Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see 240200) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. ... Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see 240200) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. The remaining cells are termed 'cytomegalic' because they are larger than typical fetal adrenal cells (Hay et al., 1981; Reutens et al., 1999). A contiguous gene syndrome involving a combination of congenital adrenal hypoplasia, glycerol kinase deficiency (307030), and Duchenne muscular dystrophy (DMD; 310200) is caused by deletion of multiple genes on chromosome Xp21 (see 300679).
Weiss and Mellinger (1970) described an X-linked form of congenital adrenal hypoplasia in 3 of 4 brothers, each of whom had a different father. Histologically, there was hypoplasia of the adrenal cortex and lack of organization of the ... Weiss and Mellinger (1970) described an X-linked form of congenital adrenal hypoplasia in 3 of 4 brothers, each of whom had a different father. Histologically, there was hypoplasia of the adrenal cortex and lack of organization of the cortex into cords, as well as clumps of large pale-staining cells. Several other families consistent with X-linked inheritance had been reported (e.g., Boyd and MacDonald, 1960; Uttley, 1968; Stempfel and Engel, 1960). Brochner-Mortensen (1956) described Addison disease in 2 brothers and 2 of their maternal uncles. Three of the patients had died at ages 19, 26, and 33 years. In brothers reported by Meakin et al. (1959), the diagnosis was made in the elder at 9 years of age and in the second at 6 years of age. Congenital adrenal hypoplasia with hypogonadotropic hypogonadism (HHG) was observed by Hay (1977), who suggested that hypogonadism might be a consequence of absence of adrenal androgen secretion. Hay et al. (1981) described 5 boys with cytomegalic adrenocortical hypoplasia who had been followed for many years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty, and when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone and inadequate pituitary reserve of gonadotropin. Treatment with either testosterone or gonadotropin resulted in advances in pubertal staging in all 5 patients. Hay et al. (1981) noted that the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia is a common finding. Prader et al. (1975), Golden et al. (1977), and Zachmann et al. (1980) also described this association. Martin (1971) described a pair of brothers in whom the signs of Addison disease developed at age 5. Gonadotropin deficiency was later demonstrated in both brothers (Martin, 1980). An extensive Greenlandic pedigree was reported by Petersen et al. (1982). Over 5 generations, 11 boys had died with a clinical picture of adrenocortical insufficiency within 3 weeks of birth. In 3 treated males who survived, the adrenal glands could not be identified by computed tomography. Pubertal development was delayed in 2 patients aged 14 years. Subsequently, Schwartz et al. (1997) identified a missense mutation (300473.0008) in the DAX1 gene in 3 affected members of this Greenlandic family. Reutens et al. (1999) described the clinical features and genetic alterations in 6 families with AHC. Most patients presented within the first year of life with variable signs and symptoms, including hyperpigmentation, salt-wasting crisis, vomiting, and malaise. One patient had a delayed presentation at the age of 7 years, after a hypotensive episode and hyponatremia during an acute asthma attack. A review of the literature showed an apparent bimodal distribution for age at diagnosis. The majority of patients were diagnosed within the first 2 months of life, and another group of patients were diagnosed from 1 to 11 years. Nonsense mutations in the DAX1 gene were identified in 3 cases, and frameshift mutations resulting in a premature stop codon were found in the other 3 families. There were no obvious genotype/phenotype correlations. The authors concluded that the clinical presentation of DAX1 mutations is variable and emphasized the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC. The review of Kletter et al. (1991) suggested that gonadotropin deficiency is an integral part of X-linked cytomegalic adrenocortical hypoplasia. Zachmann et al. (1992) found progressive high frequency hearing loss developing at about the age of 14 years in 3 brothers with X-linked congenital adrenal hypoplasia associated with gonadotropin deficiency. All 3, aged 22, 20, and 18 years, had developed progressive high frequency hearing loss at about 14 years of age. They were doing well on replacement therapy with hydrocortisone, fluorohydrocortisone, and long-acting testosterone. High resolution chromosomal analysis showed no structural anomalies. Although no statement was made concerning the sense of smell, the gonadotropin deficiency may have represented Kallmann syndrome (308700). Jones et al. (1995) reported the case of a Hispanic boy with congenital adrenal hypoplasia who had coal-black hyperpigmentation at birth. Both parents were of light complexion. Usually hyperpigmentation in this condition appears gradually over a period of months to years. Following steroid therapy, the patient's color began to lighten, and at week 7 of life the infant had pigmentation intermediate between coal-black and the color of his Hispanic mother. By 6 months of age, the infant's skin color was similar to that of his mother. Tabarin et al. (2000) reported an unusually mild case in a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development (Tanner stage 3) and undiagnosed incomplete HHG. The patient noted that puberty had occurred at about age 16, and that he had impaired libido and infrequent erections. Severe oligospermia was detected. A mutation in the DAX1 gene (300473.0020) was found, extending the clinical spectrum of the disease to include a milder disorder with delayed onset of symptoms. Domenice et al. (2001) reported a 2-year-old Brazilian boy with a DAX1 mutation (300473.0024). Initial clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. Testosterone levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce testosterone levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and testosterone levels to the prepubertal range. The authors concluded that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.
