Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency (ORPHA:90795)
A rare form of classic congenital adrenal hyperplasia (CAH) characterized by glucocorticoid deficiency, hyperandrogenism, hypertension and virilization in females.
Epidemiology
It accounts for approximately 5-8% of CAH cases and has an annual incidence of 1/100,000-200,000 live births.
Clinical description
Severe virilization is seen in the external genitalia of girls while boys appear normal at birth. If the disorder is not recognized during the neonatal period, both girls and boys undergo rapid postnatal growth with accelerated growth velocity and accelerated skeletal maturation, hypertension, premature adrenarche and precocious puberty leading to reduced adult height. There is also a life-long risk for acute adrenal insufficiency.
Etiology
The disease is caused by a mutation in the CYP11B1 gene that is located on chromosome 8 q21. Steroid 11-beta-hydroxylase deficiency causes decreased cortisol secretion and hypertension due to accumulation of glucocorticoid (GC) and mineralocorticoid precursors.
Diagnostic methods
Diagnosis of girls with classic CAH due to 11-beta-hydroxylase deficiency (11beta-OHD) is usually at birth when virilization of external genitalia is present. Signs of adrenal insufficiency present in both sexes during the second week of life. However, salt wasting is very uncommon, which may delay the time of diagnosis compared with CAH due to 21-hydroxylase deficiency (21-OHD), because of continued mineralocorticoid receptor stimulation due to elevated desoxycorticosterone (DOC) secretion. Serum levels of 11-desoxycortisol, DOC, androstenedione, 17-OH pregnenolone and ACTH are elevated. 17-OH progesterone may be slightly elevated. Simultaneous measurement of these steroids by liquid chromatography with tandem mass spectrometry (LC-MS/MS) is the most convenient method for diagnosis of 11beta-OHD. CAH can be diagnosed prenatally by genotyping through chorionic villus sampling to obtain fetal DNA as early as gestational week 10-12 in families with known CYP11B1 pathogenic genotypes. Methods involving invasive sampling should only be performed if the results will lead to changes in approach or treatment. National systematic screening programs may diagnose cases of 11beta-OHD CAH at birth due to slightly elevated 17-OH progesterone.
Differential diagnosis
Differential diagnosis is CAH due to 21-OHD. 17-OH progesterone may be elevated in the newborn, leading to misdiagnosis of 21-OHD.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member or in case of genital abnormalties diagnosed antenatally in girls.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
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 GC replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal growth and puberty, and normal health without hypertension. Hydrocortisone is usually given to children as GC replacement therapy (10-15mg/m2/day divided into 2 or 3 doses). Dosage is monitored and should be increased during times of stress or intercurrent disease. There is a risk of developing acute adrenal insufficiency (see this term), hypertension and other complications due to chronic hyperandrogenemia in case of poorly controlled disease. Excessive treatment with GC causes cushingoid features and metabolic and cardiovascular disturbances. In all cases, excess mineralocorticoid causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, and psychologists, is important.
Prognosis
Life expectancy may be reduced as patients with CAH have a risk of acute adrenal insufficiency, hypertension and higher metabolic and cardiovascular risk. Poor disease control may increase the risk of acute adrenal insufficiency, hypertension, metabolic and cardiovascular morbidities, testicular adrenal rest tumors (TARTs), menstrual irregularity and subfertility.

                            Last update: 
                            February 2022


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


                                * European Reference Network