X-Linked Adrenal Hypoplasia Congenita

[Adrenal Hypoplasia Congenita, Congenital Adrenal Hypoplasia, X-Linked AHC. Includes: Complex Glycerol Kinase Deficiency, Isolated X-Linked Adrenal Hypoplasia Congenita]

Clinical Diagnosis

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.

Testing

Adrenal 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 the DMD gene or immunohistochemical staining of dystrophin on muscle biopsy.

• Deletions of the X chromosome that include the NR0B1 (DAX1) gene can be detected by FISH studies using a NR0B1 cosmid probe and by other deletion/duplication analysis.

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

Table 1. FISH Testing Used in AHC with Complex Glycerol Kinase Deficiency

Gene Symbol	Test Method	Mutations Detected	Detection Rate in Individuals with AHC with Complex GKD	Test Availability
NR0B1	FISH	Deletion	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 bandXp21.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. NR0B1 is the only gene 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 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in Isolated X-Linked Adrenal Hypoplasia Congenita

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1		Test Availability
			Positive Family History	Negative Family History
NR0B1	Sequence analysis	Point mutations	Nearly 100%	50%-70%	Clinical
	Deletion/duplication analysis 2, 3	Partial- or whole-gene or contiguous-gene deletions	Unknown	Unknown

1. 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) Disorders

The 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.

Natural History

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].

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.

Genotype-Phenotype Correlations

When X-linked AHC is caused by a point mutation in the NR0B1 gene, no 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.

Prevalence

The incidence of X-linked AHC is estimated at 1:12,500 live births [McCabe 2001]. No specific populations are known to be at greater or lesser risk for this disorder.

Evaluations Following Initial Diagnosis

To 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 Manifestations

Adrenal 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.

Surveillance

If 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 Avoid

Stress is to be avoided, if possible. If unavoidable (e.g., surgery, febrile illness, trauma), dosage of steroids should be increased two- to threefold.

Testing of Relatives at Risk

If 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 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.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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 mutation.

• 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 a de novo gene mutation, in which case the mother is not a carrier.

• The percent of male probands with a negative family history who have a de novo mutation 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 disease-causing mutation 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 the possibility of germline mosaicism exists.

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 mutation. No son will inherit the NR0B1 mutation.

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 upon their gender and family relationship and the carrier status of the proband's mother).

Carrier Detection

• Carrier testing is available to at-risk women in families in which the affected family member has a point mutation in the NR0B1 gene.

• Carrier testing is available to at-risk women in families in which the affected family member has a deletion of the X chromosome detectable by FISH studies using a NR0B1 cosmid probe.

Risk to Family Members — Complex Glycerol Kinase Deficiency

The specific deletion in a family runs true in the family. Some families have deletions involving the genes causing AHC, GKD, and DMD, while other families may have deletions that involve the genes causing AHC and GKD 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 upon 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 upon their gender, family relationship, and the carrier status of the proband's mother).

Related Genetic Counseling Issues

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.

DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particuarly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is available for pregnancies at risk for X-linked AHC caused either by deletions of NR0B1 detectable by FISH analysis or by an identified mutation in NR0B1. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained from chorionic villus sampling (CVS) at about 10-12 weeks' gestation or from amniocentesis usually performed at about 15-18 weeks' gestation. Further evaluation of cells from male fetuses using either FISH with a NR0B1 probe can determine if the deletion identified in the family is present; DNA analysis can determine if the mutation identified in the family is present.

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 available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 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