ABSTRACT

Congenital adrenal hypoplasia is a rare cause of primary adrenocortical failure, which was first described in 1948. During the last two decades, the genetic basis for several forms of familial adrenal insufficiency syndromes has been elucidated. The molecular mechanisms for these disorders involve a broad spectrum of cellular and physiologic processes, including metabolism, nuclear protein import, oxidative stress defense-mechanisms, and regulation of cell cycle. Adrenal hypoplasia can occur: 1) secondary to defects in transcription factors involved in pituitary development or 2) defects in ACTH synthesis and secretion; 3) as a primary defect in the development of the adrenal gland; 4) as part of rare syndromes associated with adrenal hypoplasia/aplasia, which are inherited in an autosomal recessive or autosomal dominant manner; and 5) in the context of chromosomal abnormalities. Early diagnosis and management are crucial because of the life-threatening nature of the condition. Depending on the etiology, adrenal crisis may occur in early infancy or could insidiously develop over the course of childhood or adolescence. Moreover, some of these conditions previously thought to occur only in childhood, may also be diagnosed later in adulthood and present with variable phenotypes, including isolated infertility or disorders of sex differentiation. The clinical manifestations of primary adrenal insufficiency (PAI) result from deficiency of all adrenocortical hormones (aldosterone, cortisol, androgens). The acute presentation can be precipitated by physiologic stress, such as surgery, trauma, or an intercurrent infection. Patients may present with signs and symptoms of complete adrenal insufficiency, usually early in life, including hypoglycemic convulsions, hyponatremia, hyperkalemia, metabolic acidosis or later with hyperpigmentation, vomiting and poor weight gain. It should be remembered, that the most common cause of PAI in children is congenital adrenal hyperplasia due to 21-hydroxylase deficiency and can be excluded by measuring baseline or ACTH-stimulated 17-hydroxyprogesterone levels in serum. Screening for autoimmune Addison disease includes detection of 21-hydroxylase antibodies. Males with negative 21-hydroxylase antibodies should be tested for adrenoleukodystrophy measuring very–long-chain fatty acids concentrations in plasma. The presence of alacrima in patients with PAI should raise suspicion for Triple A syndrome, whereas the combination of PAI and hypogonadotropic hypogonadism in a male patient point towards X-linked adrenal hypoplasia congenita. To date, molecular genetic testing is commercially available for the identification of several genes involved in adrenal hypoplasia syndromes. The early identification of these diseases can have important prognostic and therapeutic implications for patients with respect to surveillance for associated conditions, initiation of early treatment or screening of family members who are at risk. Adrenal insufficiency is potentially life threatening, thus treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in adrenal crisis. Therapy consists of life-long replacement therapy with glucocorticoids and mineralocorticoids. Hypogonadism or other associated disorders should be treated appropriately. Screening of family members for the disease or carrier status may also be indicated and can be critical for family planning. When a monogenic cause of adrenal failure is identified, genetic counseling is indicated. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The adrenal glands consist of two anatomically and functionally distinct subunits, the cortex and the medulla. The adrenal cortex secretes glucocorticoids, mineralocorticoids and androgens. The glucocorticoid, cortisol, is secreted by the cells of the intermediate zona fasciculata. Its secretion is tightly regulated by the hypothalamic corticotropin-releasing hormone (CRH) and vasopressin (AVP) and by the pituitary adrenocorticotropic hormone (ACTH) (1). Glucocorticoids regulate a broad spectrum of physiologic functions essential for life and play an important role in the maintenance of basal and stress-related homeostasis. The mineralocorticoid, aldosterone, is produced by the outer adrenal zona glomerulosa. This steroid regulates water and electrolyte homeostasis and its secretion is primarily under the control of the renin-angiotensin system, although it may be weakly influenced by ACTH. The adrenal androgens, dehydroepiandrosterone (DHEA), its sulfate (DHEA-S) and androstenedione, are secreted by the inner zona reticularis under the control of ACTH.

CONGENITAL ADRENAL HYPOPLASIA

Congenital adrenal hypoplasia is a rare cause of primary adrenocortical failure, which was first described in 1948. It has an estimated frequency of 1:12,500 live births (2). During the last decade there have been significant advances in our understanding of the genetic etiology of several forms of adrenal insufficiency with a presentation in infancy or childhood. Several of these conditions affect adrenal development and are commonly known as adrenal hypoplasia. Adrenal hypoplasia may be due to (3-9):

1.

