: human observational study): the Brazilian series of 12 families, with new NR0B1 rearrangements and variants [42]; the Japanese series of Xp21 deletions with neurodevelopmental impairment and literature review [30]; the first case of normal puberty with azoospermia and normal testosterone, from Belo Horizonte [57]; cases of Xp21 deletion from Poland and other centres and a review of the contiguous deletion syndrome [108, 109, 131, 178]; cases of glycerol kinase deficiency identified through laboratory discrepancy in adults [113, 115]; and the systematic review of NR0B1 duplications [83]. In the field of guidelines, the OPTIMIZE DMD consortium published the revised PJ Nicholoff protocol and a review of PAI in dystrophinopathy, both based on expert consensus without a Delphi process or formal grading, a limitation declared by the authors [143, 144]. In the regulatory field, the givinostat process was finalised in Brazil in August 2026, and the revision of the Inocort® SmPC dates from April 2026 [150, 163]. A 2026 Endocrine Reviews review of DAX-1 synthesises mechanistic data (preclinical and review level) [51]. A 2026 review of the treatment of hypogonadism states that kisspeptin remains under investigation and that giving gonadotropins in infancy to reproduce minipuberty has uncertain long-term reproductive benefit [179].

7.19. Agents and situations to avoid

In PAI, dexamethasone should be avoided for replacement (risk of cushingoid effects and absence of mineralocorticoid activity, which may precipitate a crisis) and, in children, long-acting synthetic glucocorticoids [34]. In the Coimbra case, previous prednisolone suppressed ACTH and may have compromised growth [67]. Abrupt withdrawal of glucocorticoids, omission of doses perioperatively and switching formulation without monitoring are avoidable causes of crisis [29, 126, 156]. In glycerol kinase deficiency, lipid-lowering drugs for pseudohypertriglyceridaemia, IV solutions containing glycerol or lipids, prolonged fasting, alcohol and fasting or ketogenic diet tests should be avoided [31, 125]. In a deletion that includes DMD, statins and suxamethonium should be avoided [29]. Vamorolone combined with mineralocorticoid antagonists increases the risk of hyperkalaemia and requires potassium measurement one month after the combination is started [170].

7.20. Pregnancy and lactation

X-linked AHC rarely affects women, but the pregnancy recommendations apply to symptomatic female carriers, to women with IMAGe and to women with PAI of another cause in the family. The guideline suggests at least one review per trimester, an increase in hydrocortisone according to progress, especially in the third trimester, preference for hydrocortisone and avoidance of dexamethasone, which is not inactivated by the placenta, and a stress dose in active labour, similar to that for major surgery [34]. The Society for Endocrinology stresses that hydrocortisone is inactivated in the placenta and does not affect the fetus, and that high doses should not be refused to a pregnant woman in crisis [127]. In women with IMAGe, there is an increased risk of PAI and of cephalopelvic disproportion at delivery, and follow-up should be endocrinological [3]. DMD carriers should have a cardiological assessment [78]. The sources consulted do not describe lactation data specific to these entities; the Brazilian PCDT advises against fludrocortisone during breastfeeding (section 7.22) [129].

7.21. Transition to adulthood

GeneReviews has no transition section. The Endo-ERN guideline covers the move from pubertal induction to adult replacement and recommends discussing the testosterone and gonadotropin options and sperm cryopreservation before setting the adult regimen [35]. Glucocorticoid and mineralocorticoid replacement is lifelong and moves from dosing by body surface area to the fixed adult dose; education on stress doses, the emergency card and the injection kit should be reviewed with the young person, and not only with the parents [34]. Follow-up of dystrophinopathy, in deletions that include DMD, follows the Care Considerations for transition (part 3) [147].

