21-hydroxylase deficiency overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2]
Overview
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH CAH) also known as (CAH1) accounts for about 95% of diagnosed cases of congenital adrenal hyperplasia, and congenital adrenal hyperplasia in most contexts refers to 21-hydroxylase deficiency Congenital adrenal hyperplasia was first discovered by Luigi De Crecchio, an Italian anatomist. Congenital adrenal hyperplasia due to 21-hydorxylase deficiency is caused by mutations in the CYP21A2 gene. The prevalence of congenital adrenal hyperplasia due to 21-hydroxylate deficiency ranges between 6.6 to 7.6 per 100,000 individuals. The incidence of congenital adrenal hyperplasia due to 21-hydroxlase deficiency is approximately 7.1 per 100,000 births. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency usually affects individuals of the Ashkenazi Jews and Mediterranean race, and the Ashkenazi Jews to Mediterranean race ratio is approximately 1 to 3. Congenital adrenal hyperplasia due to 21-hydorxylase deficiency must be differentiated from other causes of adrenal hyperplasia such as 11-β hydroxylase deficiency and 17-α hydroxylase deficiency. Symptoms of congenital adrenal hyperplasia due to 21-hydorxylase deficiency include dehydration, vomiting, and weight loss. Late symptoms include virilization and infertility. The most potent risk factor in the development of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is presence of family history of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The mainstay of therapy for congenital adrenal hyperplasia due to 21-hydorxylase deficiency is glucocorticoid replacement.
Historical Perspective
Congenital adrenal hyperplasia was first discovered by Luigi De Crecchio, an Italian pathologist in 1865. Explanation of hormonal aspects and molecular characteristics remained unclear until 1980. From 1980 scientists started to describe enzymes and molecular basis of 21-hydroxyase deficiency.
Classification
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency may be classified into two subtypes based on severity and time of onset: classical and non-classical forms. Classic form includes two subtypes salt wasting and non-salt wasting 21-hydroxylase deficiency.
Pathophysiology
In patients with 21-hydroxylase deficiency, there is a defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion. The resulting adrenal stimulation leads to increased production of androgens. More than 95% of all cases of CAH are caused by 21-hydroxylase deficiency (21-OHD); The clinical manifestation of congenital adrenal hyperplasia is closely related to the type and severity of disease. The severity of disease relates to the mutation type which is caused enzyme inactivity or hypoactivity. There is a lack of enzyme in classical type of 21-hydroxylase deficiency; while in the nonclassical form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production. Responsible gene for 21 OH deficiency is CYP21A. This gene is located within the human leucocyte antigen class III region of chromosome 6. Meiotic recombination events occurs in this genomic region as a result of the high degree of sequence homology between CYP21A2 and its pseudogene CYP21A1. Approximately 70% of CYP21A2 disease is due to gene conversion and micro-deletions in CYP21A1 gen.
Causes
Causes of 21-hydroxylase deficiency include mutations in CYP21A1 and CYP21A2 gene on chromosome 6. Approximately 70% of CYP21A2 disease is due to gene conversion and micro-deletions in CYP21A1 gen; around 25% to 30% are chimeric genes due to large deletions. Less common causes are due to de novo mutations because of high variability of the CYP21A2 locus. Also chromosome 6 uniparental disomy is rare cause of 21-hydroxylase deficiency with an unknown prevalence.
Differentiating Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency from other Diseases
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency must be differentiated from 11-β hydroxylase deficiency, 17-α hydroxylase deficiency, androgen insensitivity syndrome, 3β-Hydroxysteroid Dehydrogenase, polycystic ovarian syndrome, hyperprolactinemia, cushing syndrome, and adrenal tumor.
Epidemiology and Demographics
Worldwide, the incidence of 21-hydroxilase deficiency classic salt wasting type is 5 per 100,000 persons. Prevalence varies according to ethnicity and geographic area; ranges from a low of 3.57 per 100,000 persons in Chinese population to a high of per 100,000 persons with an average prevalence of 357 per 100,000 persons in Yupik Eskimos in Alaska. This disease usually affects individuals of the Ashkenazi Jews and Mediterranean race. The classic type affects approximately 1 in 16,000 live births. Non-classic type is one of the most common autosomal recessive disorders in humans and affects approximately 1 in 1000 individuals, but in up to 1–2% among inbred populations, such as Eastern European (Ashkenazi) Jews. Incidence for 21-hydroxylase deficiency is more prevalent in some ethnic groups, particularly in remote geographic regions such as Alaskan Yupiks. The non-classic form is one of the most common autosomal recessive diseases. The prevalence of the non-classic form may differ from 1 in 1000 to 1 in 100, with the higher prevalence among Mediterraneans, Hispanics, and Eastern European Jews.
Risk Factors
The most potent risk factors in the development of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is presence of family history of congenital adrenal hyperplasia due to 21-hydroxylase deficiency and being in certain ethnic groups, particularly Ashkenazi Jews and Yugoslavians and Yupik Inuits.
Screening
According to Endocrine Society Clinical Practice Guideline, screening for 21-hydroxylase deficiency by measuring 17a-hydroxyprogesterone is recommended for all newborns. The Endocrine Society's Clinical Practice Guideline recommends that genetic counseling be provided for individuals who are planning to conceive, and there is a family history of 21-hydroxylase deficiency.
Natural History, Complications and Prognosis
If left untreated, patients with 21-hydroxylase deficiency may progress to develop complications. Common complications of 21-hydroxylase deficient congenital adrenal hyperplasia include short stature, adrenal crisis, infertility, and precocious puberty. The prognosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is generally good with treatment.
Diagnosis
History and Symptoms
Symptom of 21-hydroxylase deficiency ranges from severe to mild or asymptomatic forms, depending on the degree of 21-hydroxylase enzyme deficiency. There are three main clinical phenotypes: classic salt-wasting, classic non-salt-wasting (simple virilizing), and non-classic (late-onset). In classical type, main symptoms can be sever hypotension due to adrenal crises, ambiguous genitalia in females, and no symptoms or larger phallus. In non-classic types, infants and male patients may have no symptoms and females may show virilization symptoms after puberty.
Physical Examination
Patients with 21-hydroxylase deficient usually appear underweight and dehydrated. Physical examination is usually remarkable for hypotension and virilization.
Laboratory Findings
Laboratory findings consistent with the diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency differs in each disease type. 17-hydroxyprogesterone level and cosintropin stimulation test can be used to diagnosis.
Ultrasound
On ultrasound, congenital adrenal hyperplasia due to 21-hydroxylase deficiency is characterized by enlarged, wrinkled, and cerebriform adrenal glands. Also testicular masses can be seen in the setting of classical disease.
CT Scan
On abdominal CT scan, 21-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the adrenal glands.
MRI
On abdominal MRI, 21-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the adrenal glands.
Treatment
Medical Therapy
The mainstay of therapy for congenital adrenal hyperplasia due 21-hydroxylase deficiency is glucocorticoid replacement.
Surgery
Surgery is not the first-line treatment option for patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Surgical reconstruction of abnormal genitalia is usually reserved for severely virilized girls.
Primary Prevention
There are no primary preventive measures available for congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Secondary Prevention
Continued monitoring of hormone balance and careful readjustment of glucocorticoid dose is helpful in controlling fertility and preventing adrenal crisis in patient with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.