Secondary to defects in transcription factors involved in pituitary development (e.g. HESX1, LHX4, SOX3) or defects in ACTH synthesis (TPIT), processing and release (e.g. POMC or PC1);

2.

Part of an ACTH resistance syndrome [MC2R/ACTH receptor, MRAP, AAAS (triple A syndrome), StAR, CYP11A1, MCM4, NNT, TXNRD2, GPX1, PRDX3 mutations];

3.

A primary defect in the development of the adrenal gland itself (primary/congenital adrenal hypoplasia; X-linked form/DAX1 gene mutations or deletions, autosomal recessive form/SF-1 gene mutations or deletions, autosomal recessive form of uncertain etiology, IMAGe syndrome, MIRAGE syndrome, Familial steroid-resistant nephrotic syndrome with adrenal insufficiency due to SGPL1 deficiency);

4.

Part of rare syndromes associated with adrenal hypoplasia/aplasia, which are inherited in an autosomal recessive (Meckel-Gruber syndrome, Pena-Shokeir syndrome, Pseudotrisomy 13, Hydrolethalus syndrome, Galloway-Mowat syndrome) or autosomal dominant (Pallister-Hall syndrome) manner; and

5.

In the context of chromosomal abnormalities (tetraploidy, triploidy, trisomy 18, trisomy 21, 5p duplication, monosomy 7 and the 11q syndrome), which are often associated with central nervous system (CNS) abnormalities.

There are two distinct histological patterns of the adrenal cortices in this rare syndrome, the miniature adult and cytomegalic forms. In the miniature adult form of adrenal hypoplasia congenital (AHC), the small amount of residual adrenal cortex is composed primarily of permanent adult cortex with normal structural organization. The miniature adult form is either sporadic or inherited in an autosomal recessive manner, and is frequently associated with abnormal CNS development, including anencephaly or pituitary gland abnormalities.

In the cytomegalic form of AHC, the residual adrenal cortex is structurally disorganized with scattered irregular nodular formations of eosinophilic cells, with the adult permanent zone absent or nearly absent. Enlarged cells are present, some with abundant vacuolated cytoplasm. The cytomegalic form is generally considered to be X-linked, but there may be one or more autosomal genes associated with this phenotype (6, 10, 11).

Genetic causes of adrenal hypoplasia and aplasia syndromes are summarized in Table 1. However, this review focuses on ACTH resistance syndromes and disorders of adrenal gland development.

ADRENAL HYPOPLASIA AS PART OF AN ACTH RESISTANCE SYNDROME

ACTH resistance syndromes include two distinct genetic disorders, both of which are inherited in an autosomal recessive manner and are characterized by ACTH insensitivity:

1.

Familial Glucocorticoid Deficiency (FGD)

2.

Allgrove syndrome or Triple A syndrome

Familial Glucocorticoid Deficiency (FGD)

Familial (isolated) glucocorticoid deficiency (FGD), which is also known as hereditary unresponsiveness to ACTH, is a rare autosomal recessive disorder characterized by glucocorticoid deficiency (12, 13). The underlying genetic defect is known in approximately 70% of patients with FGD.

CLINICAL AND LABORATORY FEATURES OF FGD

Patients with FGD are usually diagnosed during the neonatal period or in early childhood. However, the oldest affected member of the kindred, carrying MCM4 and TXNRD2 mutations (see Genetics below), presented at the age of 8.5 years and 10.8 years, respectively (14, 15). Patients with FDG may present with hypoglycemic seizures, hyperpigmentation, recurrent infections, transient neonatal hepatitis, failure to thrive, collapse and coma. The long-term neurological sequelae of FGD can vary from learning difficulties to spastic quadriplegia, which may reflect the severity and number of hypoglycemic episodes in childhood. There may be a family history of unexplained neonatal death, history of other family member(s) affected with FGD and/or parental consanguinity (12, 16).