7.22. Brazil: clinical protocol and therapeutic guidelines of the Ministry of Health

The PCDT for adrenal insufficiency was approved by Portaria Conjunta SAES/SCTIE n.º 20, of 24 November 2020, based on CONITEC Recommendation Report n.º 562, and revoked Portaria n.º 1170/SAS/MS of 2015; the text consulted is the full copy of the ordinance hosted by the Sociedade Brasileira de Pediatria, and an update by Portaria n.º 415, of 13 April 2021, mentioned by a state web page, was not confirmed [129]. The protocol does not deal with AHC in particular and covers PAI of all causes, central insufficiency and Addisonian crisis (ICD-10 E27.1, E27.2) [129]. The main difference from the Endocrine Society guideline is the maintenance glucocorticoid: the PCDT states that oral hydrocortisone, the preferred option, is not available in Brazil, and recommends prednisone or prednisolone sodium phosphate, whereas the US guideline suggests hydrocortisone in three or four doses in children and advises against long-acting synthetic glucocorticoids in them [34, 129]. The ANVISA open-data CSV lists hydrocortisone registrations without stating the pharmaceutical form, so it does not allow the 2020 statement of unavailability to be verified [163].

The PCDT loading dose for the newborn (20 mg) is lower than the 25 mg (Society for Endocrinology and BSPED for those under 1 year) and the 4 mg/kg (BSPED, newborns) [126, 127, 129]. Prednisolone in X-linked AHC has the drawbacks illustrated by the Coimbra case (suppression of ACTH and possible impairment of growth), so, where oral hydrocortisone is accessible, the guideline remains the reference [34, 67]. The PCDT advises against fludrocortisone during breastfeeding, because small quantities pass into breast milk; the US guideline does not address lactation [34, 129]. The protocol also recommends identification (bracelet, chain or card) with emergency contacts and patient education to prevent crises [129].

8. Reproductive Options and Family Counselling

8.1. X-linked AHC: recurrence risks

Inheritance is X-linked recessive. The father of an affected boy is neither affected nor hemizygous. In a family with more than one affected individual, the mother is an obligate heterozygote; if a woman has more than one affected son with no other affected relatives and the variant is not detected in leucocyte DNA, germline mosaicism is very likely [1]. When the boy is the only affected individual, the mother may be a carrier or the variant may have arisen de novo; the proportion of de novo cases is unknown, probably low, and the 2026 Japanese series described a de novo complete deletion of NR0B1, and a 2026 paediatric review started from a boy with a de novo variant [1, 30, 180]. A heterozygous mother transmits the variant in 50% of pregnancies: boys who inherit it are affected and girls are carriers, rarely with PAI or HH. If the mother is negative in leucocyte DNA, the risk to siblings is slightly above that of the population (less than 1%) owing to theoretical germline mosaicism [1]. Most affected men are infertile; with medically assisted reproduction (MAR), all daughters would be heterozygous (rarely symptomatic) and no son would inherit the variant [1]. Maternal aunts and their offspring are at risk [1]. GeneGuidance warns that a carrier mother cannot be declared unaffected without assessment, given the case of PAI with dystrophinopathy due to skewed X inactivation [33, 106].

8.2. Xp21 deletion

Most mothers are carriers; de novo deletion is possible, in an unknown proportion [1]. In the mother of a child with an Xp21 deletion and no family history, CMA is performed [1]. With a heterozygous mother, the risk is 50% per pregnancy, with affected boys and heterozygous girls who are rarely symptomatic; with a mother without the deletion, the risk is low (less than 1%) but above that of the population [1]. Carriers of deletions that include DMD and IL1RAPL1 may have mild muscle symptoms, raised CK or developmental delay owing to skewed X inactivation, and should have a cardiological assessment because of the risk of cardiomyopathy [30, 78, 107]. Men with a deletion that includes DMD do not reproduce [1]. Within a family, affected members as a rule share the same deletion, which allows the phenotype of a newly affected boy to be anticipated [1]. The Serbian series shows the value of family screening: early diagnosis of the second infant allowed the mother and sister to be identified as carriers, after the first, with late diagnosis, had died suddenly at 7 months [110].

8.3. Isolated glycerol kinase deficiency

Isolated deficiency is also X-linked recessive; identification of the GK variant allows female carriers and asymptomatic men to be recognised [31]. In the 78-year-old Spanish man, the diagnosis led to identification of an affected maternal nephew [113].

8.4. Xp21 duplication (DSS)

The mother of more than one affected individual is an obligate heterozygote; in a simplex case, the mother may be a carrier, the duplication may be de novo or there may be mosaicism, and most patients with a small duplication inherited it from an unaffected carrier mother [28]. With a carrier mother, the risk is 50% per pregnancy: 46,XY siblings who inherit it are affected and heterozygous 46,XX sisters are generally unaffected; the father does not need to be tested [28]. In the systematic review, maternal inheritance was found in 63.3%, with asymptomatic carriers except for one [83]. Offspring of affected individuals are unlikely; with MAR, the duplication would be transmitted to all 46,XX daughters and to no 46,XY son [28].

