Practice Essentials
Adrenocorticotropic hormone (ACTH) deficiency due to any cause and defects in the ACTH receptor results in hypoplasia of the adrenal cortex. However, this article focuses on primary disorders of adrenal gland formation (ie, primary adrenal hypoplasia). [1, 2, 3]
Four forms of congenital adrenal hypoplasia have been identified, as follows:
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An X-linked form (OMIM 300200) is caused by a mutation or deletion of the DAX1 gene (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region of the X chromosome, also called the NR0B1 gene) on the X chromosome. [4, 5, 6, 7, 8] This form is usually associated with hypogonadotropic hypogonadism. [9, 10] It may be part of a contiguous chromosome deletion, which may include congenital adrenal hypoplasia, Duchenne muscular dystrophy (OMIM 310200), and glycerol kinase deficiency (OMIM 307030).
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The autosomal recessive form is due to a mutation or deletion of the gene that codes for steroidogenic factor 1 (SF-1) on chromosome 9q33 (OMIM 184757). [11] This form is also associated with hypogonadotropic hypogonadism.
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An autosomal recessive form of uncertain etiology (OMIM 240200) has also been identified.
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A form of adrenal hypoplasia associated with intrauterine growth retardation, metaphysial dysplasia, and genital abnormalities has been identified (ie, intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies [IMAGe] association; OMIM 300290). [12]
Pathophysiology
The roles of DAX1 and the undefined autosomal recessive gene in development of the adrenal cortex are not understood. [13] DAX1 appears to be necessary for differentiation of the definitive adult adrenal cortex but not the fetal adrenal cortex because the latter is preserved in patients who have deletions of DAX1. The autosomal recessive gene appears to be important in the development of both the fetal adrenal cortex and the definitive adult adrenal cortex because both are hypoplastic in this form of congenital adrenal hypoplasia.
Etiology
X-linked congenital adrenal hypoplasia is due to mutation in, or deletion of, the DAX1 (AHCH) gene. The AHCH gene is located on chromosome bands Xp21.3-Xp21.2 and is thought to code for a nuclear receptor; however, the ligand for this particular nuclear receptor is not known, and hence, it is called an orphan nuclear receptor.
The DAX1 gene is also expressed in an alternatively spliced transcript, DAX1a. DAX1 and DAX1a appear to heterodimerize and also dimerize with SF1. [13] DAX1 appears to suppress expression of the SF1- regulated steroidogenic acute regulatory (StAR) protein promoter. How loss of this function results in loss of hypothalamic and adrenal cortical development remains unclear. DAX1 also appears to function as an antitestis gene by acting antagonistically to the sex-determining region (SRY). [14] In mice, DAX1 or AHCH is essential for the maintenance of spermatogenesis. Lack of the gene product causes progressive degeneration of the testicular germinal epithelium independent of abnormalities in gonadotropin and testosterone production. These changes result in male sterility. Excess expression of DAX1 in the male mouse results in reversal of phenotypic sex.
DAX1 gene mutations result in significant genotypic-phenotypic variability. [15, 16, 17, 13]
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In one family, a DAX1 mutation resulted in congenital adrenal hypoplasia and hypogonadotropic hypogonadism in two brothers. A normal phenotype was found in the affected maternal grandfather, and hypogonadotropic hypogonadism with normal adrenal function was found in a maternal aunt who was homozygous for the mutation. [18]
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The "minipuberty" infancy may be preserved. [19] Ovaries are intact in affected women.
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Observations in the SF1 knockout mouse and in humans indicate that mutations in SF1 result in congenital adrenal hypoplasia and hypogonadotropic hypogonadism as well. In contrast to DAX1 mutations, however, the phenotype in SF1 defects extends to XY sex reversal (ie, XY karyotype and female external genital appearance), persistence of müllerian structures in XY individuals, and failure of gonadal development (streak gonads).
DAX1 and SF1 messenger ribonucleic acid (mRNA) are expressed in the developing urogenital ridge, gonads, adrenal gland, pituitary gland, and hypothalamus, suggesting a dose-dependent role for both of these genes interacting as transcription factors important in a cascade of developmental gene expression. [20]
Because the gene involved in the autosomal recessive form of the disease is not known, the cause is even less understood.
Epidemiology
International statistics
Congenital adrenal hypoplasia is rare. Although the frequency has been estimated in Japan at 1 case per 12,500 births, clinical experience indicates that this disease is not as common as congenital adrenal hyperplasia due to 21-hydroxylase deficiency (incidence is approximately 1 per 10,000-15,000 births worldwide).
Sex- and age-related demographics
Because one form of congenital adrenal hypoplasia is X-linked, the disease occurs more commonly in males.
Patients with congenital adrenal hypoplasia generally present in infancy with signs of adrenal insufficiency. However, the age of onset widely varies, and some cases are not identified until the patient is an adult. [21] Ouyang et al reported the case of a male patient who did not receive a diagnosis of congenital adrenal hypoplasia until he was 22 years old, when he experienced a slipped capital femoral epiphysis. Addison disease had initially been diagnosed in this patient after he had developed systemic pigmentation at age 2. [22]
Prognosis
Prognosis of untreated congenital adrenal hypoplasia is poor if the disorder is unrecognized or untreated, and death is a common outcome.
With proper treatment and compliance, patients can live a normal life span without limitations.
Hypogonadotropic hypogonadism is nearly certain to develop secondary to DAX1 mutations or deletions. Infertility is common.
If the gene for muscle dystrophin is absent as a contiguous gene deletion, Duchenne muscular dystrophy (OMIM 310200) results, and the prognosis is poor.
Morbidity/mortality
Congenital adrenal hypoplasia is a lethal disease unless promptly recognized and appropriately treated. With proper medical treatment, patients do well unless they are also affected with Duchenne muscular dystrophy. Glycerol kinase deficiency, if present, does not result in morbidity but results in hyperglycerolemia. This may be recognized by factitiously elevated serum triglyceride concentrations.
Patients with congenital adrenal hypoplasia due to a mutation or deletion of DAX1 or SF1 (gene name NR5A1) develop hypogonadotropic hypogonadism. Some patients with the X-linked form have been found to have sensorineural deafness (OMIM 300200). Patients with IMAGe association also have intrauterine growth retardation and skeletal and genital abnormalities.
Complications
The main complications of adrenal hypoplasia include hypotension, electrolyte abnormalities, hypoglycemia, and death.
Complications of excessive administration of glucocorticoids are growth failure, obesity, striae, hypertension, hyperglycemia, and cataracts.
Excess mineralocorticoid administration can cause hypertension and hypokalemia.
Patients with X-linked congenital adrenal hypoplasia and defects in SF1 develop hypogonadotropic hypogonadism. Watch for this and treat appropriately if puberty does not occur in a timely fashion. Curiously, the minipuberty that occurs in the newborn period appears to be preserved. Most of these patients also experience testicular atrophy and are infertile.
Perform screening for hearing deficits since some patients with X-linked congenital adrenal hypoplasia have been described to have sensorineural (high-frequency) hearing deficits.
Patient Education
Patients should be advised to wear medical alert bracelets or anklets that alert medical personnel to the diagnosis of adrenal insufficiency and the need for glucocorticoid therapy in times of stress.
Caretakers must be educated about the consequences and the potentiality of death if adequate replacement therapy is not provided.
Teach patients and caretakers how to give supplemental glucocorticoid in times of illness or traumatic stress. Also, teach them how to give injectable glucocorticoid when the patient is vomiting or unable to take the stress doses orally. This information must be periodically reinforced because caretakers are often reluctant to give injectable medication.
Advise family to seek medical help early if the patient becomes ill.