The clinical manifestations of FGD reflect resistance to ACTH. The typical hormonal profile in FGD is a combination of low cortisol but high plasma ACTH concentrations, in the presence of normal plasma renin activity and aldosterone concentrations. Most patients with FGD have markedly elevated ACTH concentrations, which correlate with the degree of ACTH resistance. Hyperpigmentation is often observed during the first months of life owing to the effect of ACTH on the melanocortin-1 receptors in melanocytes (12).

ADRENAL IMAGING

In the MRI or CT scans, the adrenal glands appear small in size.

HISTOPATHOLOGY

Absence of fasciculata or reticularis cells and disorganization of glomerulosa cells have been observed (17).

GENETICS

FGD was first described by Shepard et al. (18) in 1959, when he reported two siblings with “familial Addison’s disease”. It took 30 years for the first inactivating ACTH receptor mutations to be detected (19, 20). To date, FGD has been associated with mutations in seven genes: MC2R (ACTH receptor/melanocortin 2 receptor) (OMIM 202200), MRAP (MC2R accessory protein) (OMIM 607398), StAR (steroidogenic acute regulatory protein) (OMIM 201710), CYP11A1 (cytochrome P450, family 11, subfamily A, polypeptide 1) (OMIM 613743), NNT (nicotinamide nucleotide transhydrogenase) (OMIM 614736), MCM4 (the mini chromosome maintenance-deficient 4 homolog gene) (OMIM 609981), TXNRD2 (thioredoxin reductase 2) (OMIM 617825), GPX1 (Glutathione Peroxidase 1) and PRDX3 (peroxiredoxin 3) (9, 21,). Mutations in the MC2R and MC2R accessory protein (MRAP) account for approximately 50% of all cases.

The ACTH receptor MC2R is a 7-membrane G-protein coupled receptor located almost exclusively in the adrenocortical cells. To date, more than 50 mutations have been described in the MC2R gene (Human Gene Mutations Database, www.hgmd.cf.ac.uk) and represent the most common cause of FGD (25% of cases, FGD type 1) (8, 16). Some of them are shown in Table 2. FGD type 1 patients usually present in early childhood. Tall stature has been observed in some cases (22).

TABLE 2:

Mutations of the MC2R in FGD Patients

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Mutation	Probable Effect of Mutation	Reference
p.D107G	Failure to bind ACTH	Aza-Carmona et al,13.
p.R145C	Trafficking defect	Aza-Carmona et al,13.
c.459_460insC	Translation frame shift after codon 154 and a premature termination codon at 248 of the MC2R mRNA (p.I154fsX248)	Al Kandari et al,43.
p.Leu225Arg	Unknown	Akin et al,44.
K289fs	Impaired cell surface expression (Loss of C terminus of MC2R)	Hirsch et al,45.
G116V	Impaired cell surface expression	Collares et al,46.
T159K	Impaired cell surface expression	Elias et al,47.
D20N	Possible loss of ligand affinity	Chung et al,48.
H170L	Loss of signal transduction	Chung et al,48
D103N	Loss of signal transduction and loss of ligand affinity	Berberoglu et al,49, Chung et al,48.
R137W	Loss of signal transduction	Ishii et al,50.
P273H	Possible structural disruption	Wu et al,51.
S120R	Possible structural disruption	Tsigos et al,20,52.
R201X	Truncated receptor	Tsigos et al,20.
S74I	Possible loss of ligand affinity	Clark et al,19.
I44M	Possible loss of ligand affinity	Weber et al,53.
Y254C	Possible structural disruption	Tsigos et al,52,54.
R146H	Loss of signal transduction	Weber et al,53.
R128C	Loss of signal transduction	Weber et al,53 .
L192fs	Truncated receptor	Weber et al,53.
D107N	Loss of ligand affinity and loss of signal transduction	Naville et al,55, Chung et al,48.
C251F	Possible structural disruption	Naville et al,55.
G217fs	Truncated receptor	Naville et al,55.
p.Pro281GlnfsX9	Frameshift mutation	Delmas et al,56.