8.5. IMAGe, IMAGe-I, MIRAGE and NR5A1

IMAGe is autosomal dominant with maternal imprinting: only maternal transmission causes disease. In a family of 24 individuals, the 7 affected individuals inherited the variant from the mother, and the unaffected ones inherited it from the father (n = 9) or did not have it (n = 8) [3, 46, 181]. The children of a heterozygous woman have a 50% probability of inheriting it and being affected; those of a heterozygous man, a 50% probability of inheriting it without being affected, but carrier daughters will transmit the disease to the next generation. With a negative mother and confirmed maternity, the variant is de novo or there is maternal mosaicism, and the risk to siblings is less than 1% [3]. IMAGe-I is autosomal recessive (biallelic POLE variants), which implies a 25% risk for each sibling when both parents are carriers [49]. MIRAGE is autosomal dominant and almost always de novo, and GeneGuidance refers to the GeneReviews review of monosomy 7 predisposition syndromes as a complementary source [182]; rarely it is inherited from a heterozygous parent without features owing to somatic rescue, as in the asymptomatic mother who also had a somatic loss-of-function variant on the same allele [4]. Parents should be tested, ideally in non-haematopoietic DNA; a negative parental result leaves a risk slightly above that of the population, owing to germline mosaicism and to false negatives due to loss of the chromosome 7 carrying the variant [4]. Carrier relatives should be assessed for early myelodysplasia [4]. In the founding series, the variants arose de novo in all families with parental DNA available, except in one family with two affected siblings, in which parental germline mosaicism was suspected [120]. In families with NR5A1 variants, the same variant may have very different presentations, and heterozygous 46,XX women are generally asymptomatic, some with premature ovarian insufficiency [28, 174]. Some variants allow testicular development and fertility, possibly with MAR [28]. A woman with premature ovarian insufficiency and an NR5A1 variant (including microdeletion) may transmit it to a 46,XY son with DSD, so the finding has implications for offspring before conception; the incomplete penetrance of heterozygous p.(Arg92Trp) and p.(Arg92Gln), with healthy carriers of both sexes, prevents the phenotype from being predicted from the genotype [7, 19].

8.6. Cascade testing and presymptomatic diagnosis

Once the familial NR0B1 variant has been identified, asymptomatic boys in the maternal line should be tested, because about 40% only become manifest in childhood or later and presymptomatic diagnosis allows replacement to be started before a crisis [1, 73]. The authors of the Japanese family recommend genetic confirmation in all boys in the family, given the variability of onset with the same variant [72]. A male newborn at risk, without prenatal diagnosis, should have a biochemical evaluation in the first days: electrolytes and cortisol may initially be normal and change progressively, basal ACTH is useful if the result is rapid, and the corticotropin test shows a reduced response in affected boys [1]. Identification of heterozygous women requires the familial variant or deletion or, without an affected individual available, NR0B1 sequencing followed by CMA [1]. The Brazilian series stresses that molecular diagnosis allows affected relatives to be detected before symptoms, in a context in which two families had brothers who had died early without a known cause [42].

8.7. Prenatal and preimplantation diagnosis and planning

Prenatal testing and PGT are possible when the familial variant is known; fetal sex is usually determined first [1]. Counselling should be done before pregnancy and offered to young adults who are carriers, at risk or affected; DNA banking is useful when the molecular diagnosis has not been confirmed [1]. In the Japanese family in 2025, the couple chose not to have invasive prenatal diagnosis and fetal ultrasound suggested the difference between the affected and the healthy fetus [128]. In a newborn boy at risk not tested prenatally, the delivery plan should provide for early biochemical evaluation and access to hydrocortisone [1].

