APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
Genes: HSDB

3-beta-hydroxysteroid dehydrogenase deficiency
HSDB
3-beta-HSD
Adrenal and gonadal type II

Severe electrolyte imbalance
Salt loss
Male pseudohermaphroditism
Hypospadias
Adrenal crisis
Female virilization

Adrenal Hyperplasia II

Clinical Characteristics

General description (for patients):   

Adrenal hyperplasia of all types can cause a life-threatening illness and this type is no exception.  The severe electrolyte imbalance results from a so-called “adrenal crisis" with salt loss so severe as to cause death.  This disorder is also a cause of ambiguous genitalia among females, and in males, an abnormally placed urethral opening called hypospadias.

Medical description:   

This hormonal disorder is a cause of adrenal crisis with severe electrolyte imbalances that can be fatal.   Death, however, can even follow normal hormone replacement.  Some homozygotes have normal salt retention.  It is also a cause for pseudohermaphroditism with ambiguous genitalia and virilization in females.   Males often have hypospadias.

Genetics: 

This seems to be an autosomal recessive disorder based on the sibships reported.  The molecular genetics is less clear as several HSDB genes can be involved.  Presumed type II disease with a 35G>A change in the HSD3B2 gene has been reported in the Lancaster Co., PA, Amish.  There are a number of allelic forms reported but it is of interest that several families with classic 3-beta-HSD deficiency resulting from the same G>A transition have been reported in eastern Switzerland where Anabaptists originated.  The locus for HSD3B2 is on chromosome one (1p13.1).

Treatment: 

Hormonal and electrolyte replacement therapy.  Chromosomal studies should be used to accurately determine gender in children.
PROGNOSIS:  Variable.  Young children and infants may have severe disease requiring urgent intervention whereas others may grow into adults without adrenal crisis.  Pubertal development abnormalities should be monitored and treated with appropriate hormones.

Ancillary treatments and support: 

Dependent upon symptoms.

Specialists and specialty centers:  

Pediatrician, endocrinologist.

References:

Rheaume, E., Simard, J., Morel, Y., Mebarki, F., Zachmann, M., Forest, M.G., New, M.E., and Labrie, F.: Congenital adrenal hyperplasia due to point mutations in the type II 3-beta-hydroxysteroid dehydrogenase gene.  Nature Genet. 1: 239-245, 1992.  PubMed ID: 1363812

Puffenberger, E.G.:  Genetic Heritage of the Old Order Mennonites of Southeastern Pennsylvania.  Am. J. Hum. Genet. Part C (Semin. Med. Genet) 121: 18-31, 2003.  PubMed ID: 12888983

Bongiovanni, A.M.:  The adrenogenital syndrome with deficiency of 3-beta-hydroxysteroid dehydrogenase.  J. Clin. Invest. 41: 2086-2092, 1962. PubMed ID: 13968789

Resources:

Congenital Adrenal Hyperplasia Network

Associated Graphics