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00019616-200611000-00004ReportThe EndocrinologistThe Endocrinologist© 2006 Lippincott Williams & Wilkins, Inc.16November 2006 p 311-312Ambiguous Genitalia Without Clitoromegaly in a Girl With Classic Congenital Adrenal HyperplasiaCase ReportNabhan, Zeina M. MD*; Rink, Richard C. MD†; Eugster, Erica A. MD*From the *Section of Pediatric Endocrinology, Department of Pediatrics and the †Department of Pediatric Urology, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana.Reprints: Zeina M. Nabhan, MD, Pediatric Endocrinology/Diabetology, Riley Hospital for Children, Room 5960, 702 Barnhill Drive, Indianapolis, IN 46202. E-mail: [email protected] adrenal hyperplasia (CAH) is an autosomal-recessive disorder characterized by a defect in cortisol biosynthesis with >95% of cases being the result of 21-hydroxylase deficiency. Girls affected with classic 21-hydroxylase deficiency usually present at birth with ambiguous genitalia, including clitoromegaly, labial fusion, and a urogenital sinus. We report a female infant with classic CAH secondary to 21-hydroxylase deficiency in whom clitoromegaly was absent despite other signs of androgen excess.Girls with classic congenital adrenal hyperplasia (CAH) exhibit significant phenotypic variability. However, even in the most mildly affected cases, clitoromegaly is invariably present. This is the first report of a female infant with classic CAH secondary to 21-hydroxylase deficiency in whom clitoromegaly was absent despite posterior labial fusion and a urogenital sinus.CASE REPORTA 5-month-old white girl was referred to our institution for genital surgery. She was born by vaginal delivery at 38 weeks’ gestation to a 31-year-old G2 P1 mother. Pregnancy was uncomplicated except for gestational diabetes, which was controlled by diet and exercise. During her pregnancy, the mother did not have signs of virilization and was not on any medications. There was no family history of endocrine disorders.After birth, the infant was noted to have posterior labial fusion with what was described as a “normal-appearing clitoris.” The urethral opening was reported to be difficult to visualize. Pediatric urology and endocrinology were consulted. Initial evaluation included serum 17 hydroxyprogesterone (17-OHP) and electrolytes, both of which were normal. A karyotype was 46, XX. Imaging studies revealed a normal uterus and ovaries and a short common urogenital sinus. The infant was diagnosed with simple anatomic fusion of the labia and was discharged home at 2 days on antibiotic prophylaxis for urinary tract infections. Although her initial newborn screen (NBS) was normal, a repeat NBS at 3 weeks of age was significant for an elevated 17-OHP. No follow-up serum was obtained at this time.At 3.5 months of age, the infant was seen by her urologist for correction of the posterior labial fusion. A repeat serum 17-OHP and electrolytes were done. After consultation with a local endocrinologist, she was diagnosed with “partial” 21-hydroxylase deficiency and was started on hydrocortisone. Baseline and subsequent laboratory values are summarized in Table 1.JOURNAL/endst/04.03/00019616-200611000-00004/table1-4/v/2021-02-17T201820Z/r/image-tiff Laboratory Values in the InfantAt 5 months of age, physical examination was remarkable for posterior labial fusion with minimal pigmentation and rugation, one perineal opening, and a normal clitoris measuring 0.5 cm × 0.6 cm (Fig. 1). Vaginoscopy and cystoscopy confirmed the presence of a short urogenital sinus measuring 2 cm in length. Genetic mutational analysis of the 21-hydroxylase gene (CYP21A2) revealed an intron2G (A/C → G) mutation in one allele and a large gene conversion in the second allele confirming the diagnosis of 21-hydroxylase deficiency. The large gene conversion refers to a 30-kb deletion between the 21-hydroxylase pseudogene and CYP21A2 gene, which results in a nonfunctional gene product.JOURNAL/endst/04.03/00019616-200611000-00004/figure1-4/v/2021-02-17T201820Z/r/image-png Genitalia at 5 months of age. Note the presence of posterior labial fusion without clitoromegaly.DISCUSSIONCongenital adrenal hyperplasia is the most common cause of ambiguous genitalia in females with >95% of cases being the result of 21-hydroxylase deficiency.1,2 Severely affected females usually present with clitoromegaly, labial fusion, and a urogenital sinus. However, virilization of the external genitalia occurs within a broad spectrum of severity with the least affected girls having mild clitoromegaly alone.The CYP21A2 gene encoding for the 21-hydroxylase enzyme is located in the HLA class III region on the short arm of chromosome 63 along with a highly homologous nonfunctional pseudogene. Most mutations are the result of either unequal crossing over during meiosis between the active gene and the pseudogene4 or gene conversion.5 Several studies have shown that common mutations in the CYP21A2 gene result in phenotypes that are not always concordant with genotype.6–10 Among these mutations, Intron2G (A/C → G), which results in aberrant splicing,10 is especially