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Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

ORPHA90794
Synonym(s) Classic 21-OHD CAH
Prevalence 1-9 / 100 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • E25.0
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (classical 21 OHD CAH) is the most common form of congenital adrenal hyperplasia (CAH; see this term), characterized by simple virilizing or salt wasting forms that can manifest with genital ambiguity in females, and in both sexes with adrenal insufficiency with dehydration, hypoglycemia in the neonatal period that can be lethal if untreated, and hyperandrogenia.

The prevalence is about 1/14,000.

Classical 21 OHD CAH can be divided into 2 clinical groups: simple-virilizing or salt wasting (see these terms). Clinical signs of classical 21 OHD CAH are observed prenatally or at birth. Girls present with ambiguous genitalia (clitoromegaly, partially fused labia majora with rugae, common urogenital sinus) and the extent of virilization can vary from a nearly male appearance to minimal clitoromegaly. A normal uterus and various degrees of abnormal vaginal development are seen. The external genitalia in boys are normal. Salt wasting forms of CAH lead to symptoms of dehydration and hypotension in the first few weeks of life due to aldosterone deficiency. They can develop failure to thrive, hyponatremia, hyperkalemia, acidosis and hypoglycemia which can be life threatening if not treated immediately. Hyperandrogenia manifests with accelerated growth velocity and accelerated skeletal maturation (leading to short stature in adulthood), advanced bone age, premature pubarche and precocious puberty during childhood, acne and hirsutism, menstrual problems, subfertility, and metabolic disturbances and obesity during adulthood.

The disease is caused by a mutation in the CYP21A2 gene located on chromosome 6p21 which controls cortisol and aldosterone production.

Diagnosis of girls with classical CAH is usually at birth when ambiguous genitalia are present. Fetuses can be diagnosed for CAH prenatally by measuring 17-hydroxy-progesterone (17-OHP) levels found in amniotic fluid. National systematic screening programs in most European countries diagnose cases of CAH at birth.

Differential diagnoses include other forms of CAH, polycystic ovary syndrome (PCOS) or any diseases with androgen excess.

Prenatal testing is available by either chorionic villus sampling (CVS) during the 10th -12th week of gestation or by amniocentesis during the 15th -18th week by measuring the enzyme activity of 17-OHP.

As classic CAH follows an autosomal recessive pattern of inheritance, genetic counseling is possible.

Prenatal treatment with dexamethasone can be administered to female fetuses at risk of developing classical CAH. When administered before the 9th week of gestation, it prevents the excessive androgen production responsible for genital ambiguity in females. If diagnosed after birth, vaginoplasty surgery is usually performed on girls in the first year of life. Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal growth and puberty. Hydrocortisone is usually given to children as glucocorticoid (GC) replacement therapy (10-15mg/m2/day divided into 2 or 3 doses) and 9alpha-fludrocortisone for mineralocorticoid (MC) replacement. Dosage is monitored and modified during times of stress. There is a risk of developing acute adrenal insufficiency (see this term) and other complications due to chronic hyperandrogenia. Excessive treatment with GC causes cushingoid features, and excess MC causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, psychologists, is important.

With proper treatment patients should have a normal life expectancy.

Expert reviewer(s)

  • Pr Juliane LEGER

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Detailed information

Summary information
Clinical practice guidelines
  • FR (2011,pdf)
  • EN (2010)Patient Inform
Article for general public
  • FR (2009,pdf)
Clinical genetics review
  • EN (2013)
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