Muscatelli et al. (1994) demonstrated that mutations in the DAX1 gene give rise to X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism. In 14 patients with AHC, AHC and glycerol kinase deficiency, and AHC-GKD-DMD, DAX1 was deleted. In 11 ... Muscatelli et al. (1994) demonstrated that mutations in the DAX1 gene give rise to X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism. In 14 patients with AHC, AHC and glycerol kinase deficiency, and AHC-GKD-DMD, DAX1 was deleted. In 11 AHC families, and 1 sporadic case, point mutations were found in the coding region of the DAX1 gene (see, e.g., 300473.0001-300473.0005). All AHC patients over 14 years of age and with only point mutations in DAX1 were also found to have hypogonadotropic hypogonadism. However, in 4 sporadic cases and a single familial case of AHC, no point mutations were found, suggesting genetic heterogeneity. Zhang et al. (1998) identified 14 new mutations in 17 families with AHC, bringing the total number of families with AHC studied to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. In a patient who presented at 28 years of age with hypogonadotropic hypogonadism but no clinical evidence of adrenal dysfunction and who was shown to have compensated primary adrenal failure by biochemical testing, Mantovani et al. (2002) identified a missense mutation in the NR0B1 gene (Y380D; 300473.00025), which caused partial loss of function in transient gene expression assays. The authors concluded that partial loss-of-function mutations in DAX1 can present with HHG and covert adrenal failure in adulthood. In a 20-year-old male with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure, Ozisik et al. (2003) identified a nonsense mutation in the NR0B1 gene (Q37X; 300473.0029). Using a combination of in vitro translation assays and transfection studies, the authors demonstrated that the mutation, which was predicted to cause severe truncation of the protein, was associated with a milder phenotype due to the expression of a partially functional DAX1 protein generated from an alternate in-frame translation start site. In an 11-year-old prepubertal Dutch boy with mild AHC involving isolated mineralocorticoid deficiency, Verrijn Stuart et al. (2007) identified a missense mutation in the N terminus of DAX1 (W105C; 300473.0030). In transfection studies, the W105C mutant caused only mild loss of function, and structure-function analysis suggested that mutations in the N terminus are compensated by the presence of repeat LXXLL motifs that mediate DAX1 interactions with other proteins. The mutation, which was not found in 100 Dutch controls, was present in the proband's mother; it was also present in 3 asymptomatic male relatives, indicating phenotypic heterogeneity.
X-linked adrenal hypoplasia congenita (X-linked AHC) is suspected in males presenting in the first month of life with acute adrenal insufficiency, in males with adrenal failure later in infancy, and in rare cases, in males with delayed puberty, associated with mild or subclinical adrenal insufficiency. ...
