Antley-Bixler syndrome (ABS) is a rare multiple anomaly syndrome comprising radiohumeral
synostosis, bowed femora, fractures of the long bones, premature fusion of the calvarial
sutures, severe midface hypoplasia,
proptosis,
choanal atresia, and, in some,
ambiguous genitalia. Of fewer than 40 patients described to date, most have been sporadic, although reports of parental consanguinity and affected sibs of both sexes suggests autosomal recessive inheritance in some families. Known genetic causes among sporadic cases of ABS or ABS-like syndromes are missense mutations in the IgII and IgIII regions of FGFR2, although the assignment of the diagnosis of ABS to such children has been disputed. A third cause of an ABS-like phenotype is early in utero exposure to
fluconazole, an inhibitor of
lanosterol 14-alpha-demethylase. The fourth proposed cause of ABS is digenic inheritance combining heterozygosity or homozygosity for
steroid 21-hydroxylase deficiency with effects from a second gene at an unknown locus. Because
fluconazole is a strong inhibitor of
lanosterol 14-alpha-demethylase (CYP51), we evaluated
sterol metabolism in lymphoblast cell lines from an ABS patient without a known FGFR2 mutation and from a patient with an FGFR2 mutation and ABS-like manifestations. When grown in the absence of
cholesterol to stimulate
cholesterol biosynthesis, the cells from the ABS patient with
ambiguous genitalia but without an FGFR2 mutation accumulated markedly increased levels of
lanosterol and dihydrolanosterol. Although the abnormal
sterol profile suggested a deficiency of
lanosterol 14-alpha-demethylase, mutational analysis of its gene, CYP51, disclosed no obvious pathogenic mutation in any of its 10 exons or exon-intron boundaries.
Sterol metabolism in lymphoblasts from the phenotypically unaffected mother was normal. Our results suggest that ABS can occur in a patient with an intrinsic defect of
cholesterol biosynthesis at the level of
lanosterol 14-alpha-demethylase, although the genetic nature of the deficiency remains to be determined.