8.8. Counselling of minors

Testing of at-risk minor boys has direct medical benefit, because the disease is treatable and lethal without treatment, and GeneGuidance notes that the absence of a ClinGen actionability assertion does not reflect the clinical urgency [1, 33]. The sources consulted do not specifically deal with carrier testing in asymptomatic girls; clinical assessment of carriers of deletions that include DMD has its own indication because of the cardiac risk [78]. Psychological support is recommended for issues of hormone replacement and fertility [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The incidence of X-linked AHC due to NR0B1 is unknown; GeneReviews estimates less than 1 per 70,000 boys, based on Lin and colleagues (2006) and Guran and colleagues (2016), and knows of no populations with increased or decreased risk [1]. Orphanet assigns it a prevalence class of 1–9/100,000 (mean value 8/100,000), but cites GeneReviews itself as the source, which makes the class inconsistent with the original estimate (less than 1.4/100,000 boys); GeneGuidance uses 1.4/100,000 as the upper limit in boys, and the figure for the overall population is about half [8, 33]. Gau and colleagues give a range of 1/70,000 to 1/600,000 male births, by indirect attribution to the founding articles and to Lin and colleagues [30]. No primary population source was identified. Xp21 deletion syndrome has a prevalence below 1/1,000,000, with about 100 published cases; glycerol kinase deficiency, in all its forms, has more than 100 published male patients [23, 31, 178]. For IMAGe, GeneReviews counts 31 individuals from 19 families and Orphanet 28 cases (2014 source); for MIRAGE, GeneReviews counts 44 patients (2020) and Orphanet 19 (2016–2017 sources); the figures differ according to the date of the source and do not measure prevalence [3, 4, 25, 26]. Dystrophinopathies affect about 1 in 3600 live-born boys worldwide [29].

9.2. Proportion in paediatric PAI cohorts

The proportions of NR0B1 variants in the cohorts measure relative frequency among selected patients and not population prevalence (section 5.6). The values range from 58% of 46,XY boys referred for adrenal hypoplasia (United Kingdom and international collaboration, 2006) to 18 of 59 families in Japan, 12 of 95 children in Turkey and 7.7% of 155 children in the United Kingdom [65, 96, 133, 134]. Complete deletion of NR0B1 represents about 10–25% of X-linked AHC and contiguous deletion about 5–7% in the large cohorts [30]. The differences reflect the inclusion criteria: the 2021 British cohort excluded from the count 51 boys diagnosed by clinical testing, and the Japanese cohort included patients with biochemically uncharacterised PAI [133, 134].

9.3. United States, Europe and populations with founder effects

The sources consulted do not describe incidence studies in the United States; the American data available are clinical, such as the family with glycerol kinase deficiency studied by Shah and colleagues [79]. In Europe and the Mediterranean basin, the series from the United Kingdom, Turkey and Israel are the largest, and there are recent reports from Poland, Serbia, Spain and Georgia [65, 96, 97, 109, 110, 113, 133, 140]. In NR5A1, the pair of variants in cis p.Gly123Ala/p.Pro129Leu, described in a Senegalese female infant with ovarian insufficiency and in men from the Congo and Tunisia with azoospermia or severe oligozoospermia, has only been found in people of African origin, which suggests a founder effect; p.(Arg92Trp) shares a 1.5 Mb haplotype in affected carriers from unrelated European families [7]. In Saudi Arabia, with 70% consanguinity, four recurrent pathogenic variants in ABCD1, NR0B1 and MC2R in 10 families suggest founder effects, and X-linked inheritance was the most common [135]. In Quebec, the Saguenay–Lac-Saint-Jean region, with a proven founder effect, concentrates families with glycerol kinase deficiency due to p.Asn288Asp on a shared haplotype; the frequency in the population has not been estimated [10, 14]. In Greenland, a five-generation pedigree with the NR0B1 p.Asn440Ile variant had 11 male neonatal deaths before the diagnosis [5, 6]. In the Turkish cohorts, high consanguinity increases the weight of autosomal recessive forms in the differential [96, 136].

9.4. Portugal and Brazil

In Portugal, the Hospital Pediátrico de Coimbra described in 2025 a case of late-onset X-linked AHC in a migrant boy, and a Lisbon group (Hospital Beatriz Ângelo and the Reference Centre for Inherited Metabolic Diseases of Hospital de Santa Maria) described an Xp21 deletion without NR0B1, with dystrophinopathy and glycerol kinase deficiency; the authors state that no cases of complex glycerol kinase deficiency had previously been published in the Portuguese literature [67, 78]. In Brazil, the series from the Universidade Estadual de Campinas (UNICAMP) and university hospitals of the Southeast and South brought together 13 boys from 12 families, and the Hospital das Clínicas of the Universidade Federal de Minas Gerais described the case with normal puberty and azoospermia [42, 57]. No incidence data were found for either country, which does not demonstrate that none exist.