DiagnosisClinical DiagnosisX-linked adrenal hypoplasia congenita (X-linked AHC) is suspected in males presenting in the first month of life with acute adrenal insufficiency, in males with adrenal failure later in infancy, and in rare cases, in males with delayed puberty, associated with mild or subclinical adrenal insufficiency. TestingAdrenal insufficiency A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic. Note: Measurement of the basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as the level may be within normal limits. Once primary adrenal insufficiency is diagnosed, further testing is appropriate to distinguish X-linked AHC from the salt-losing form of congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency. The serum concentration of adrenal androgens and the cortisol precursor 17-hydroxyprogesterone are normal or low in X-linked AHC, whereas they are characteristically elevated in 21-hydroxylase deficiency. Imaging studies. Abdominal CT scan or MRI reveal small adrenal glands. The apparent absence of the adrenal glands on imaging studies is difficult to interpret, as it may be caused by extreme hypoplasia or aplasia of the adrenal glands, as well as by ectopia of normal-sized adrenal glands. Evaluation for the contiguous gene deletion syndrome, AHC with complex glycerol kinase deficiency (GKD). X-linked AHC may be part of a contiguous gene deletion syndrome that includes glycerol kinase deficiency (GKD) and, in some individuals, Duchenne muscular dystrophy (DMD). GKD is diagnosed by measurement of serum concentration of triglycerides and urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method). DMD is suspected if the serum concentration of creatine kinase (CK) is elevated; the diagnosis is confirmed by molecular genetic testing of DMD or immunohistochemical staining of dystrophin on muscle biopsy. Deletions of the X chromosome that include NR0B1 (DAX1) can be detected by FISH studies using a NR0B1 cosmid probe and by other deletion/duplication analysis. Table 1. Summary of FISH Testing Used in AHC with Complex Glycerol Kinase DeficiencyView in own windowGene SymbolTest MethodMutations DetectedDetection Rate in Individuals with AHC with Complex GKDTest AvailabilityNR0B1FISHDeletion 100%Clinical Chromosome analysis. Routine cytogenetic testing is typically normal in individuals with complex glycerol kinase deficiency, except in rare cases of very large deletions of the short arm of chromosome X involving band Xp21. Molecular Genetic Testing Gene. NR0B1 is the only gene known to be associated with X-linked adrenal hypoplasia congenita. Clinical testing Sequence analysis. Sequence analysis detects mutations in nearly 100% of males with isolated X-linked AHC and a positive family history of AHC and in 50%-70% of males with isolated AHC and no other affected family members. Table 2. Summary of Molecular Genetic Testing Used in Isolated X-Linked Adrenal Hypoplasia CongenitaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1 Test Availability Family History PositiveNegativeNR0B1Sequence analysisPoint mutationsNearly 100% 50%-70%Clinical Deletion / duplication analysis 2, 3Partial-, whole-, or contiguous-gene deletions UnknownUnknown1. Affected individuals do not have evidence of complex glycerol kinase deficiency.2. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation dependent probe amplification (MLPA), or array CGH may be used.3. No deletions involving NR0B1 have been detected by microarray CGH, but since many platforms based on oligoarray provide probe coverage for NR0B1, detection by CGH is theoretically possible, and should be confirmed by FISH.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Clinical uses Confirmatory diagnosis Carrier detection Prenatal diagnosis Genetically Related (Allelic) DisordersThe only phenotypes associated with mutations of NR0B1 are X-linked adrenal hypoplasia congenita and the contiguous gene deletion syndrome, adrenal hypoplasia congenita with complex glycerol kinase deficiency.
Most males with X-linked adrenal hypoplasia congenita (AHC) present in shock with acute adrenal insufficiency during the first month of life. In one series of 18 affected individuals, the age of onset ranged from one week to three years, with three weeks being the median age of onset [Peter et al 1998]. In another series, four of ten individuals presented between one and seven years of age [Reutens et al 1999]. Intrafamilial variability in age of onset occurs [Wiltshire et al 2001]. Exceptional cases present in adulthood with a primarily reproductive phenotype (i.e., late puberty, infertility) [Tabarin et al 2000]. In these individuals, residual glucocorticoid and mineralocorticoid activity present in the hypoplastic adrenal cortex may explain the late onset. These individuals may not have overt adrenal dysfunction, but rather only biochemical evidence of compensated adrenal failure, such as high serum ACTH concentration [Mantovani et al 2002]....
