Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis.
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.
Shackleton
Cedric
C
Children's Hospital Oakland Research Institute, Oakland, California 94609, USA. cshackelton@chori.org
Marcos
Josep
J
Malunowicz
Ewa M
EM
Szarras-Czapnik
Maria
M
Jira
Petr
P
Taylor
Norman F
NF
Murphy
Nuala
N
Crushell
Ellen
E
Gottschalk
Michael
M
Hauffa
Berthold
B
Cragun
Deborah L
DL
Hopkin
Robert J
RJ
Adachi
Masanori
M
Arlt
Wiebke
W
D000015:Abnormalities, Multiple / Q000175:diagnosis*; D000293:Adolescent; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000175:diagnosis*; D005260:Female; D006801:Humans; D007223:Infant; D017880:Limb Deformities, Congenital / Q000175:diagnosis*; D008297:Male; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism; D013256:Steroids / Q000378:metabolism / Q000652:urine*; D013577:Syndrome
D013256:Steroids; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase