Smith–Lemli–Opitz syndrome is a defect in cholesterol biosynthesis due to disruption of the enzyme 7-dehydrocholesterol reductase (DHCR7) (19). Common findings in infancy are microcephaly, cleft palate, syndactyly of the second and third toes, post-axial polydactyly, congenital heart defects, gastrointestinal issues (e.g., pyloric stenosis), atypical genital and undescended testes (46,XY) and characteristic facial features (20). AI or impaired stress response can occur, but are surprisingly rare (21, 22). Elevated 7-dehydrocholesterol is diagnostic, coupled with genetic testing.

Steroidogenic acute regulatory protein (STAR) plays a key role in cholesterol transport into the mitochondria, whereas the P450 cholesterol side-change cleave enzyme (P450scc, encoded by CYP11A1) catalyzes the conversion of cholesterol to pregnenolone (Figure 1) (23, 24). These proteins are both required for adrenal (glucocorticoid, mineralocorticoid) and gonadal (testosterone, estrogen) steroid synthesis. Severe disruption causes salt-losing AI in all children and female-typical external genitalia in 46,XY infants. The onset of PAI usually occurs at around 3–4 weeks of age in complete STAR deficiency (also known as “congenital lipoid adrenal hyperplasia”), as build-up of intracellular cholesterol takes time to cause cellular damage (“two-hit hypothesis”) (25). In contrast, infants with a severe P450scc deficiency usually present with salt-losing PAI at around 7-10 days (26, 27). Partial disruption of these proteins results in predominant glucocorticoid insufficiency in childhood (27–31).

The most common cause of PAI in the first month of life is congenital adrenal hyperplasia (CAH) (23). In virtually all populations, 21-hydroxylase deficiency (21-OHD, CYP21A2) is most prevalent, with an incidence of 1:10,000–1:20,000 (although geographical hotspots occur) (32, 33). Other rare forms of CAH include 11 beta-hydroxylase deficiency (CYP11B1) (especially in Jewish populations originating from Morocco), 3 beta-hydroxysteroid dehydrogenase deficiency (HSD3B2), 17 alpha-hydroxylase deficiency (CYP17A1) and P450 oxidoreductase deficiency (POR), all of which have specific presentations and biochemical profiles (Table 1) (23).

Approximately 80% of 46,XX girls with confirmed 21-OHD have atypical genitalia at birth, so any baby with genital differences and non-palpable gonads should be considered as having 21-OHD until proven otherwise (33, 34). Progressive salt loss usually results in hyperkalemia and hyponatremia at around 5–7 days of life, mandating urgent monitoring and treatment once the diagnosis is made. Boys (46,XY) with 21-OHD have no obvious signs at birth and usually present in a salt-losing adrenal crisis between 1 and 2 weeks of age, so many countries include 17-hydroxyprogesterone in their newborn screening program. More detailed reviews of CAH and its management are presented elsewhere (32, 33).

X-linked congenital adrenal hypoplasia (adrenal hypoplasia congenita, AHC) primarily affects boys and is associated with disruption of the nuclear receptor, DAX-1 (encoded by NR0B1) (35, 36). This condition presents with salt-losing PAI in the first 2 months of life (40%), or more insidiously with AI in childhood (37). Late-onset forms of the condition have also been described (38–40).

X-linked AHC has three main features: PAI, hypogonadotropic hypogonadism (HH) in adolescence, and impaired spermatogenesis (41). Some boys may paradoxically have macrophallia at birth, and initial presentation with either isolated mineralocorticoid insufficiency or isolated glucocorticoid insufficiency is reported (42, 43). Growth hormone insufficiency has also been diagnosed in a small subset of boys (37, 44–46).

Boys with PAI and HH in adolescence almost invariably have X-linked AHC, especially if there is a family history of X-linked adrenal dysfunction. Even without such a history, we found that approximately 40% of boys presenting with salt-losing AI in the first two months of life had X-linked AHC, once more common conditions such as CAH had been excluded (47). Approximately two-thirds of boys have pathogenic missense or loss-of-function (stop gain, frameshift) variants in DAX-1/NR0B1, around one-sixth have a localized deletion of this gene on the X-chromosome (Xp21), and one-sixth have a larger Xp contiguous gene deletion syndrome that can involve genes causing glycerol kinase deficiency (GKD), ornithine transcarbamylase deficiency (OTC) and Duchenne Muscular Dystrophy (DMD) (47). Very rarely, girls have X-linked AHC due to skewed X-inactivation (48). Establishing this diagnosis early allows prompt recognition and management of both the PAI and potential associated conditions (39). Families can be counseled about risk in brothers or in the maternal family, and presymptomatic boys diagnosed (49).

Steroidogenic factor-1 (SF-1/NR5A1) is a related nuclear receptor considered as a “master-regulator” of adrenal and reproductive development (36). Severe disruption of SF-1 has very rarely been associated with early-onset PAI in 46,XX girls and 46,XY phenotypic female babies with testicular dysgenesis, usually due to disruption of key DNA-binding elements of this transcription factor (50, 51). In contrast, more than 200 individuals and families with heterozygous pathogenic variants in SF-1/NR5A1 have been reported, having a wide spectrum of reproductive phenotypes (from gonadal dysgenesis through to male factor infertility or primary ovarian insufficiency and ovotesticular DSD) (36, 52–54). To date, adrenal function is normal in most of these individuals.

AI associated with IUGR/FGR can occur as part of IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia, genitourinary anomalies) (55, 56). Children usually present with salt-losing PAI in early life. Other variable features include frontal bossing, impaired glucose tolerance, and hearing loss.

Classic IMAGe syndrome is associated with gain-of-function variants in the cell-cycle repressor, CDKN1C (56). This is a paternally-imprinted (maternally-expressed gene), so is usually inherited from the mother, but can occur de novo. IMAGe-associated pathogenic variants are localized within a very specific motif in the PCNA-binding motif of CDKN1C, causing impaired cell cycle S-phase progression (57). Variants neighboring this motif can cause IUGR/Russell-Silver Syndrome phenotypes with normal adrenal function (58, 59). Of note, loss-of-function of CDKN1C is associated with Beckwith-Wiedemann syndrome, an “overgrowth” syndrome, highlighting how different changes in one gene can have opposing phenotypes (58).

Recently, an “IMAGe-like” syndrome with AI and immunodeficiency (infections, lymphopenia, hypogammaglobulinemia) has been reported (60). These children have profound postnatal growth restriction, distinctive facial features, hip dysplasia and hypoplastic patellae. This condition results from pathogenic biallelic variants in polymerase epsilon-1 (POLE1, Pol ε), often involving a heterozygous intronic variant (c.1686 + 32C>G). POLE1 is a DNA polymerase that interacts with PCNA in S-phase DNA replication.

Another multisystem growth restriction syndrome associated with adrenal hypoplasia is MIRAGE syndrome (myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy) (61, 62). Infants with severe forms of MIRAGE are born preterm and develop salt-losing PAI in early life. Recurrent infections (viral, bacterial and fungal), anemia/thrombocytopenia, nephropathy, severe enteropathy, esophageal reflux and aspiration are common, and 46,XY children have penoscrotal hypospadias or gonadal (testicular) dysfunction with a female phenotype. Mortality is high and children who survive show long-term growth restriction. As many of these features are found in sick, preterm, growth-restricted babies, it is likely that this condition is under-diagnosed.

MIRAGE syndrome results from heterozygous gain-of-function missense mutations in the growth repressor, sterile alpha domain containing 9 (SAMD9) (61, 62). These changes usually occur de novo and restrict cell growth and division, potentially through reduced recycling of growth factor receptors. SAMD9 also plays a role in innate viral immunity and host defense.

One interesting aspect of MIRAGE syndrome is how secondary genetic events can dynamically modify the phenotype through “revertant mosaicism.” For example, development of progressive, somatic monosomy 7 in cis (i.e., on the same allele) “removes” the deleterious gain-of-function mutation in SAMD9 allowing a clonal growth advantage of these affected cells, especially in the hematopoietic system, and reversal of the postnatal anemia and thrombocytopenia (61, 62). However, monosomy 7 is linked to the development of myelodysplastic syndrome, which can lead to leukemia if other genetic changes occur. Interestingly, somatic loss-of-function (nonsense or frameshift) changes or uniparental disomy in cis can also “remove” the mutant allele and ameliorate the phenotype (5, 62–64). Increasingly, children with milder MIRAGE-like features are being reported, many with normal adrenal function (65).

SeRKAL syndrome (female sex reversal and dysgenesis of kidneys, adrenals, and lungs) has been reported in a single family with homozygous disruptive mutations in WNT4, a signaling molecule implicated in adrenal development (66). Other historic reports have rarely described AI with Pena–Shokeir syndrome type I (DOK7, RAPSN), pseudotrisomy 13, Galloway–Mowat syndrome (WDR73), Pallister–Hall syndrome (GLI3, with pituitary defects) and Meckel–Gruber syndrome (MKS1) (67).