Natural HistoryMost males with X-linked adrenal hypoplasia congenita (AHC) present in shock with acute adrenal insufficiency during the first month of life. In one series of 18 affected individuals, the age of onset ranged from one week to three years, with three weeks being the median age of onset [Peter et al 1998]. In another series, four of ten individuals presented between one and seven years of age [Reutens et al 1999]. Intrafamilial variability in age of onset occurs [Wiltshire et al 2001]. Exceptional cases present in adulthood with a primarily reproductive phenotype (i.e., late puberty, infertility) [Tabarin et al 2000]. In these individuals, residual glucocorticoid and mineralocorticoid activity present in the hypoplastic adrenal cortex may explain the late onset. These individuals may not have overt adrenal dysfunction, but rather only biochemical evidence of compensated adrenal failure, such as high serum ACTH concentration [Mantovani et al 2002].Adrenal insufficiency. The initial clinical presentation is typically acute, with vomiting, feeding difficulty, dehydration, and shock caused by a salt-wasting episode. Hypoglycemia, frequently presenting with seizures, may be the first symptom. The initial presentation of adrenal failure is either spontaneous or related to an intercurrent stress (e.g., infection, gastrointestinal disorder, surgery). If untreated with glucocorticoids and mineralocorticoids, adrenal insufficiency is rapidly lethal as a result of hyperkalemia, acidosis, hypoglycemia, and shock. If not recognized and treated, acute adrenal insufficiency and its complications of hypoglycemia and shock may result in neurologic abnormalities and developmental delay. Bilateral infantile striatal necrosis has been reported. The adrenal insufficiency crisis is usually accompanied by varying degrees of hyperpigmentation caused by increased pituitary production of POMC (proopiomelanocortin). One affected newborn with coal-black hyperpigmentation of the skin sparing the palms and soles has been reported. Hyperpigmentation present at the time of diagnosis typically regresses with appropriate steroid therapy. Hypogonadotropic hypogonadism (HH). HH is of mixed hypothalamic and pituitary origin, consistent with the expression of NR0B1 in the hypothalamus and the pituitary. The "mini puberty" of infancy is normal in affected boys, suggesting that the loss of function of the hypothalamic-pituitary-gonadal axis occurs after early infancy. HH may also cause cryptorchidism. Typically, delayed puberty (onset after age 14 years) caused by HH is observed in affected males. Without testosterone treatment, secondary sexual characteristics do not appear. Fertility of individuals with AHC has been poorly studied. Azoospermia has been reported in several individuals and treatment of HH with exogenous gonadotropin therapy or pulsatile GnRH has not restored normal spermatogenesis [Seminara et al 1999, Mantovani et al 2006]. Developmental delay. Developmental delay may be seen in individuals with X-linked AHC. Its occurrence is related to two factors: the initial medical management of adrenal insufficiency and the type of genetic defect. Large deletions of Xp may include, in addition to NR0B1, a locus responsible for mental retardation. Deletion of this latter locus may be responsible for developmental delay in individuals with AHC. Hearing loss. Progressive high-frequency sensorineural hearing loss starting at about 14 years of age has been described in two individuals whose NR0B1 status is unknown [Zachmann et al 1992, Liotta et al 1995]. Other. In one male with a missense mutation in NR0B1 (DAX1), tall stature and renal ectopy were associated with adrenal insufficiency [Franzese et al 2005]. Carrier females. Carrier females may occasionally have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism, possibly caused by skewed X-chromosome inactivation. In one instance, a female homozygous for a NR0B1 mutation (which may result from gene conversion) had isolated hypogonadotropic hypogonadism [Merke et al 1999]. Two nephews with the same mutation had the complete AHC syndrome. Another carrier female presenting with extreme pubertal delay has been described [Seminara et al 1999]. Histopathology. The adrenal cortex may be structurally disorganized with irregular nodular formations of eosinophilic cells and a nearly absent adult cortex. This is described as the cytomegalic form of AHC.
When X-linked AHC is caused by a point mutation in NR0B1, no correlation exists between the location or type of mutation and the clinical phenotype. ...
Genotype-Phenotype CorrelationsWhen X-linked AHC is caused by a point mutation in NR0B1, no correlation exists between the location or type of mutation and the clinical phenotype.
The differential diagnosis includes congenital adrenal hyperplasia (CAH) caused by the following:...