In 2005, a second gene was identified, located at 21q22.1 and encoding MC2R accessory protein (MRAP), a 19-kDa single-transmembrane domain protein. In humans, MRAP is expressed in the adrenal cortex, pituitary, brain, testis, ovary, breast, thyroid, lymph node, skin, and fat. This protein serves as an essential cofactor of MC2R to promote its trafficking from the endoplasmic reticulum to the cell surface and subsequent signaling in response to ACTH (16, 23-25). Mutations in MRAP are responsible for a further 15-20% of FGD cases (FGD type 2). Most patients with FGD type 2 present in the neonatal period or in very early infancy. However, missense MRAP mutations are associated with a milder phenotype and late onset adrenal insufficiency (AI) (26). Interestingly, obesity has been reported in a patient harboring homozygous MRAP mutations and his heterozygous family members, whereas the only unaffected member of the family had normal weight (25). Studies on Mrap-/- mice demonstrated the important role of MRAP plays in both steroidogenesis and the regulation of adrenal cortex zonation. Mrap-/- mice were shown to have isolated GC deficiency with normal aldosterone and catecholamine production and small adrenal glands with gross impairment of the adrenal capsular morphology and cortex zonation. Furthermore, progenitor cell differentiation was significantly impaired, with dysregulation of WNT4/b-catenin and sonic hedgehog pathways (27). MRAP mutations are summarized in Table 3.

TABLE 3:

Mutations of the MRAP in FGD Patients

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Mutation	Probable Effect of Mutation	References
c.106+2_3dupTA	Skipping of exon 3 (No protein or lack transmembrane domain)	Jain et al,16.
c.3G>A	Unknown	Chung et al,57, Collares et al,46, McEachern et al,58.
c.175T>G	Full-length protein with amino acid change-impaired cAMP generation	Hughes et al,59.
c.76T>C	Full-length protein with amino acid change-impaired cAMP generation	Hughes et al,59.
c.106+2insT	Skipping of exon 3 (No protein or lack transmembrane domain)	Chung et al,57, Metherell et al,23.
c.106+1G>T	Skipping of exon 3 (No protein or lack transmembrane domain)	Chung et al,57, Metherell et al,23
c.106+1G>A	Skipping of exon 3 (No protein or lack transmembrane domain)	Chung et al,57, Metherell et al,23.
c.106+1G>C	Skipping of exon 3 (No protein or lack transmembrane domain)	Chung et al,57, Metherell et al,23.
c.106+1delG	Skipping of exon 3 (No protein or lack transmembrane domain)	Chung et al,57., Metherell et al,23., Akin et al60.
c.33C>A	Shortened protein if translated	Chan et al,12.
c.17-23delACGCCTC	Shortened protein if translated	Modan-Moses et al,61.
c.128delG (p.V44X)	Frameshift mutation causing a premature termination (V44X) in exon 4	Metherell et al,23, Rumie et al,25

Interestingly, mutations in steroidogenic acute regulatory protein (StAR) and more rarely cytochrome P450 family 11 subfamily A member 1 (CYP11A1) have also been detected in patients with FGD (StAR: approximately 5% of FGD patients). Mutations in these two enzymes usually result in Congenital Lipoid Adrenal Hyperplasia (CLAH), a severe disorder with both adrenal and gonadal steroid insufficiencies. However, certain, partial loss-of-function mutations may be associated with a milder phenotype with no gonadal derangement, termed non-classic CLAH (NCLAH). To date, nine StAR mutations have been reported in patients with NCLAH. Of note, affected individuals require life-long monitoring of both adrenal and gonadal function because their disorder may evolve. Hypogonadism and infertility may occur in adulthood. (28-31).

Recently, mutations in the mini chromosome maintenance-deficient 4 (MCM4) homolog gene have been identified in an Irish travelling community presenting with a variant of FGD. These patients had short stature, chromosomal breakage, natural killer cell deficiency and progressive primary adrenal insufficiency (PAI) characterized by ACTH resistance with glucocorticoid deficiency and normal mineralocorticoids (MC) levels. Typically, patients started with normal adrenal function and developed PAI over time. The MCM4 gene, mapped on 8q11.2 chromosome, is part of a heterohexameric helicase complex, which is important for DNA replication and genome integrity. MCM4 deficiency leads to genomic instability and is associated with increased incidence of cancer and developmental defects. Therefore, it is recommended that patients carrying this mutation are followed-up closely. The c.71-1insG splice site mutation found in the Irish travelling community was predicted to lead to a frameshift with a prematurely terminated translation product (p.Pro24ArgfsX4) (32, 33).