Familial Glucocorticoid Deficiency Type 1 (FGD1) is a recessive condition that results from pathogenic variants in the ACTH receptor (melanocortin 2 receptor, MC2R) (68, 69). Children sometimes present in the first weeks of life with signs of cortisol insufficiency (hypoglycemia/convulsions, prolonged jaundice) and marked hyperpigmentation. Genuine mineralocorticoid insufficiency is very rare, but transient salt loss or dilutional hyponatremia can occur, sometimes leading to a misdiagnosis of adrenal hypoplasia (70, 71). FGD1 can also present later in childhood with recurrent infections, hyperpigmentation, and lethargy. Generally, children respond very well to glucocorticoid replacement, but ACTH concentrations can be difficult to suppress.

A similar form of ACTH-resistance results from disruption of the melanocortin 2 receptor accessory protein, MRAP (72). MRAP traffics MC2R to the adrenal cell membrane surface, so disruption of its function (usually due to splicing defects in exon 3) impairs ACTH signaling (68, 73, 74). Affected children usually present with severe glucocorticoid insufficiency and hyperpigmentation in the first few months of life.

Defects in nicotinamide nucleotide transhydrogenase (NNT) are a well-established cause of isolated PAI in children, and occasionally additional features such as early puberty have been reported (68, 75, 76). This condition mostly presents after 1 year of age but has been reported as early as 4 months of age. To date, defects in thioredoxin reductase 2 (TNXRD2) are reported in a single family (sometimes with cardiac defects), and present in mid- or later childhood (77).

Triple A syndrome is a well-established condition linking PAI (“Addison disease”), with alacrima and achalasia of the esophagus (78, 79). This condition results from disruption of the protein aladin (encoded by AAAS), a potential nucleoporin component that may also influence cellular stress (80–82). Alacrima is often present from birth but is difficult to diagnose. Other features usually develop in childhood, or in the second decade of life (83, 84). Progressive neurological and autonomic dysfunction can also co-occur, so this is an important diagnosis to consider.

Disruption of minichromosome maintenance 4 (MCM4) causes mild PAI together with short stature and immunodeficiency (85). To date, this is only reported in individuals of Irish Traveller ancestry, and typically manifests in mid-childhood. As noted above, partial (non-classic) high steroidogenic blocks (STAR and CYP11A1) can present in childhood with PAI. Non-classic STAR defects are sometimes termed FGD3 (27–31).

SGPL1 deficiency is a novel sphingolipidosis that results from impaired breakdown of sphingosine 1-phosphate (87–89). Key features are PAI (sometimes with adrenal calcifications) and steroid-resistant nephrotic syndrome (SRNS), as well as ichthyosis, neurological dysfunction, primary hypothyroidism, lymphopenia and undescended testes. Many children present with PAI in the first year of life (hyperpigmentation, or adrenal crisis), although some first present with SRNS and the use of steroid treatment may delay the adrenal phenotype. Other features are variable and can appear or progress with time.

Adrenoleukodystrophy (ALD) is a very important cause of PAI because of associated progressive neurological features (90). The X-linked form of ALD due to defects in ABCD1 usually presents in childhood, and sometimes with adrenal-only features. Thus, all boys with undiagnosed causes of PAI should have long-chain fatty acids measured and there are some calls for newborn screening to increase early detection, since allogenic hematopoietic stem cell transplantation may reduce the progression of cerebral X-ALD in patients with early stages of disease, and hematopoietic stem cell gene therapy has been investigated (91–94). In contrast, “neonatal adrenal leukodystrophy” is now classified as part of the “Zellweger Spectrum Disorders” (with Zellweger syndrome/cerebrohepatorenal syndrome, infantile Refsum disease and rhizomelic chondrodysplasia punctata type 1) (95). This spectrum of disorders results from defects in peroxisomal function (13 different PEX genes and others) and has many features including hypotonia, seizures, hepatic dysfunction and renal cysts. PAI has been reported, usually in childhood or with an impaired stress response (96), so screening after 1 year of age has been recommended (95).

Mitochondrial defects have a range of causes and presenting features. Adrenal dysfunction occurs in rare cases, more often associated with large scale mitochondrial DNA deletions (e.g., Kearns-Sayre and Pearson syndromes), but also pathogenic variants in other related genes (e.g., MK-TK, MRPS7, QRSL1, NDUFAF5, GFER) (86, 97).

Wolman disease (primary xanthomatosis) results from disruption of lysosomal acid lipase (LIPA), and is associated with AI (often with adrenal calcifications), failure to thrive, hepatosplenomegaly and anemia in the first few months of life. It is a lysosomal storage disorder that is usually fatal, although improvements with enzyme replacement treatment (sebelipase alfa) are reported (98–100).