The current era of expanded carrier screening has been successful in identifying couples at increased risk for having a child with certain genetic conditions, but also poses genetic counseling and testing challenges. One example is 21-hydroxylase deficiency (21-OHD), which is caused by genetic variants in the CYP21A2 gene. Twenty-one OHD has 2 clinical forms, classic and non-classic; the classic form frequently results in ambiguous genitalia (virilization) and/or life-threatening salt-wasting episodes while the non-classic form is much less severe, but more common. Traditionally, prenatal diagnosis of 21-OHD was offered only when there was known family history of an affected child or a prenatal ultrasound finding of ambiguous genitalia, both of which are associated with the severe, classic form of 21-OHD. Some genetic laboratories offering expanded carrier screening include CYP21A2 analysis, which has identified more at-risk couples who are then offered diagnostic fetal testing. However, what is not always clear to the provider is that certain variants in the CYP21A2 gene are often specific to each clinical type and the couple may only be at risk for having a child with the non-classic form of 21-OHD rather than the classic form. It is especially important for providers to be aware of the distinction between these 2 clinical forms and the associated CYP21A2 variants so that patients have the most accurate information and are appropriately counseled about which clinical form their children are at risk for.
What is 21-OHD?
Twenty-one hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia (CAH), a family of genetic conditions associated with an increased production of androgens, is inherited in an autosomal recessive pattern. The gene associated with 21-OHD, CYP21A2, has 7 common pathogenic variants, some of which are associated with a specific clinical type. As mentioned above, there are 2 clinical forms of 21-OHD, classic and non-classic. The form is determined by the amount of the 21-hydroxylase enzyme present; lower enzyme levels result in classic/severe form, whereas higher enzyme levels are associated with non-classic/mild form. Clinical features of each form are below:
Classic form:
- newborn onset
- 75% of cases have salt-wasting, which can be life-threatening in the newborn period if not identified and treated promptly
- 25% of cases have simple-virilizing effects, which only affects females.
Non-classic form:
- later age of onset
- precocious (early) puberty, accelerated growth with advanced bone age resulting in reduced adult height, and acne.
- females have an increased risk of infertility1
Is 21-OHD common?
Yes, in terms of genetic disorders. The classic form occurs in approximately 1 in 15,000 live births 2. Non-classic CAH has a much higher incidence, approximately 1 in 100, with the frequency being higher in individuals of Ashkenazi Jewish ancestry (1 in 27).
How is 21-OHD identified?
The clinical diagnosis of classic CAH due to 21-OHD is typically made by a combination of clinical and biochemical findings, which include: ambiguous genitalia in a female fetus/infant, either by prenatal ultrasound finding or in the newborn period; abnormal newborn screening results; and/or abnormal biochemical testing (see below). 21-OHD is included in many state newborn screening programs. If a newborn screen is positive for CAH, biochemical testing is typically used to confirm the diagnosis. Biochemical findings that confirm a clinical diagnosis in both classic and non-classic forms include elevated 17-hydroxyprogesterone levels, increased adrenal androgens, and/or plasma renin activity. It is important to note that the findings of ambiguous genitalia and salt-wasting crises are seen only in the classic form of 21-OHD due to extremely low enzyme activity.
Non-classic 21-OHD is typically not identified in infancy, but when a child goes through early puberty or when a female has issues with conceiving2. The diagnosis can be confirmed with biochemical testing. In some cases, adults are found to have 21-OHD after having expanded carrier screening as a part of their routine prenatal care.
What does the specific variant tell us about clinical presentation?
It is well established that some of the common variants in the CYP21A2 gene are typically associated with the milder, non-classic form of the disease, such as the Val281Leu variant (aka V281L/c.844G>T). Affected individuals who have at least 1 copy of the V281L variant are expected to be affected with the milder, non-classic form of CAH. The correlation between genotype and phenotype may be less certain for other known genetic variants.
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