Sorted By Test Name - Mayo Medical Laboratories

CYPKP
89082
transcriptionally active genetic segment.
Useful For: Third-tier confirmatory testing of positive congenital adrenal hyperplasia (CAH) newborn
screens An adjunct to measurement of basal and adrenocorticotropic hormone -1-24-stimulated
17-hydroxyprogesterone, androstenedione, and other adrenal steroid levels in the diagnosis of atypical or
nonclassical cases of CAH Carrier detection of CYP21A2 mutations and genetic counseling An adjunct to
measurement of amniotic fluid 17-hydroxyprogesterone and androstenedione measurements in the
antenatal diagnosis of 21-hydroxylase deficiency
Interpretation: All detected alterations will be evaluated according to American College of Medical
Genetics and Genomics (ACMG) recommendations (Genet Med 2008:10[4]:294-300). Variants will be
classified based on known, predicted, or possible pathogenicity and reported with interpretive comments
detailing their potential or known significance.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Collett-Solberg PF: Congenital adrenal hyperplasias: from clinical genetics
and biochemistry to clinical practice, part I. Clin Pediatr 2001;40:1-16 2. Mercke DP, Bornstein SR, Avila
NA, Chrousos GP: NIH conference: future directions in the study and management of congenital adrenal
hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med 2002;136:320-334 3. Speiser PW, White
PC: Medical progress: congenital adrenal hyperplasia. N Engl J Med 2003;349:776-788
21-Hydroxylase Gene (CYP21A2), Known Mutation
Clinical Information: Congenital adrenal hyperplasia (CAH) is one of the most common inherited
syndromes, with an incidence rate of 1:10,000 to 18,000 livebirths. The condition is characterized by
impaired cortisol production due to inherited defects in steroid biosynthesis. The clinical consequences of
CAH, besides diminished cortisol production, depend on which enzyme is affected and whether the loss
of function is partial or complete. In >90% of CAH cases, the affected enzyme is 21-steroid hydroxylase,
encoded by the CYP21A2 gene located on chromosome 6 within the highly recombinant human
histocompatibility complex locus. Since sex steroid production pathways branch off proximal to this
enzymatic step, affected individuals will have increased sex steroid levels, resulting in virilization of
female infants. If there is some residual enzyme activity, a nonclassical phenotype results, with variable
degrees of masculinization starting in later childhood or adolescence. On the other end of the severity
spectrum are patients with complete loss of 21-hydroxylase function. This leads to both cortisol and
mineral corticosteroid deficiency and is rapidly fatal if untreated, due to loss of vascular tone and salt
wasting. Because of its high incidence rate, testing for 21-hydroxylase deficiency included in most US
newborn screening programs, typically by measuring 17-hydroxyprogesterone concentrations in blood
spots by immunoassay. Confirmation by other testing strategies (eg, LC-MS/MS, CAHBS/84113
Congenital Adrenal Hyperplasia [CAH] Newborn Screening, Blood Spot), or retesting after several
weeks, is required for most positive screens because of the high false-positive rates of the immunoassays
(due to physiological elevations of 17-hydroxyprogesterone in premature babies and immunoassay
cross-reactivity with other steroids). In a small percentage of cases, additional testing will fail to provide a
definitive diagnosis. In addition, screening strategies can miss many nonclassical cases, which may
present later in childhood or adolescence and require more extensive steroid hormone profiling, including
testing before and after adrenal stimulation with adrenocorticotropic hormone (ACTH)-1-24. For these
reasons, genetic diagnosis plays an important ancillary role in classical cases, and is even more important
in nonclassical cases. In addition, the high carrier frequency (approximately 1:50) for CYP21A2
mutations makes genetic diagnosis important for genetic counseling. Finally, genetic testing may play a
role as an adjunct to biochemical testing of amniotic fluid in antenatal diagnosis of 21-hydroxylase
deficiency. However, accurate genetic diagnosis continues to be a challenge, because most of the
mutations arise from recombination events between CYP21A2 and its highly homologous pseudogene,
CYP21A1P (transcriptionally inactive). In particular, partial or complex rearrangements, with or without
accompanying gene duplication events, which lead to reciprocal exchanges between gene and
pseudogene, can present severe diagnostic challenges. Comprehensive genetic testing strategies must
therefore allow accurate assessment of most, or all, known rearrangements and mutations, as well as
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