Differential DiagnosisThe differential diagnosis includes congenital adrenal hyperplasia (CAH) caused by the following:The salt-losing form of 21-hydroxylase deficiency (21-OHD), the most common disorder to consider in the differential diagnosis of X-linked AHC. 21-OHD also typically presents with an acute, salt-wasting episode of adrenal insufficiency in the neonatal period. Serum concentration of cortisol precursors (e.g., 17-OH progesterone) are elevated in 21-OHD, but normal or low in X-linked AHC. 21-OHD is inherited in an autosomal recessive manner. Deficiency in 11 hydroxylase The following disorders may present with symptoms similar to those seen in X-linked AHC: ACTH deficiency is caused by mutations in TBX19, which presents with glucocorticoid (but not mineralocorticoid) insufficiency and unmeasurable serum concentration of ACTH (with and without corticotropin-releasing hormone stimulation). Congenital adrenal lipoid hyperplasia may present in a manner similar to AHC; however, adrenal imaging usually reveals enlarged and fatty adrenal glands. Individuals with a 46,XY karyotype have ambiguous genitalia or complete sex reversal with normal-appearing female external genitalia. Adrenal hypoplasia congenita, autosomal recessive form, is the "miniature adult" type of adrenal hypoplasia; the adrenal cortex is composed of a small amount of permanent adult cortex. Familial glucocorticoid deficiency and ACTH resistance is caused by mutations in MCR2 encoding the ACTH receptor; the form of adrenal hypoplasia is miniature and mineralocorticoid secretion is normal. Several syndromes and chromosomal abnormalities have AHC as one feature:Syndromes include Pena-Shokeir syndrome, type 1 (OMIM 208150); holoprosencephaly, alobar type; Meckel syndrome (OMIM 249000); and IMAGe syndrome (intrauterine growth retardation, metaphyseal dysplasia, AHC, genital abnormalities). Chromosomal abnormalities include tetraploidy, triploidy, trisomy 19, trisomy 21, 5p duplication, monosomy 7, and 11q- syndrome.
To assess the extent of disease in an individual diagnosed with X-linked adrenal hypoplasia congenital, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo assess the extent of disease in an individual diagnosed with X-linked adrenal hypoplasia congenital, the following evaluations are recommended:Serum and urine concentration of electrolytes Serum concentration of glucose and ACTH Assessment of arterial blood gases Typically, affected individuals who are in shock have hyponatremia, hyperkalemia, hypoglycemia, acidosis, very elevated serum concentration of ACTH, and increased urinary excretion of sodium. Treatment of ManifestationsAdrenal insufficiency. Episodes of acute adrenal insufficiency are usually treated in an intensive care unit with close monitoring of blood pressure, hydration, clinical status, and serum concentration of glucose and electrolytes. Individuals are treated by the IV administration of saline, glucose, and cortisol (e.g., Solu-Cortef). If the serum concentration of electrolytes does not improve, a mineralocorticoid (fludrocortisone) is added or the dose of Solu-Cortef is increased. Once the initial acute episode has been treated, affected individuals are started on replacement doses of glucocorticoids and mineralocorticoids and oral supplements of sodium chloride (NaCl). Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. Maintenance hormone treatment is often best managed by a pediatric endocrinologist. Dosages must be increased with stress, such as intercurrent illness, surgery, or trauma. In the case of surgery or trauma, steroid doses need to be increased five- to tenfold. Death from acute adrenal insufficiency in individuals known to have X-linked adrenal hypoplasia congenita may still occur if steroid replacement therapy is not adequate, particularly during times of stress.Steroid replacement therapy is monitored clinically and hormonally by an endocrinologist. ACTH levels should normalize when replacement therapy is adequate. A sudden rise in ACTH despite steroid treatment has revealed the presence of a pituitary adenoma [De Menis et al 2005].The wearing of a Medic Alert® bracelet is strongly recommended.Hypogonadotrophic hypogonadism. If there is evidence of HH, treatment with increasing doses of testosterone to induce puberty may be necessary and should be monitored by a pediatric endocrinologist. SurveillanceIf puberty has not started by age 14 years, serum concentration of LH and FSH are monitored (basal concentration and GnRH-stimulated concentration) to evaluate for the possibility of HH.Agents/Circumstances to AvoidStress is to be avoided, if possible. If unavoidable (e.g., surgery, febrile illness, trauma), dosage of steroids should be increased two- to threefold.Evaluation of Relatives at RiskIf the genetic status of an at-risk male relative has not been established during pregnancy, testing should be performed as soon as possible after birth to clarify genetic status so that adrenocortical hormone replacement therapy can be initiated without delay and adrenal crises avoided.