9.5. Special populations

Infants are the highest-risk group: mineralocorticoid surveillance should be intensive in the first 2 years, with particular care in salt or fluid restriction, losses through vomiting or diarrhoea and extreme heat [1]. Younger age is a risk factor for crisis in the Japanese cohort [155]. Adults with PAI of unexplained cause and HH or infertility are a population to be tested [55]. Patients with Xp21 deletion and intellectual disability require adapted emergency plans and educational support [30, 35]. In migrant patients, the lack of previous records may delay diagnosis, as in the Coimbra case [67].

9.6. European network and patient associations

Endo-ERN (https://endo-ern.eu/) covers the disease through the thematic groups MTG1 (Adrenal), MTG6 (hypothalamic and pituitary conditions) and MTG7 (sex development and maturation), with a directory of reference centres; EURO-NMD (https://ern-euro-nmd.eu/) covers dystrophinopathy, and MetabERN (https://metab.ern-net.eu/) glycerol kinase deficiency [37]. The associations with verified web pages are the National Adrenal Diseases Foundation (USA, https://www.nadf.us/), the Addison's Disease Self-Help Group (United Kingdom, https://www.addisonsdisease.org.uk/), Adrenal Insufficiency United (USA, https://aiunited.org/), the Pituitary Foundation (United Kingdom, https://www.pituitary.org.uk/), dsdfamilies (https://www.dsdfamilies.org/), Parent Project Muscular Dystrophy (USA, https://www.parentprojectmd.org/) and Duchenne UK (https://www.duchenneuk.org/); in Portugal, the Associação Portuguesa de Neuromusculares (https://apn.pt/), and in Brazil the Associação Brasileira de Distrofia Muscular (https://abdim.org/) [1, 37]. The BSPED provides paediatric PAI cards and leaflets (https://www.bsped.org.uk/adrenal-insufficiency), and the Society for Endocrinology the NHS steroid emergency card and sick-day rules [126, 127]. No Portuguese or Brazilian association specific to PAI was identified, which does not demonstrate that none exists.

10. Illustrative Clinical Case

10.1. Complex Xp21 deletion with IL1RAPL1, NR0B1, GK and DMD (Japan, 2026)

Gau and colleagues described a Japanese newborn, the son of non-consanguineous parents, born by caesarean section at 37 weeks and 6 days weighing 2386 g (−1.52 SD), 47 cm long, with an Apgar score of 8 at 5 minutes [30]. On day 1 he was transferred because of generalised hyperpigmentation and adrenal glands difficult to visualise on abdominal ultrasound (Figure 1A and 1B of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC12996724/figure/F1/). He had no genital ambiguity, micropenis or cryptorchidism, and there was no initial salt wasting: sodium 143 mEq/L, potassium 3.7 mEq/L, pH 7.438 and glucose 96 mg/dL. ACTH was 6420 ng/L, cortisol 0.7 µg/dL, aldosterone below 0.4 pg/mL, renin activity 13.2 ng/mL/h and 17-OHP 1.2 ng/mL. He was treated with IV fluids, electrolytes, hydrocortisone and fludrocortisone, with good weight gain (Figure 1C) [30]. Persistently raised CK raised the suspicion of a contiguous gene syndrome; urinary organic acid analysis by gas chromatography-mass spectrometry showed excessive glycerol excretion, and array-CGH identified arr Xp21.1p21.3(GRCh37:X:29,096,607–31,516,964)x0, with gains at both ends (X:28,611,286–28,829,824)x3 and (X:31,852,489–32,001,787)x3, spanning IL1RAPL1 (exons 3–11), NR0B1, GK and DMD (exons 57–79), a duplication–deletion–duplication rearrangement described as novel [30]. Development was delayed: head control at 8 months, rolling over at 10 months and, at 1 year, 7835 g (−1.7 SD), not sitting and with a developmental quotient of 57; magnetic resonance imaging at 8 months showed no lesions attributable to crises. His 2-year-old sister had mild delay, a waddling gait, a positive Gowers sign, raised CK and the same deletion, and the mother had raised CK and the same deletion, with a milder phenotype that the authors attributed to X inactivation [30].

