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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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X-Linked Adrenal Hypoplasia Congenita

Synonyms: Adrenal Hypoplasia Congenita, Congenital Adrenal Hypoplasia, X-Linked AHC

, MB, MD, PhD, FRCPCH and , MD, PhD, FACMG.

Author Information
, MB, MD, PhD, FRCPCH
Clinical and Molecular Genetics
Institute of Child Health
University College London
London, United Kingdom
, MD, PhD, FACMG
Departments of Human Genetics, Pediatrics, and Urology
University of California School of Medicine, Los Angeles
Los Angeles, California

Initial Posting: ; Last Update: October 17, 2013.

Summary

Disease characteristics. X-linked adrenal hypoplasia congenita (X-linked AHC) is characterized by infantile-onset acute primary adrenal insufficiency at an average age of three weeks in approximately 60% of affected individuals. Onset in approximately 40% is in childhood. A few individuals present in adulthood with delayed-onset adrenal failure or partial hypogonadism due to partial forms of X-linked AHC. Adrenal insufficiency typically presents acutely in male infants with vomiting, feeding difficulty, dehydration, and shock caused by a salt-wasting episode. Hypoglycemia (sometimes presenting with seizures) or isolated salt loss may be the first symptom of X-linked AHC. Cortisol may be low or within the normal range, which is inappropriately low for a sick child. In older children, adrenal failure may be precipitated by intercurrent illness or stress. If untreated, adrenal insufficiency is rapidly lethal as a result of hyperkalemia, acidosis, hypoglycemia, and shock. Affected males typically have delayed puberty (onset age >14 years) or arrested puberty caused by hypogonadotropic hypogonadism (HH). Early pubertal development with pubertal arrest has been reported in some cases. Males with classic X-linked AHC are infertile despite treatment with exogenous gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH), although testicular sperm extraction-intracytoplasmic sperm injection (TESE-ICSI) has been successful in one case. Carrier females may very occasionally have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism as a result of skewed X-chromosome inactivation.

Diagnosis/testing. Primary adrenal failure characterized by hyponatremia, hyperkalemia, acidosis, and an elevated serum concentration of ACTH in the presence of normal or low serum concentration of 17-hydroxyprogesterone presenting in a male in the first month or two of life strongly suggests X-linked AHC. Nearly 100% of affected individuals with a positive family history consistent with X-linked inheritance have an identifiable mutation in NR0B1 (previously known as DAX1), the only gene in which mutations are known to cause X-linked AHC. Approximately 50% of males with AHC who have no other affected family members have an identifiable mutation in NR0B1. Individuals with an isolated deletion of NR0B1 or a contiguous gene deletion including the glycerol kinase gene (GK) with or without deletion of DMD (the gene encoding dystrophin) can be identified by fluorescent in situ hybridization (FISH) using a NR0B1 cosmid probe or other deletion/duplication testing methods.

Management. Treatment of manifestations: Episodes of acute adrenal insufficiency usually require admission to an intensive care unit with close monitoring of blood pressure, hydration, clinical status, and serum concentration of glucose and electrolytes. Treatment includes the IV administration of saline, glucose, and hydrocortisone. Follow-up includes lifelong replacement doses of glucocorticoids and mineralocorticoids and oral supplements of sodium chloride (NaCl) in younger children. Steroid replacement must be increased during periods of illness or stress. Steroid replacement therapy must be monitored by an endocrinologist and appropriate plans for episodes of sickness should be available. Affected individuals with hypogonadotropic hypogonadism are likely to need increasing doses of testosterone to induce puberty. Long-term management of adrenal steroid replacement and testosterone replacement should be undertaken by an experienced endocrinologist.

Surveillance: Monitoring of serum concentrations of LH, FSH, testosterone, and inhibin B if puberty has not started by age 14 years; induction of puberty at a similar time course as the peer group is preferable; monitoring of testosterone levels in those who undergo spontaneous puberty to evaluate for pubertal arrest; psychological counseling to discuss issues related to hormone replacement therapy and fertility.

