ß 2006 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 140A:1797 – 1803 (2006)
Rapid Publication
Linking Antley–Bixler Syndrome and Congenital Adrenal Hyperplasia: A Novel Case of P450 Oxidoreductase Deficiency L. Williamson,1 W. Arlt,2 C. Shackleton,3 R.I. Kelley,4 and S.R. Braddock5* 1
University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 2 Division of Medical Sciences, University of Birmingham, United Kingdom 3 Children’s Hospital Oakland Research Institute, Oakland, California 4 Kennedy Krieger Institute, Baltimore, Maryland 5 University of Missouri, Columbia, Missouri Received 1 February 2006; Accepted 25 May 2006
The Antley–Bixler syndrome (ABS) is a multiple congenital malformation syndrome with craniosynostosis, radiohumeral synostosis, femoral bowing, choanal atresia or stenosis, joint contractures, urogenital abnormalities and, often, early death. Autosomal recessive and dominant inheritance have been postulated, as has fluconazole teratogenesis. Mutations in POR (P450 (cytochrome) oxidoreductase, an essential electron donor to enzymes participating in cholesterol biosynthesis), have been identified in some patients with the ABS phenotype. Recent evidence suggests that these mutations cause attenuated steroid hydroxylation, which in
turn, causes congenital adrenal hyperplasia (CAH) with ambiguous genitalia in both sexes and glucocorticoid deficiency. Here, we report on a new patient with findings of both ABS and CAH that further illustrates how low maternal estriol at prenatal screening can serve as a marker steroid facilitating early diagnosis. ß 2006 Wiley-Liss, Inc.
Key words: Antley–Bixler syndrome; congenital adrenal hyperplasia; P450 (cytochrome) oxidoreductase; maternal serum unconjugated estriol; steroidogenesis
How to cite this article: Williamson L, Arlt W, Shackleton C, Kelley RI, Braddock SR. 2006. Linking Antley–Bixler syndrome and congenital adrenal hyperplasia: A novel case of P450 oxidoreductase deficiency. Am J Med Genet Part A 140A:1797–1803.
INTRODUCTION
The Antley–Bixler syndrome (ABS) is a multiple congenital malformation syndrome with craniosynostosis, severe mid-face hypoplasia, proptosis, choanal atresia and stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radiohumeral synostosis, long-bone fractures, femoral bowing, and urogenital abnormalities [Antley and Bixler, 1975; Hassell and Butler, 1994; LeHeup et al., 1995; Crisponi et al., 1997]. Until recently, the diagnosis was based on clinical features alone, and many of those cases were severe with early death, usually from respiratory failure [Escobar et al., 1988; DeLozier-Blanchet, 1989]. The etiology for ABS has been considered heterogeneous throughout the literature with both autosomal dominant and autosomal recessive modes of inheritance postulated, as well as fluconazole teratogenesis and pregnancy luteoma [Schinzel et al., 1983; Hassell and Butler, 1994; Aleck and Bartley,
1997; Reardon et al., 2000; Roth et al., 2000]. Mutations in the gene encoding for fibroblast growth factor receptor 2 (FGFR2) were previously suggested as a cause of ABS including autosomal dominant cases with an ABS-like phenotype. However, these cases represent a unique condition, not ABS [Chun et al., 1998; Gorlin, 1999; Gripp et al., 1999; Reardon et al., 2000; Tsai et al., 2001]. An important breakthrough in understanding the pathogenesis of ABS occurred when Reardon et al. [2000] reported alteration of steroid biogenesis in 7 of 16 patients with the syndrome. Some of the females in that series had ambiguous genitalia. Other reports on the
*Correspondence to: Dr. S.R. Braddock, University of Missouri Hospital and Clinics, Department of Child Health, Section of Genetics, One Hospital Drive, Columbia, MO 65212. E-mail:
[email protected] DOI 10.1002/ajmg.a.31385
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
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WILLIAMSON ET AL.