The case brings together the central lessons of the class: low 17-OHP with raised ACTH and renin distinguishes AHC from CAH; the initial absence of salt wasting does not exclude mineralocorticoid deficiency (aldosterone was undetectable); CK and urinary glycerol point to contiguous deletion; and CMA defines the extent, including IL1RAPL1, which explains the developmental delay independently of the crises [30, 32]. The authors recommend a full developmental assessment and not attributing the delay prematurely to the crises; in the second case of the same series, with deletion of NR0B1 and IL1RAPL1 without GK or DMD, the delay was attributed to the crises until 10 years of age, when the intelligence quotient was 48 [30]. The management described is in line with the replacement guidelines, and the assessment of the symptomatic carriers (sister and mother) illustrates the need for clinical assessment of the women in the family [33, 34].

10.2. Late-onset X-linked AHC with a previous diagnosis of CAH (Portugal, 2025)

Nico and colleagues, from the Hospital Pediátrico de Coimbra, described a 13-year-old migrant boy referred with “CAH” diagnosed at 4 years because of persistent fatigue, without records, treated with prednisolone 3.9 mg/m²/day and fludrocortisone 300 µg/day, without salt-wasting crises and with occasional infections during which he increased the glucocorticoids [67]. He had no hyperpigmentation, blood pressure was normal, he weighed 28.4 kg and measured 127 cm (z −4.34), was prepubertal and bone age was 7 years. Basal ACTH was below 5.0 pg/mL (suppression by prednisolone), cortisol 0.6 µg/dL, aldosterone 16.0 pg/mL and DHEA-S below 0.15 µg/mL [67]. He was switched to hydrocortisone 10 mg/m²/day in three doses and fludrocortisone 50 µg/day; CYP21A2 MLPA was negative in the proband and in a half-brother. During follow-up, ACTH rose to 731, 1099, 420 and 492 pg/mL, while 17-OHP (0.04 ng/mL), DHEA-S and androstenedione remained low; hydrocortisone was adjusted to 13 and 12.5 mg/m²/day [67]. At 14 years and 11 months he was still prepubertal, with testosterone below 0.1 ng/mL, FSH 1.3 mIU/mL and LH 0.2 mIU/mL, consistent with HH. The combination of PAI and HH led to next-generation sequencing, which identified the hemizygous variant NM_000475.5:c.1292del p.(Ser431IlefsTer6) in exon 2, until then described only in early-onset disease [9, 67]. At 15 years he started IM testosterone 25 mg/month, with Tanner stage II at 6 months (testes of 5–6 mL) and an increase to 50 mg/month, with a height z-score of −3.53 [67]. The pedigree (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC12783928/figure/FIG1/) shows the mother as an obligate carrier, a 7-year-old maternal half-brother with a similar biochemical profile and an asymptomatic 21-month-old maternal half-brother, both awaiting genetic testing [67].

This case shows the risk of a “CAH” label without confirmation: fludrocortisone at 300 µg/day was three times the guideline’s initial paediatric dose (100 µg/day), and the guideline also advises against prednisolone and other long-acting glucocorticoids in children; prednisolone suppressed ACTH, masking the biochemical clue [34, 67]. The diagnostic clue was the persistently low adrenal androgens despite raised ACTH [67]. The same variant presented in the 1st month in a Brazilian boy, which illustrates the absence of genotype-phenotype correlation [42].

11. Prognosis and Long-Term Follow-Up

11.1. Natural history without and with treatment

Without replacement, the PAI of X-linked AHC is rapidly lethal through hyperkalaemia, acidosis, hypoglycaemia and shock and, if unrecognised, may leave neurological sequelae [1]. The Brazilian series illustrates the burden of mortality before diagnosis: two families had brothers who died early without a known cause (one at 37 days, with vomiting and dehydration) and two had cardiorespiratory arrest [42]. With treatment, survival depends on the prevention of crises: death from a crisis can still occur in known patients if replacement is not adjusted to stress or fluid losses [1]. In adult PAI in general, the frequency of crises is 6.6–8.3 per 100 patient-years, with mortality of 0.5 per 100 patient-years in a prospective study; in Japanese paediatric PAI, 4.27 per 100 person-years; these figures refer to PAI in general and not specifically to AHC [34, 155]. Family 10 of the Brazilian series stopped glucocorticoids and mineralocorticoids for one year, after 3–4 years of treatment, and resumed them, which shows that the need for replacement persists [42]. Without testosterone, secondary sexual characteristics remain incomplete, and infertility due to azoospermia is the rule in the classic form, with the only published paternity obtained by testicular sperm extraction and ICSI [1, 36]. Height may be compromised by late diagnosis and glucocorticoid overtreatment, as in the Coimbra case (height z-score −4.34 at 13 years) [34, 67].