Agents/circumstances to avoid: Unnecessary physiologic stress. Surgical procedures should be carefully planned.

Genetic counseling. X-linked adrenal hypoplasia is inherited in an X-linked recessive manner. The risk to sibs depends on the mother's carrier status. If the proband's mother is a carrier, male sibs have a 50% chance of having X-linked AHC and female sibs have a 50% chance of being carriers. Most males with AHC are infertile. Germline mosaicism is possible but uncommon. Carrier testing of at-risk female relatives and prenatal testing for pregnancies of women who are carriers are possible if the NR0B1 pathogenic variant or deletion has been identified in a family member.

GeneReview Scope

X-Linked Adrenal Hypoplasia Congenita: Included Disorders
  • Complex glycerol kinase deficiency
  • Isolated X-linked adrenal hypoplasia congenita

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

X-linked adrenal hypoplasia congenita (X-linked AHC) is suspected in males presenting in the first (or second) month of life with acute adrenal insufficiency, in males with adrenal failure later in childhood, and in rare cases, in males with partial hypogonadism or delayed-onset adrenal insufficiency presenting in young adulthood.

Testing

Adrenal insufficiency

  • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal failure. An impaired cortisol response is usually seen after cosyntropin stimulation.

    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. A normal-range cortisol in a clinically sick child is inappropriately low. In some other individuals salt loss may be the presenting feature and cortisol insufficiency may develop with time.
  • 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.
  • Boys presenting with primary adrenal failure in childhood may need to have other causes excluded (see Differential Diagnosis).

Imaging studies. Abdominal CT scan or MRI may reveal small adrenal glands. Ultrasound imaging is less specific but avoids radiation exposure inherent in CT imaging and the need for sedation required for MRI imaging in a potentially sick child.

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.

Molecular Genetic Testing

Gene. NR0B1 (historically known as DAX1) is the only gene in which mutations are known to cause isolated X-linked adrenal hypoplasia congenita.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Isolated X-Linked Adrenal Hypoplasia Congenita

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency 3
Affected Males Carrier Females
NR0B1Sequence analysis 4Sequence variants 5Nearly 50% 5, 6>90% 7
Duplication/deletion analysis 8(Multi)exonic or whole-gene deletionUnknown 9~10% 

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

6. Negative family history

7. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

8. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Partial, whole-gene, and contiguous gene deletions have been reported. See HGMD, Table A, and Table 2.

Evaluation for the contiguous gene deletion syndrome, AHC as a part of complex glycerol kinase deficiency. X-linked AHC may be part of a contiguous gene deletion syndrome (referred to as complex glycerol kinase deficiency) 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, if a mutation is not identified, immunohistochemical staining of dystrophin on muscle biopsy.
  • 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.

Table 2 summarizes FISH testing for this disorder (see also Table 1).

Table 2. Testing Used in Complex Glycerol Kinase Deficiency

Gene 1 Test MethodMutations Detected 2Detection Rate in Persons with AHC with Complex GKD
NR0B1FISHDeletion 100%
Deletion/duplication analysis 3Whole-gene deletions as a part of a contiguous gene deletion 4100%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

4. Deletion/duplication analysis and CMA are likely to be more precise in identifying the length of the deleted region and the genes involved.

Testing Strategy

To confirm/establish the diagnosis of isolated AHC in a proband

To confirm/establish the diagnosis of complex glycerol kinase deficiency in a proband. If complex glycerol kinase deficiency is suspected based on clinical symptoms and/or levels of plasma creatine kinase and urine glycerol:

Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and only in rare cases develop clinical findings related to the disorder as a result of skewed X-inactivation [Shaikh et al 2008]. (2) Identification of female carriers requires either (a) prior identification of the pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no pathogenic variant is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Description