abnormalities in sterol biosynthesis followed from that work [Kelley et al., 2002; Shackleton and Malunowicz, 2003; Adachi et al., 2004a; Shackleton et al., 2004b]. After excluding mutations in genes encoding for enzymes apparently impaired, including steroid 17-alpha-monooxygenase (CYP17A1), steroid 21-monooxygenase (CYP21A2) and lanosterol 14-alpha-demethylase (CYP51A1) [Adachi et al., 1999; Reardon et al., 2000; Kelley et al., 2002], mutations in P450 (cytochrome) oxidoreductase (POR) were identified as the cause of ABS [Arlt et al., 2004; Fluck et al., 2004; Adachi et al., 2004b]. These mutations alter steroidogenesis [Kelley et al., 2002; Arlt et al., 2004; Fluck et al., 2004; Adachi et al., 2004b; Shackleton et al., 2004b; Fukami et al., 2005; Huang et al., 2005; Miller, 2005] by disrupting the ability of POR to transfer electrons from NADPH to 17-alpha-monooxygenase and steroid 21-monooxygenase, resulting in apparent combined 17-alphamonooxygenase and steroid 21-monooxygenase deficiency, a variant of congenital adrenal hyperplasia (CAH) first described in 1985 [Peterson et al., 1985]. Here, we present a patient with a mild ABS phenotype, ambiguous genitalia, impaired steroidogenesis, and mutations in POR. This patient provides further evidence of a causal relationship between POR, CAH, and ABS and supports POR deficiency as a cause of low maternal estriol [Cragun et al., 2004; Shackleton et al., 2004a; Fukami et al., 2005], a finding that may help to facilitate early, prenatal diagnosis in siblings of the index patient.
growth, acne, or virilization. The family history was noncontributory. The patient has a healthy male sibling. At initial examination as a newborn, weight was 2.4 kg (25–50th centile), birth length was 50.5 cm (75–90th centile), occipitofrontal circumference (OFC) was 32 cm (25–50th centile), and crown rump length was 32.5 cm. Apgar scores were 9 and 9. There was brachycephaly with a flat occiput, frontal bossing, and broad forehead, suggesting craniosynostosis. In addition, there was significant mid-face hypoplasia with a small mouth (Figs. 1 and 2). Further examination documented patent cranial sutures and excess nuchal skin. There was decreased extension of the elbows. Genitalia were ambiguous, equivalent to Prader stages III–IV with complete labial fusion from the perineum extending anteriorly to just inferior to an enlarged clitoris (Fig. 3). Estrogen cream was started for the fused labia. Given the possibility of CAH, cortisone, Florinef, and salt supplementation were started and continued following elevated 17-OH progesterone levels before and after cosyntropin stimulation (Table I). Cranial, ovarian, uterine, and adrenal sonograms were normal. Skeletal survey at 5 weeks was normal except for advanced bone age of 6 months. There was no evidence of craniosynostosis, femoral bowing, or radiohumeral synostosis. With age, her physical features have become less distinctive and she has done well (Figs. 4–6). A midface advancement is planned in the next few years. A second skeletal survey showed delayed ossification
MATERIALS AND METHODS Clinical Report
The patient was first evaluated in the neonatal intensive care unit because of ambiguous genitalia and dysmorphic features. She was born at 36 weeks gestation via Cesarean secondary to breech presentation and decreased fetal movement to a 22-year-old G2P2 woman and a nonconsanguineous 23-year-old man. During pregnancy, two undetectable maternal serum unconjugated estriol (MSuE3) levels, the second of which was done at 18 weeks; normal chromosomes (46,XX) on amniocytes; and normal fetal morphology on ultrasound at 20 weeks were documented. Maternal DHEA sulfate (DHEA-S), DHEA, and estradiol were obtained. The DHEA-S and DHEA were within the normal ranges (DHEA-S was 0.4 mg/ml [normal range
