Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis

• Published in: American journal of medical genetics. Part A 2004-07, Vol.128A (3), p.223-231
• Main Authors: Shackleton, Cedric, Marcos, Josep, Malunowicz, Ewa M., Szarras-Czapnik, Maria, Jira, Petr, Taylor, Norman F., Murphy, Nuala, Crushell, Ellen, Gottschalk, Michael, Hauffa, Berthold, Cragun, Deborah L., Hopkin, Robert J., Adachi, Masanori, Arlt, Wiebke
• Format: Article
• Language: English
• Subjects: 17-hydroxylase deficiency; 21-hydroxylase deficiency; Abnormalities, Multiple - diagnosis; Adolescent; Antley-Bixler syndrome; Child, Preschool; Craniofacial Abnormalities - diagnosis; dystostosis; Female; genital ambiguity; Humans; Infant; Limb Deformities, Congenital - diagnosis; Male; P450 oxidoreductase; Steroid 17-alpha-Hydroxylase - metabolism; Steroid 21-Hydroxylase - metabolism; steroid biosynthesis; Steroids - metabolism; Steroids - urine; Syndrome
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.30104

Antley–Bixler syndrome (ABS, MIM 207410) is a skeletal abnormality syndrome primarily affecting head and limbs. Little is known of the origin of the condition but inactivating mutations in the fibroblast growth factor receptor (FGFR2) has been found in some patients. Genital ambiguity is seen occasionally in this condition, suggesting possible disordered steroidogenesis in early pregnancy. We report the steroid excretion of eight patients diagnosed with the syndrome and one with a related condition, a mild phenotype of the disorder since skeletal and genital abnormalities were not evident. The steroid excretion pattern was consistent and very distinctive in all nine patients. Metabolites of the two primary precursors of steroid hormones, pregnenolone and progesterone, were elevated as were the classical diagnostic metabolites for 17‐ and 21‐hydroxylase deficiencies. Cortisol production was typically within the normal range but generally had blunted response to ACTH. Androgen metabolite excretion tends to be low in patients over 2 months of age, but may be elevated in the newborn period. The metabolome suggested attenuated steroid hydroxylation (including 17,20‐lyase activity) although underlying cause is yet to be established. Mutations in CYP17 and CYP21 have not been found and currently the prime suspect is an abnormality in an essential redox partner (P450 oxidoreductase). This paper proposes use of the distinctive steroid metabolome as the primary biochemical parameter for diagnosis of ABS, at least the form not associated with FGFR2 mutations. © 2004 Wiley‐Liss, Inc.