Natural History

Most males with X-linked adrenal hypoplasia congenita (AHC) present in shock with acute adrenal insufficiency during the first month or two 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 and review of the literature at the time, 48/71 children presented in the first two months of life whereas 23/71presented between age one and nine years [Reutens et al 1999]. Intrafamilial variability in age of onset occurs [Wiltshire et al 2001], although in families where two brothers are affected the younger one is usually diagnosed earlier as clinical suspicion is greater [Achermann et al 2001]. Exceptional cases present in early adulthood with a primarily reproductive phenotype (i.e., late puberty, infertility) [Tabarin et al 2000] or delayed-onset adrenal failure [Mantovani et al 2002, Ozisik et al 2003, Guclu et al 2010]. 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 (e.g., high serum ACTH concentration) [Mantovani et al 2002]. In some cases, progressive adrenal dysfunction occurs resulting in clinically significant adrenal failure in early adulthood [Guclu et al 2010].

Adrenal insufficiency. The initial clinical presentation is typically acute – especially in infancy, 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). Mineralocorticoid deficiency may be the presenting feature of X-linked AHC in some cases [Wiltshire et al 2001, Verrijn Stuart et al 2007].

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 in rare cases.

The adrenal insufficiency crisis is usually accompanied by varying degrees of hyperpigmentation caused by increased pituitary production of POMC (proopiomelanocortin). Indeed, the original report of X-linked AHC described an affected newborn with “coal-black hyperpigmentation” of the skin sparing the palms and soles [Sikl 1948]. Hyperpigmentation present at the time of diagnosis typically regresses over time with appropriate steroid therapy.

Hypogonadotropic hypogonadism (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. Cryptorchidism has been reported in several cases but has not emerged as a common feature of X-linked AHC. Indeed, macrophallia (large penis) at birth and some signs of early puberty in childhood have now been reported in a subset of boys with X-linked AHC [Domenice et al 2001, Landau et al 2010].

Typically, delayed puberty (onset age >14 years) caused by HH is observed in affected males during adolescence. A proportion of boys may enter puberty and show progression to around Tanner Stage 3 (or 6-8 cc testes) but pubertal arrest at this point is common. Without testosterone treatment, full attainment of secondary sexual characteristics is unlikely to occur and testosterone supplementation is needed to support growth and bone mineralization.

Fertility of individuals with AHC has been poorly studied. Azoospermia has been reported in individuals with classic X-linked AHC and severe oligospermia has been found in some individuals with partial forms of this condition [Tabarin et al 2000]. Treatment of HH with exogenous gonadotropin therapy or pulsatile GnRH has not restored normal spermatogenesis [Seminara et al 1999, Mantovani et al 2006].

Recently, fertility was achieved in a man with classic early-onset X-linked AHC who underwent testicular sperm extraction-intracytoplasmic sperm injection (TESE-ICSI) having had fairly extensive gonadotropin treatment in the past [Frapsauce et al 2011]. It is not yet known whether this success will be possible in general or whether this represents an isolated case. See Genetic Counseling for issues related to recurrence risks for children born to affected men.

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 intellectual disability (e.g. IL1RAPL1). Deletion of this latter locus may be responsible for developmental delay in some individuals with X-linked AHC.

Hearing loss. Progressive high-frequency sensorineural hearing loss starting at about age 14 years has been described in two individuals whose NR0B1 status is unknown [Zachmann et al 1992, Liotta et al 1995]. To the authors’ knowledge no further cases of hearing loss associated with classic X-linked AHC have been reported.

Other. In one male with a missense mutation in NR0B1, tall stature and renal ectopy were associated with adrenal insufficiency [Franzese et al 2005].

Carrier females may very occasionally have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism, potentially 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 pathogenic variant had the complete AHC syndrome. Another carrier female presenting with extreme pubertal delay has been described [Seminara et al 1999].

A girl with mild adrenal failure and Duchenne muscular dystrophy has also been reported [Shaikh et al 2008]. In this case molecular studies were performed to confirm extremely skewed X-chromosome inactivation in the region of Xp21 that resulted in differential expression of the disrupted allele.

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, as the remaining cells resemble the large cells typically seen in the fetal adrenal gland [Sikl 1948].

Genotype-Phenotype Correlations

In X-linked AHC caused by a point mutation in NR0B1 no clear correlation exists between the location or type of mutation and the clinical phenotype.

