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] Ahmad Al Maradni, M.D. [3]
Overview
21-hydroxylase deficiency is the most common type of congenital adrenal hyperplasia. Congenital adrenal hyperplasia was first discovered by Luigi De Crecchio, an Italian pathologist in 1865. Gene responsible for 21-hydroxylase deficiency is CYP21A. This disease may be classified into two subtypes: classic and non-classic forms. 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. Symptom of 21-hydroxylase deficiency ranges from severe to mild or asymptomatic forms, depending on the degree of 21-hydroxylase enzyme deficiency. In classic type, main symptoms can be severe hypotension due to adrenal crisis, ambiguous genitalia in females, and no symptoms or larger phallus in males. In non-classic types, infants and male patients may have no symptoms and females may show virilization symptoms after puberty. 17-hydroxyprogesterone level and cosyntropin stimulation test can be used to diagnosis. Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of dexamethasone, for genetically diagnosed intranatal patients; also hydrocortisone and fludrocortisone may be used in children and adults. Treatment for non-classic type of 21-hydroxylase deficiency in children includes hydrocortisone until puberty and in women oral contraceptive pills for regulating menstrual cycle.
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
21-hydroxylase deficiency may be classified into two types based on severity and time of onset: classic and non-classic 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. 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 causes enzyme inactivity or hypo activity. There is a lack of enzyme in classic type of 21-hydroxylase deficiency; while in the non-classic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production. Responsible gene for 21-hydroxylase 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 gene.
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 microdeletions in CYP21A1 gene; 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
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 6.25 in 100,000 live births. Non-classic type is one of the most common autosomal recessive disorders in humans and affects approximately 100 in 100,000 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 100 in 100,000 to 1000 in 100,000, with a higher prevalence among Mediterraneans, Hispanics, and Eastern European Jews.
Risk Factors
The most potent risk factors in the development of 21-hydroxylase deficiency is presence of family history of 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 17-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 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 crisis, ambiguous genitalia in females, and no symptoms or larger phallus in males. 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 deficiency usually appear underweight and dehydrated. Physical examination is usually remarkable for hypotension and virilization.
Laboratory Findings
Laboratory findings consistent with the diagnosis of 21-hydroxylase deficiency differs in each disease type. 17-hydroxyprogesterone level and cosintropin stimulation test can be used to diagnosis.
Ultrasound
On ultrasound, 21-hydroxylase deficiency is characterized by enlarged, wrinkled, and cerebriform adrenal glands. Also testicular masses may be seen in the setting of classic 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
Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of dexamethasone, for genetically diagnosed intranatal patients, and hydrocortisone and fludrocortisone in may be used in children and adults. Treatment for non-classic type of 21-hydroxylase deficiency in children includes hydrocortisone until puberty and in women oral contraceptive pills for regulating menstrual cycle. Men with non-classic type of 21-hydroxylase deficiency are asymptomatic and they do not need treatment.
Surgery
Surgery is not the first-line treatment option for patients with 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 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 21-hydroxylase deficiency.
References