Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (ORPHA:90794)
A form of congenital adrenal hyperplasia (CAH) characterized by simple virilizing or salt wasting forms that can manifest with abnormal genital development with variable levels of virilization in females and with adrenal insufficiency in both sexes, and that presents with dehydration and hypoglycemia (which can be lethal if left untreated) in the neonatal period, as well as hyperandrogenia.
Epidemiology
Classic CAH due to 21-hydroxylase deficiency (21-OHD) is the most common form of CAH with a prevalence estimated at 1/14,000.
Clinical description
Classic 21-OHD CAH can be divided into 2 clinical groups: simple-virilizing or salt wasting. Clinical signs are observed prenatally or at birth. Girls present with abnormal genital development with variable levels of virilization, ranging 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 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 reduced adult height), advanced bone age, premature pubarche and precocious puberty during childhood, and acne and hirsutism, menstrual problems, subfertility, obesity, and metabolic and cardiovascular disturbances during adulthood. Males with poor hormonal control may develop small testes and benign testicular adrenal rest tumors (TARTs).
Etiology
The disease is caused by a mutation in the CYP21A2 gene located on chromosome 6p21.3 which controls cortisol and aldosterone production.
Diagnostic methods
Girls are usually diagnosed at birth when virilization of external genitalia is present. Signs of adrenal insufficiency present during the second week of life in both sexes. Newborn screening programs in most European countries diagnose cases of CAH at birth through 17-hydroxy-progesterone (17-OHP) analysis.
Differential diagnosis
Differential diagnoses include other forms of CAH, polycystic ovary syndrome (mainly for non-classical CAH) or any diseases with androgen excess.
Antenatal diagnosis
Prenatal diagnosis can be achieved by measuring 17-OHP levels in amniotic fluid during the second trimester of gestation or by genotyping through chorionic villus sampling to obtain fetal DNA as early as gestational week 10-12 in families with known CYP21A2 pathogenic genotypes. Methods involving invasive sampling should only be performed if the results will lead to changes in approach or treatment.
Genetic counseling
As classic 21-OHD CAH follows an autosomal recessive pattern of inheritance, genetic counseling is possible.
Management and treatment
Prenatal treatment with dexamethasone can be administered to female fetuses at risk of developing classic CAH, but this procedure is still controversial due to potential side effects. When administered before the 9th week of gestation, it prevents the excessive androgen production responsible for genital virilization in females. If diagnosed after birth, vaginoplasty surgery is usually performed on girls but the timing of the surgery is still debated. Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal health, 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 should be increased during times of stress or intercurrent disease. There is a risk of developing acute adrenal insufficiency and other complications due to chronic hyperandrogenemia in case of poorly controlled disease. Excessive treatment with GC causes cushingoid features, metabolic and cardiovascular disturbances. Excess MC causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, psychologists, is important.
Prognosis
Life expectancy may be reduced as patients with CAH have a risk of acute adrenal insufficiency and higher metabolic and cardiovascular risk. Poor disease control may increase the risk of these conditions, as well as of TARTs, menstrual irregularity and subfertility.

                            Last update: 
                            February 2022


                            - Expert reviewer(s): 
                            Pr Juliane LEGER | Endo-ERN*


                                * European Reference Network