Nomenclature

The term "congenital adrenal hypoplasia" is used less and less because it is easily confused with the much more common disorder, congenital adrenal hyperplasia. Both terms can be abbreviated as "CAH," further adding to potential confusion. Thus, adrenal hypoplasia congenita (AHC) is the preferred term.

Prevalence

The incidence of X-linked AHC is unknown. It has been widely estimated at 1:12,500 live births [McCabe 2001], but such figures were based on limited historic data that included secondary forms of AHC and anencephaly. Other estimates have put the figure at less than 1:70,000 males [Lin et al 2006]. No specific populations are known to be at greater or lesser risk for this disorder.

Differential Diagnosis

The 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, in which affected individuals may experience a transient salt-losing phase before salt retention occurs

The following disorders may present with symptoms similar to those seen in X-linked AHC:

  • ACTH deficiency presents with glucocorticoid (but not mineralocorticoid) insufficiency and low or unmeasurable serum concentration of ACTH (with and without corticotropin-releasing hormone stimulation). Isolated ACTH deficiency can result from alterations in TBX19, POMC, or PCSK1. ACTH deficiency can also occur as part of multiple pituitary hormone deficiency.
  • Congenital adrenal lipoid hyperplasia may present with salt-losing adrenal failure in a manner similar to AHC. Congenital adrenal lipoid hyperplasia is caused either by mutation of the gene encoding steroidogenic acute regulatory protein (StAR) or by CYP11A1 deficiency. Individuals with disruption of StAR or CYP11A1 and a 46,XY karyotype classically have ambiguous genitalia or female external genitalia. Adrenal imaging usually reveals enlarged and fatty adrenal glands. However, milder defects in STAR or CYP11A1 (or in HSD3B2) can be found in males with either hypospadias or “normal” male genitalia and delayed-onset adrenal failure in childhood. Usually, the salt-loss is not severe in these cases.
  • 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. The molecular basis of this condition is currently unknown.
  • Familial glucocorticoid deficiency and ACTH resistance is caused by mutation of MC2R encoding the ACTH receptor, disruption of the MC2R accessory protein (MRAP), or disruption of nicotinamide nucleotide transhydrogenase (NNT) [Meimaridou et al 2012]. This form of adrenal hypoplasia usually has normal mineralocorticoid secretion, although transient hyponatremia can be seen in severe cases.

Several syndromes and chromosomal abnormalities have AHC or AHC-like symptoms as one feature:

  • Pena-Shokeir syndrome, type 1 (fetal akinesia deformation sequence) (OMIM 208150)
  • Holoprosencephaly, alobar type
  • Meckel syndrome (OMIM 249000)
  • SerKAL (46,XX sex-reversal.with dysgenesis of kidneys, adrenals, and lungs) caused by mutation of WNT4 (OMIM 611812)
  • IMAGe syndrome (intrauterine growth retardation, metaphyseal dysplasia, AHC, genital abnormalities) caused by mutation of CDKN1C [Arboleda et al 2012]. Growth restriction is a key component of this condition.
  • Triple A (achalasia, addisonianism, alachrima) or Allgrove syndrome caused by mutation of AAAS (OMIM 231550)
  • Natural killer cell and glucocorticoid deficiency with DNA repair defect (NKGCD) caused by disruption of minichromosome maintainance-4 (MCM4) (OMIM 609981)
  • Chromosomal abnormalities, including tetraploidy, triploidy, trisomy 19, trisomy 21, 5p duplication, monosomy 7, and 11q- syndrome

Other forms of primary adrenal failure may need to be considered in boys presenting with primary adrenal failure:

  • X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males. The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years. Adrenomyeloneuropathy (AMN) manifests most commonly in the late twenties as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops later. Approximately 20% of females who are carriers develop neurologic manifestations that resemble AMN but have later onset (age ≥35 years) and milder disease than do affected males.
  • Other metabolic causes (e.g. Wolman disease, mitochondrial disease, Smith-Lemli-Opitz syndrome)
  • Autoimmune syndromes (e.g., polyglandular endocrine disease caused by mutation of AIRE)
  • Extrinsic (e.g., mechanical, infective, or drug-related) causes

