Adrenal Hypoplasia Clinical Presentation

Updated: Nov 04, 2016
  • Author: Thomas A Wilson, MD; Chief Editor: Robert P Hoffman, MD  more...
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Presentation

History

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  • Congenital adrenal hypoplasia most commonly presents in the neonatal period but may not become apparent until later in childhood.

  • Patients often present in crisis with dehydration, hyponatremia, hyperkalemia, hypotension, or hypoglycemia.

  • Patients with adrenal hypoplasia secondary to intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies (IMAGe) association have a history of intrauterine growth retardation. Males have genital abnormalities.

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Physical

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  • Patients may demonstrate hyperpigmentation from increased serum concentrations of adrenocorticotropic hormone (ACTH).

  • Signs of dehydration are often present.

  • Hypotension and symptoms of neuroglycopenia may be present.

  • Testes are undescended in many patients; micropenis may be seen in subjects with hypogonadotropic hypogonadism. Hypospadias or cryptorchidism may be seen in patients with IMAGe association.

  • Hearing loss may be an associated finding. [14]

  • A case study by Karsli et al reported two cases of adrenal hypoplasia presenting with chronic respiratory distress. [15]

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Causes

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  • 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). [16] 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. [17, 18, 19, 13]

    • 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. [20]

    • The "minipuberty" infancy may be preserved. [21] Ovaries are intact in affected women.

    • 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. [22]

  • Because the gene involved in the autosomal recessive form of the disease is not known, the cause is even less understood.

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