ΝΝΤ (nicotinamide nucleotide transhydrogenase), a highly conserved gene, encodes a redox-driven proton pump of the inner mitochondrial membrane. This enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. Detoxification of reactive oxygen species (ROS) in mitochondria by glutathione peroxidases (GPX) depends on this NADPH for regeneration of reduced glutathione (GSH) from oxidized glutathione (GSSG) to maintain a high GSH/GSSG ratio (Figure 1). The adrenal cortex contains high amounts of P450 steroid enzymes, which use NADPH for their catalytic activity. Its function is therefore very sensitive to ROS (34). ROS may suppress StAR protein synthesis and thus inhibit steroidogenesis (9). In addition, the peroxiredoxin system (PRDX), another antioxidant defense mechanism which removes H₂O₂ and lipid peroxides also requires NADPH (9, 34). PRDX3 is a mitochondrial protein highly expressed in human adrenals. Inactivation of PRDX3 results in accumulation of H₂O₂, activation of p38 MAPK signaling pathways, suppression of StAR protein synthesis and inhibition of steroidogenesis (9, 35). Mutations in GPX1 and PRDX3 have been rarely identified in patients with FGD (9, 36).

Figure 1.

Detoxification of reactive oxygen species in the mitochondria. ΝΝΤ (nicotinamide nucleotide transhydrogenase) is a key enzyme, located in the inner mitochondrial membrane, that plays an important role in maintaining the mitochondrial redox balance. It utilizes the electrochemical proton gradient to generate NADPH from NADH and NADP. NNT provides high concentrations of NADPH for detoxification of H2O2 by the glutathione and thioredoxin pathways. Manganese superoxide dismutase catalyzes the conversion of the superoxide radical Ο2.- to H2O2. The peroxiredoxin system (PRDX), another antioxidant defense mechanism, which removes H2O2 and lipid peroxides also requires NADPH. NNT loss would result in compromised NADPH production, thereby rendering the mitochondria more susceptible to oxidative stress. Modified by Prasad et al (34) and Flück (9). StAR: Steroidogenic acute regulatory protein; CYP11A1= Cytochrome P450, family 11, subfamily A, polypeptide 1; GSR: glutathione reductase; GSH: reduced glutathione; TXNRD2: thioredoxin reductase 2; TXN2: thioredoxin 2; GLRX2: glutaredoxin 2; NNT: nicotinamide nucleotide transhydrogenase; PRDX3: peroxiredoxin 3; GPX: glutathione peroxidase; MnSOD: manganese superoxide dismutase.

NNT mutations account for 5–10% of FGD patients. The first mutations in the NNT gene were identified six years ago in 20 patients with FGD (candidate region localized on chromosome 5p13–q12), in whom mutations of MC2R, MRAP and StAR had not been detected. A novel homozygous missense mutation at exon 5 of the NNT gene was subsequently reported in a Japanese patient and was predicted to have a loss-of-function effect (c.644T>C, p.Phe215Ser) (37, 38). In mice with Nnt loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased ROS levels.

It is of great interest, that two patients from non-consanguineous parents of East Asian and South African origin were diagnosed with FGD at the ages of 21 and 8 months respectively, caused by compound heterozygous mutations in NNT, i.e. a heterozygous intron 20 mutation (pseudoexon activation) in combination with a heterozygous stop-gain mutation in exon 3 of NNT gene (p.Arg71) (21).

Recent studies provide new insights into the effects of NNT deletion. Altered mitochondrial morphology, lower ATP content and increased ROS levels have been observed in fibroblasts derived from a patient harboring biallelic NNT mutations (35). Most recently, it was shown that both NNT loss and overexpression can negatively affect steroidogenesis and cause redox imbalance, resulting in reduced protein levels of two mitochondrial antioxidant enzymes (Prdx3 and thioredoxin reductase 2/Txnrd2) and CYP11A1. Transcriptomic analysis of Nnt−/− mice demonstrated upregulation of heat shock proteins, alpha- and beta-hemoglobins, possibly reflecting activations of compensatory mechanisms to cope with oxidative stress (39).