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To assess the extent of disease and needs in an individual diagnosed with X-linked adrenal hypoplasia congenita (AHC), the following evaluations are recommended:

  • Serum and urine concentrations of electrolytes
  • Assessment of renal function, including measurement of serum BUN and creatinine
  • Serum concentration of glucose, cortisol and ACTH
  • Assessment of arterial blood gases in those who are unwell
  • Measurement of aldosterone and plasma renin activity

Note: Typically, affected individuals who are in shock have hyponatremia, hyperkalemia, hypoglycemia, acidosis, very elevated serum concentration of ACTH, and increased urinary excretion of sodium. Some samples may need careful handling (e.g., ACTH) and results may only be available some days later. Therefore, it is important to document the child’s clinical condition at the time of sample collection, the source of the sample (e.g., venous, arterial), and the quality of the sample (e.g., hemolyzed) to help with future interpretation of the results.

Treatment of Manifestations

Adrenal Insufficiency

Acute episodes. 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. Correction of hyperkalemia may be needed. Individuals are treated by the IV administration of saline, glucose, and hydrocortisone (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. Adequate sodium must be provided.

Chronic treatment. 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) in younger children.

  • Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis.
  • Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist.

Treatment during stress. Steroid dosage must be increased during periods of stress (e.g., intercurrent illness, surgery, trauma); glucose and sodium may be needed.

  • Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear.
  • Children should carry appropriate documentation indicating that they are steroid deficient. 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 in one case [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.

Surveillance

If puberty has not started by age 14 years, serum concentrations of LH and FSH (basal concentration and GnRH-stimulated concentration), testosterone, and inhibin B are monitored to evaluate for the possibility of HH.

  • Some children and parents prefer the induction of puberty at the same time as the affected boy’s peer-group; this should not be delayed unnecessarily.
  • If puberty does start spontaneously it is likely to arrest; thus, careful monitoring of testosterone levels is needed.
  • Psychological counseling should be available for families and young people if needed to discuss the issues related to hormone replacement therapy and future fertility.

Agents/Circumstances to Avoid

Unnecessary physiologic stress is to be avoided, if possible, and any surgical procedures should be carefully planned. If physiologic stress is unavoidable (e.g., surgery, febrile illness, trauma), the dosage of steroids should be increased two- to threefold following local guidance for sickness/emergencies.

Evaluation of Relatives at Risk

If the genetic status of an at-risk male relative has not been established during pregnancy, genetic testing should be performed as soon as possible after birth to clarify genetic status so that glucocorticoid and mineralocorticoid hormone replacement therapy can be initiated without delay and adrenal crises can be avoided. Biochemical testing after birth should be undertaken if the genetic status of an at-risk male is unknown and the child should be closely monitored in the first few days of life. A salt-losing crisis usually takes at least seven days to manifest, during which the child is continuing to lose sodium. Initial biochemical tests of electrolytes and basal cortisol may be within normal ranges but may gradually change. The aim is to avoid a clinical salt-losing crisis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked adrenal hypoplasia is inherited in an X-linked recessive manner.

Risk to Family Members — Isolated X-Linked AHC

Parents of a proband

  • The father of an affected male will not have X-linked adrenal hypoplasia nor will he be a carrier of the pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected individual is an obligate carrier.
  • If there is only one affected individual in the family, the mother may be a carrier or the affected individual may have de novo gene mutation, in which case the mother is not a carrier.
  • The percent of male probands with a negative family history in whom mutation occurred de novo is unknown but probably low.
  • Carrier females may occasionally have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism, possibly caused by skewed X-chromosome inactivation or gene conversion.