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Adrenal Hypoplasia Congenita, X-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNR0B1Xp21.2Nuclear receptor subfamily 0 group B member 1NR0B1 @ LOVDNR0B1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Adrenal Hypoplasia Congenita, X-Linked (View All in OMIM) View in own window 300200ADRENAL HYPOPLASIA, CONGENITAL; AHC 300473NUCLEAR RECEPTOR SUBFAMILY 0, GROUP B, MEMBER 1; NR0B1Normal allelic variants. NR0B1 contains one open reading frame that starts at the ATG codon (nucleotide 1) and ends at the TAA stop codon (nucleotide 1410). A single intron of 3 kb is inserted between nucleotides 1167 and 1168. A novel isoform of NR0B1 has been described. It is encoded by the known exon 1 of NR0B1 and a previously unrecognized exon 2a present within intron 1. This novel transcript encodes the first 389 amino acids by exon 1 and the last 12 by exon 2a, and is expressed in the adrenal gland, brain, kidney, ovary, and testis [Ho et al 2004, Hossain et al 2004]. Pathologic allelic variants. In a series of 18 affected individuals from 16 families with X-linked AHC, seven families had deletions of NR0B1 (two limited to NR0B1, one extending to GK and four including NR0B1, GK, and DMD) and seven families had an intragenic mutation. In one family, no NR0B1 mutation was found; in one family, no mutation analysis was performed. In a review of 42 intragenic NR0B1 mutations from 48 families, 23 were frameshift mutations and 12 were nonsense mutations, all distributed throughout NR0B1 [Zhang et al 1998]. The six missense mutations and one single codon in-frame deletion all mapped to the C-terminal part of NR0B1, in the hydrophobic core of the putative ligand binding domain. Three additional mutations that cluster to the C-terminal region of NR0B1 have been described [Achermann et al 2001]. Many novel mutations have recently been described [Balsamo et al 2005, Choi et al 2005, Tsai & Tung 2005, Calvari et al 2006, Mantovani et al 2006]. Interestingly, only one missense mutation (p.Cys200Trp) outside the ligand binding was described, in an eight-year-old female with late-onset AHC. Her father, hemizygous for the mutation, had no overt adrenal phenotype, yet the p.Cys200Trp mutant impaired subcellular localization of NR0B1, shifting it towards the cytoplasm [Bernard et al 2006].All of the abnormal allelic variants described above include (but are not limited to) the following OMIM variants: 300200.0001 through 300200.0029.Normal gene product. The predicted size of the protein product is 470 amino acids. The protein encoded by NR0B1 has the structure of a transcription factor and is classified as an orphan nuclear receptor. It is thought to act as a negative regulator of other nuclear receptor signaling pathways. For instance, nuclear receptor 0B1 inhibits transactivation mediated by steroidogenic factor 1 (SF1). Recent evidence suggests a broader functional role for 0B1 as a negative co-regulator of estrogen receptor (ER, NR3A1-2), liver receptor homologue-1 (LRH-1, NR5A2), androgen receptor (AR, NR3C4), and progesterone receptor (PR, NR3C3), each by distinct repression mechanisms [Iyer & McCabe 2004].Nuclear receptor 0B1 also acts as a transcriptional repressor of the steroidogenic acute regulatory protein (STAR), aromatase, and LH beta [Wang et al 2001].Nuclear receptor 0B1 plays an important role in the normal development of the adrenal glands, the hypothalamus, the pituitary, and the ovary and testis. The molecular mechanism of action of nuclear receptor 0B1 is poorly understood. No physiologic target gene has been identified. Nuclear receptor 0B1 was shown to bind to DNA hairpin structures as well as polyribosomes in complexes with polyadenylated RNA. It has also been shown to interact directly with the SF1 protein. In addition to its role in the pathogenesis of X-linked AHC, NR0B1 plays a major role in sex determination. NR0B1 is located in the DSS locus, a 160-kb region in Xp21 responsible, when duplicated, for dosage-sensitive sex reversal. NR0B1 has been hypothesized to act as an antagonist of SRY, the main male sex-determining gene. Abnormal gene product. When NR0B1 is deleted or mutated with a nonsense or frameshift mutation, no nuclear receptor 0B1 or truncated nuclear receptor 0B1 is made. When a missense mutation is present in NR0B1, it is predicted to affect the normal conformation and function of nuclear receptor 0B1.