To date, more than 40 pathogenic variants of NNT gene have been identified. They are scattered throughout the gene, including abolishment of the initiating methionine, and splice, missense and nonsense mutations (35, 40, www.hgmd.cf.ac.uk). Phenotypic heterogeneity has been observed among patients carrying the same mutation or within the same family. Unlike “classic FGD”, adrenal dysfunction is not restricted to glucocorticoid deficiency, but may include mineralocorticoid deficiency as well (35, 40). AI is usually diagnosed around the first year of life, may be severe and present with hypoglycemic seizures

Although, NNT mutations have been known to affect preferentially the adrenal glands, all tissues rich in mitochondria may be affected. Extra-adrenal features have been first demonstrated in Nnt-mutant mice, which had reduced insulin secretion and high-fat diet-induced diabetes mellitus, in addition to adrenal dysfunction (27). More recently, extra-adrenal manifestations were also noted in patients harboring homozygous or compound heterozygous NNT mutations, including: precocious puberty associated with testicular nodules (Leydig cell adenoma identified in one case), hypothyroidism, hypertrophic cardiomyopathy, azoospermia associated with testicular adrenal rests and elevated FSH levels and mild plagiocephaly (40, 41).

Of note, heterozygous loss of function mutations in NNT have been recently identified in two patients presenting with left cardiac ventricular noncompaction, an autosomal-dominant cardiomyopathy, which is frequently associated with mitochondrial disorders and cardiac hypertrophy (42).

In 2014, Prasad et al described the first homozygous mutation in the thioredoxin reductase 2 (TXNRD2) gene in an extended consanguineous Kashmiri kindred presenting with FGD (stop gain mutation, c.1341T>G; p.Y447X within exon 15). The selenoprotein TXNRD2, one of three thioredoxin reductases, is mitochondria specific and contributes to the maintenance of redox homeostasis. Particularly high TXNRD2 mRNA levels have been noted in the adrenal cortex compared with the other human tissues investigated, suggesting a susceptibility of the adrenal cortex and especially zona fasciculata to oxidative stress. Given that the final step of cortisol production, which is catalyzed by CYP11B1 in the mitochondria, accounts for approximately 40% of the total electron flow from NAPDH directed at reactive oxygen species production during steroidogenesis, individuals with TXNRD2 and NNT mutations primarily develop glucocorticoid deficiency. Extra-adrenal manifestations, associated with TXNRD2 mutations have also been reported. Txnrd2 deletion in mice is embryonically lethal, resulting in fatal cardiac and hematopoietic defects. In humans, two novel heterozygous mutations in TXNRD2 were identified in 3 of 227 patients with a diagnosis of dilated cardiomyopathy, however, no data are available on their adrenal function (15, 34).

Oxidative stress has been implicated in other causes of adrenal insufficiency, including triple A syndrome and X-linked adrenoleukodystrophy (ALD). In ALD, mutations in ABCD1 (encoding the peroxisomal ABCD transporter) result in the accumulation of very long-chain fatty acids in the tissues and plasma, the toxic effects of which are thought to result from an increase in steady-state ROS production, depletion of glutathione and dysregulation of the cell redox homeostasis. The adrenal and CNS are most susceptible to the disease process (34).

PRIMARY/CONGENITAL ADRENAL HYPOPLASIA

Five forms of AHC have been identified: 1) The X-linked form (OMIM 300200) caused by a mutation or deletion of the DAX1 gene (Dosage-sensitive sex reversal Adrenal hypoplasia congenita critical region of the X chromosome gene-1; NR0B1) on the X chromosome; 2) The autosomal recessive form owing to a mutation or deletion of the gene that encodes for the steroidogenic factor 1 (SF-1)/NR5A1 on chromosome 9q33 (OMIM 184757); 3) An autosomal recessive form of uncertain etiology (OMIM 240200); and 4) The IMAGe syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital abnormalities) (OMIM 614732) 5) The MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes and Enteropathy) (OMIM 617053).

Most recently, mutations in the gene encoding sphingosine-1-phosphate (S1P) lyase 1 (SGPL1), located on chromosome 10q22.1 have been associated with a syndrome comprising primary adrenal insufficiency and steroid-resistant nephrotic syndrome 9, 10) (OMIM: 617575).

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