Sibs of a proband

  • The risk to sibs depends on the mother's carrier status.
  • If the proband's mother is a carrier, each male sib has a 50% chance of having X-linked AHC and each female sib has a 50% chance of being a carrier.
  • Germline mosaicism is possible but uncommon. If the pathogenic variant found in the proband cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Most males with AHC are infertile secondary to HH and a primary seminiferous tubule defect; however, should a male conceive through assisted reproductive technologies, all daughters will be carriers of the NR0B1 pathogenic variant. No son will inherit the pathogenic variant in NR0B1.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or of being affected (depending on their gender and family relationship and the carrier status of the proband's mother).

Carrier Detection

Carrier testing is possible for at-risk women in families in whom the affected family member has a point mutation in NR0B1.

Carrier testing is possible for at-risk women in families in whom the affected family member has a deletion detectable either by FISH studies using a NR0B1 cosmid probe or by other deletion/duplication analysis methods.

Risk to Family Members — Complex Glycerol Kinase Deficiency

The specific deletion in a family runs true in the family. Some families have deletions involving NR0B1, GK, and DMD (mutation of which results in AHC, GKD, and DMD respectively) while other families may have deletions that include NR0B1 and GK only.

Parents of a proband

  • Most mothers of individuals diagnosed with complex glycerol kinase deficiency are carriers; however, a proband may have the disorder as the result of a de novo deletion.
  • The proportion of cases caused by de novo deletions is unknown.
  • Evaluation of the mother of a child with complex glycerol kinase deficiency and no known family history of complex glycerol kinase deficiency should include FISH studies using a NR0B1 cosmid probe.

Sibs of a proband

  • The risk to the sibs of the proband depends on the carrier status of the mother.
  • If the mother is a carrier of the deletion, each male sib is at a 50% risk of being affected and each female sib is at a 50% risk of being a carrier.
  • If the mother does not have the deletion, the risk to the sibs is essentially zero.

Offspring of a proband. Males with complex GKD do not reproduce as they typically die in adolescence or young adulthood of complications from DMD, or are severely ill.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or of being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).

Carrier Detection

Carrier testing is possible for at-risk women in families in whom the affected family member has a contiguous gene deletion syndrome detectable by FISH studies or by other deletion/duplication analysis methods.

Related Genetic Counseling Issues

See Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Pedigree analysis. An in-depth family history may identify as-yet-untested male relatives possibly at risk of developing adrenal insufficiency.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Isolated X-linked AHC. If the pathogenic variant of an affected family member has been identified, prenatal diagnosis for pregnancies at increased risk for X-linked AHC is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15 to 18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Complex glycerol kinase deficiency. If the pathogenic deletion in an affected family member has been identified, prenatal diagnosis for pregnancies at increased risk for complex glycerol kinase deficiency is possible by either FISH analysis or deletion/duplication analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15 to 18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. X-Linked Adrenal Hypoplasia Congenita: Genes and Databases

Data 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 X-Linked Adrenal Hypoplasia Congenita (View All in OMIM)

300200ADRENAL HYPOPLASIA, CONGENITAL; AHC
300473NUCLEAR RECEPTOR SUBFAMILY 0, GROUP B, MEMBER 1; NR0B1

Gene structure. The NR0B1 reference sequence NM_000475.4 has two exons and 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]. The biologic significance of this transcript is unclear.

NR0B1 is the standard name for the gene but it has historically been known as DAX1 (and sometimes Ahch). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. In a series of 18 affected individuals from 16 families with X-linked adrenal hypoplasia congenita (AHC), seven families had deletions of NR0B1 (2 limited to NR0B1, 1 extending to GK, and 4 including NR0B1, GK, and DMD) and seven families had an intragenic pathogenic variant. In one family, no NR0B1 pathogenic variant was found; in one family, no mutation analysis was performed.

In a review of 42 intragenic pathogenic variants in NR0B1 found in 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 variants that cluster to the C-terminal region of NR0B1 have been described [Achermann et al 2001]. Many novel pathogenic variants 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 (C200W) outside the ligand binding was described, in a female age eight years 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].