11.2. Prognosis of the grouped entities

In Xp21 deletion, prognosis is determined by dystrophinopathy, when DMD is included, and by intellectual disability, when IL1RAPL1 is included; the 2018 GeneReviews reports death in adolescence or young adulthood, the mean age at death in Duchenne dystrophy with specialist care is about 30 years, and the 2026 GeneReviews describes increased longevity [1, 29, 77]. In isolated glycerol kinase deficiency, the long-term prognosis is very good with appropriate management, and decompensations decrease after puberty; in complex deficiency, it depends on early recognition and treatment of PAI [31]. In IMAGe, development was normal in 15 of 16 individuals with information, the oldest aged 26 years, and unexpected death from unrecognised PAI is the main avoidable risk [3, 47]. In MIRAGE, the median age at death is 3 years, about 60% of deaths are due to infection, and the oldest known patient in 2020 was 20 years old; in 2026 a 22-year-old survivor was described [4, 118]. In DSS duplication, the risk of gonadoblastoma (17%) and of germ cell tumour (2.1%) shapes follow-up [83].

11.3. Surveillance table

The surveillance recommendations for MIRAGE do not derive from formal guidelines, but from the experience of the GeneReviews authors [4]. The autoimmunity screening of the Endocrine Society guideline applies to PAI of autoimmune cause and not to AHC of confirmed genetic cause [34]. ACTH measurement is not useful for routine monitoring of hydrocortisone, because it typically remains above the reference range even with adequate replacement; a sudden rise on stable treatment should, however, be investigated, given the corticotroph adenoma described [34, 104].

12. Summary and Concluding Remarks

X-linked AHC due to NR0B1 is a cause of primary PAI in boys, with a salt-wasting crisis in the first month in about 60% and onset in childhood in about 40%, and it combines HH with a primary testicular defect. Normal or low 17-OHP with raised ACTH and renin and suppressed adrenal androgens distinguishes it from CAH, which is the first diagnosis to exclude and the most frequent wrong label. Raised CK, pseudohypertriglyceridaemia, urinary glycerol and developmental delay indicate a contiguous Xp21 deletion involving GK, DMD or IL1RAPL1, whose extent can only be defined by CMA or an equivalent copy-number analysis; sequencing alone misses deletions, which account for about a quarter of cases.

Treatment consists of replacement with hydrocortisone (about 8 mg/m²/day in children), fludrocortisone (100 µg/day) and sodium chloride until 12 months, with stress doses, an emergency card and kit; the US and British guidelines diverge in how they calculate sick-day and crisis doses, and each centre should adopt a single written scheme. Pubertal induction with testosterone starts at around 12 years with low doses, outside the conditions of the European testosterone SmPCs, and fertility, limited by the testicular defect, justifies early discussion of semen analysis and cryopreservation. In a deletion that includes DMD, corticosteroid therapy for dystrophinopathy is superimposed on permanent primary PAI, and vamorolone, a mineralocorticoid antagonist, does not replace hydrocortisone under stress. In isolated glycerol kinase deficiency, recognising pseudohypertriglyceridaemia avoids years of useless lipid-lowering drugs. The class differentials (NR5A1, IMAGe, IMAGe-I, MIRAGE) differ in inheritance, extra-adrenal features and prognosis, and MIRAGE requires non-haematopoietic DNA to avoid false negatives.

Counselling follows X-linked inheritance: the mother is a carrier in most cases, boys in the maternal line should be tested before symptoms, and female carriers of deletions involving DMD have an indication for clinical and cardiological assessment. The available prevalence estimates (less than 1 per 70,000 boys) do not derive from population studies, and the data from Portugal and Brazil come from cases and series published in 2025–2026, with no clinical trials directed at these entities.

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