notable for phenotypic heterogeneity.11 The phenotype most frequently associated with this mutation in its homozygous or hemizygous form is classic salt-wasting CAH.10 However, simple virilizing forms as well as asymptomatic individuals have been described.10,12 The lack of genotype–phenotype correlation has been postulated to be the result of extraadrenal 21-hydroxylase activity,13 gene leak, or environmental factors.1 Genetic variations in androgen sensitivity and biosynthesis have been also proposed to influence expression of signs of androgen excess in females with CAH.14The infant in this case had signs of androgen excess (posterior labial fusion and a urogenital sinus) without any evidence of clitoromegaly, which is the hallmark of hyperandrogenism in females. All previously reported virilized females with CAH have had clitoromegaly with or without additional abnormalities.6–10 The explanation for the lack of clitoromegaly in this case is unclear. One possibility is a decreased local concentration of androgen receptors making the clitoral tissues less sensitive to androgen exposure. Another possibility is variable expression of the mutation at different stages of development (high during early fetal life, low later in fetal life and at birth, then high again during neonatal life). However, neither genital skin for androgen receptor studies nor serial androgen levels were available to examine these possibilities.An additional interesting aspect of this case is that the initial NBS and serum 17-OHP were normal. The finding of an abnormal NBS at 3 weeks of life supports the practice of repeat screening for CAH adopted by some states.15 Although clearly elevated, this child's subsequent 17-OHP levels were not as high those typically seen in classic 21-hydroxylase deficiency, further emphasizing the discrepancy between her phenotypic, biochemical, and molecular genetic features.In summary, this case further expands the clinical spectrum of 21-hydroxylase deficiency in girls and highlights the importance of molecular genetic analysis in cases in which the diagnosis is in question.REFERENCES1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21- hydroxylase deficiency. Endocr Rev. 2000;21:245–291.[Context Link][Full Text][CrossRef][Medline Link]2. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:776–788.[Context Link][Full Text][CrossRef][Medline Link]3. White PC, Grossberger D, Onufer BJ, et al. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A. 1985;82:1089–1093.[Context Link][CrossRef][Medline Link]4. White PC, Vitek A, Dupont B, et al. Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 1988;85:4436–4440.[Context Link][CrossRef][Medline Link]5. Donohoue PA, Van Dop C, Mclean RH, et al. Gene conversion in salt wasting congenital adrenal hyperplasia with absent complement C4B protein. J Clin Endocrinol Metab. 1986;62:995–1002.[Context Link][CrossRef][Medline Link]6. Chin D, Speiser PW, Imperato-McGinley J, et al. Study of kindred with classic congenital adrenal hyperplasia: diagnostic challenge due to a phenotypic variance. J Clin Endocrinol Metab. 1998;83:1940–1945.[Context Link][CrossRef][Medline Link]7. Wilson RC, Mercado AB, Cheng KC, et al. Steroid 21-Hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab. 1995;80:2322–2329.[Context Link][CrossRef][Medline Link]8. Wedell A, Thilen A, Ritzen EM, et al. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestations. J Clin Endocrinol Metab. 1994;78:1145–1152.[Context Link][CrossRef][Medline Link]9. Jaaskelainen J, Levo A, Voutilainen R, et al. Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population. J Clin Endocrinol Metab. 1997;82:3293–3297.[Context Link][CrossRef][Medline Link]10. Witchel S, Bhamidipati D, Hoffman E, et al. Phenotypic heterogeneity associated with splicing mutation in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1996;81:4081–4088.[Context Link][CrossRef][Medline Link]11. Higashi Y, Tanae A, Inoue H, et al. Aberrant splicing and missense mutations cause steroid 21-hydroxylase deficiency in humans: possible gene conversion product. Proc Natl Acad Sci U S A. 1988;85:7486–7490.[Context Link][CrossRef][Medline Link]12. Witchel SS, Lee PA, Trucco M. Who is a carrier? Detection of unsuspected mutations in 21-hydroxylase deficiency. Am J Med Genet. 1996;61:2–9.[Context Link][CrossRef][Medline Link]13. Mellon SH, Miller WL. Extraadrenal steroid 21-hydroxylase action is not mediated by P450c21. J Clin Invest. 1989;84:1497–1502.[Context Link][CrossRef][Medline Link]14. Choong CS, Kemppainen JA, Zhou ZX, et al. Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol. 1996;10:1527–1535.[Context Link][CrossRef][Medline Link]15. Bradford TL Jr, Berenbaum SA, Manter-Kapanke V, et al. Results of screening 1. 9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. 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Note the presence of posterior labial fusion without clitoromegaly.Ambiguous Genitalia Without Clitoromegaly in a Girl With Classic Congenital Adrenal HyperplasiaNabhan Zeina M. MD; Rink, Richard C. MD; Eugster, Erica A. MDCase ReportCase Report616p 311-312