In a review of ten years’ experience of the analysis of NR0B1 in adrenal failure, Lin et al [2006] described 37 new cases of X-linked AHC and reviewed the published literature. They reported that NR0B1 pathogenic variants or deletions were found in 58% of boys who had a diagnosis of AHC. All eight cases where there was a family history of X-linked adrenal failure and HH had NR0B1 mutations, but NR0B1 mutations were also found in around 40% of boys who had yet to reach adolescence and where there was no family history reported. A review of 190 published cases showed that the proportion of contiguous gene deletion cases was high (38%) and that of isolated NR0B1 deletions was low (5%), which probably reflects diagnosis and publication bias for complex glycerol kinase deficiency in the past. In the series of 37 new cases described, only two (5%) had contiguous deletions whereas eight (22%) had isolated deletions of NR0B1. Overall, in both series, frameshift mutations were slightly more prevalent than nonsense or missense mutations. No pathogenic variants in NR0B1 were found in a cohort of adult patients with isolated primary adrenal insufficiency of unknown etiology.

Pathogenic variants described in this section include (but are not limited to) the variants in the OMIM entry 300473.

Normal gene product. The predicted size of the protein product NP_000466.2 is 470 amino acids. The protein encoded by NR0B1 (NM_000475.4) has the structure of a transcription factor and is classified as an orphan nuclear receptor.

The carboxyl-terminal region of NR0B1 has a structure similar to the ligand-binding domains of nuclear receptors. The amino-terminal region of NR0B1 contains repeat motifs and lacks a typical DNA-binding domain found in other nuclear receptors. Although some studies have shown that NR0B1 can bind to DNA through hairpin loops, others have shown that NR0B1 can interact directly with other factors and co-factors (e.g., NR5A1/steroidogenic factor-1) or other cellular components (e.g., polyribosomes in complexes with polyadenylated RNA). Recently, crystal studies have shown that NR0B1 can bind to NR5A2 directly as part of a complex involving two NR0B1 transcripts [Sablin et al 2008].

Nuclear receptor 0B1 plays an important role in the normal development of the adrenal glands, the hypothalamus, the pituitary, and the ovary and testis and is expressed in these tissues during development and into post-natal life. The exact biologic role of NR0B1 is unknown. Initial studies have shown that NR0B1 can act as a negative regulator of other nuclear receptor signaling pathways. For instance, nuclear receptor 0B1 inhibits transactivation mediated by steroidogenic factor 1 (SF1), and may act 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 may also act as a transcriptional repressor of other important target genes such as steroidogenic acute regulatory protein (STAR), aromatase, and LH beta [Wang et al 2001].

These repressor effects are paradoxic, as loss of NR0B1 function causes adrenal underdevelopment and endocrine dysfunction. Several more recent studies have shown that NR0B1 can activate gene transcription in certain in vitro biologic assay systems or on specific promoters [Verrijn Stuart et al 2007, Ferraz de Souza et al 2009, Xu et al 2009].

An alternative hypothesis is that NR0B1 acts as a repressor of cell cycle progression and in the differentiation of pluripotent stem cells in the developing tissues [Lalli & Sassone-Corsi 2003]. Early differentiation of these cells into mature cells without prior expansion of cell numbers could lead to early overactivity and then to subsequent hypoplasia of the organ and depletion of the pluripotent cell pool. Some evidence for this hypothesis comes from a mouse model of Nr0b1 (exon 2) deletion [Scheys et al 2011].

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 has an inactivating mutation (deletion, nonsense, frameshift), no nuclear receptor 0B1 or truncated nuclear receptor 0B1 is made. When a missense mutation is present in NR0B1, it is predicted to have a deleterious affect on the normal conformation and function of nuclear receptor 0B1, or to affect nuclear localization of the protein.

References

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Chapter Notes

Revision History

  • 17 October 2013 (me) Comprehensive update posted live
  • 7 May 2009 (cd) Revision: deletion/duplication analysis available clinically
  • 1 August 2006 (me) Comprehensive update posted to live Web site
  • 10 December 2003 (me) Comprehensive update posted to live Web site
  • 20 November 2001 (me) Review posted to live Web site
  • March 2001 (ev) Original submission
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