Undetectable maternal serum uE3 and postnatal abnormal sterol and steroid metabolism in Antley-Bixler syndrome

• Published in: American journal of medical genetics. Part A Vol. 129A; no. 1; pp. 1 - 7
• Main Authors: Cragun, Deborah L., Trumpy, Sharon K., Shackleton, Cedric H.L., Kelley, Richard I., Leslie, Nancy D., Mulrooney, Neil P., Hopkin, Robert J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.08.2004
• Subjects: 14-α-demethylase; 17-alpha-Hydroxyprogesterone - blood; 17-hydroxylase deficiency; 21-hydroxylase deficiency; Abnormalities, Multiple - genetics; Abnormalities, Multiple - metabolism; Abnormalities, Multiple - pathology; Adult; Antley-Bixler syndrome; apparent pregnene hydroxylation deficiency; Child, Preschool; cholesterol; Craniosynostoses - pathology; cytochrome p450 reductase; Estriol - blood; Face - abnormalities; Fatal Outcome; Female; genital ambiguity; Genitalia - abnormalities; Humans; Infant; Infant, Newborn; Karyotyping; low estriol; Male; Pregnancy; Pregnancy Trimester, Third; Progesterone - blood; Siblings; steroidogenesis; Steroids - metabolism; Sterols - metabolism; Syndrome
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.30170

Antley–Bixler syndrome (ABS) is a rare condition characterized by radiohumeral synostosis, craniosynostosis, midface hypoplasia, bowing of the femora, multiple joint contractures, and urogenital defects. Several reports have implicated errors of steroid or sterol metabolism in the pathogenesis of ABS. Evidence for this has included association with maternal luteomas, fetal 21‐hydroxylase deficiency, early pregnancy exposure to high‐dose fluconazole, lanosterol 14‐α‐demethylase deficiency, and a unique urinary steroid profile consistent with apparent pregnene hydroxylation deficiency (APHD). We report two sibs with classic ABS. During both pregnancies, mid‐trimester maternal serum screening demonstrated undetectable levels of uncongugated estriol (uE3). The brother had ambiguous genitalia and increased serum levels of progesterone and 17‐α‐hydroxyprogesterone. Postnatal tests performed on the sister demonstrated both the unique urinary steroid profile that defines APHD and evidence of impaired lanosterol 14‐α‐demethylase activity. Our results suggest that in at least some patients with ABS, the skeletal findings and altered steroidogenesis are not associated with genes specific to individual sterol or steroid pathways but rather are related to an element, such as NADPH cytochrome P450 reductase (CPR) or cytochrome b5 (CYb5), that is common to all of these pathways. © 2004 Wiley‐Liss, Inc.