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Abstract

Abstract 

  1. Adrenal hypoplasia congenita (AHC) has an estimated incidence of 1:12,500 live births and two distinct histological patterns to the adrenal cortices, the miniature adult and cytomegalic forms.

  2. In the miniature adult form of AHC, the small amount of residual adrenal cortex is composed primarily of permanent adult cortex with normal structural organization. The miniature adult form is either sporadic or inherited in an autosomal recessive manner, and is frequently associated with abnormal central nervous system development, including anencephaly or pituitary gland abnormalities.

  3. In the cytomegalic form of AHC, the residual adrenal cortex is structurally disorganized with scattered irregular nodular formations of eosinophilic cells, with the adult permanent zone absent or nearly absent. Enlarged cells are present, some with abundant vacuolated cytoplasm. The cytomegalic form is generally considered to be X-linked, but there may be one or more autosomal genes associated with this phenotype.

  4. X-linked AHC (MIM 300200) is caused by intragenic mutations or complete deletion of the Xp21 DAX1 gene (DSS-AHC critical region on the X chromosome, gene 1). Associated with deletion of DAX1, the Duchenne muscular dystrophy (DMD) and glycerol kinase (GK) genes may also be deleted as part of a contiguous gene syndrome. Patients with DAX1 mutations have adrenal insufficiency with glucocorticoid and mineralocorticoid deficiency, and hypogonadotropic hypogonadism (HH) of mixed hypothalamic and pituitary origin. Gonadal mosaicism for a DAX1 mutation has been reported in one family with X-linked AHC.

  5. DAX1 is an unusual member of the nuclear hormone receptor superfamily with a characteristic C-terminal putative ligand-binding domain (LBD), but an atypical N-terminal portion that is a DNA-binding domain (DBD) in the typical receptor. Because DAX1 has the structure of a transcription factor and maps to the 160 kb critical region for dosage sensitive sex reversal (DSS) within the tandem duplications among XY individuals with female or ambiguous genitalia, it is a candidate gene for the DSS locus. XY transgenic mice with overexpression of the murine homologue, Dax1, and reduced expression of SRY (sex determining region, Y chromosome) are phenotypically female. These observations suggest that DAX1 may be the hypothetical X-linked negative regulator of male gene expression that is antagonized by SRY in normal XY males.

  6. There are at least six single-gene disorders associated with adrenal hypoplasia/aplasia that have definite or apparent autosomal recessive inheritance: ACTH deficiency (MIM 201400); AHC with absent pituitary LH (MIM 202150); cytomegalic form of AHC with autosomal recessive inheritance (MIM 202155); Pena-Shokeir syndrome, type 1 (MIM 208150); holoprosencephaly 1, alobar (MIM 236100); hypoadrenocorticism, familial (MIM 240200); and Meckel syndrome (MIM 249000).

  7. A number of chromosomal abnormalities have been associated with adrenal hypoplasia. These include tetraploidy, triploidy, trisomy 18, trisomy 21, 5p duplication, monosomy 7 and the 11q syndrome. Because these patients frequently have central nervous system abnormalities, the adrenal hypoplasia is often the miniature adult form.

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