Antley-Bixler Syndrome With Genital Anomalies And Disordered Steroidogenesis

A number sign (#) is used with this entry because of evidence that Antley-Bixler syndrome with disordered steroidogenesis (ABS1) is caused by homozygous or compound heterozygous mutation in the gene encoding cytochrome P450 oxidoreductase (POR; 124015) on chromosome 7q11.

A form of Antley-Bixler syndrome with normal steroidogenesis (ABS2; 207410) is a distinct disorder caused by mutation in the FGFR2 gene (176943). Congenital adrenal hyperplasia without Antley-Bixler skeletal anomalies can also result from POR mutations (613571).

Description

The Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome characterized by radiohumeral synostosis present from the perinatal period. There is a wide spectrum of anomalies seen in ABS; other features include midface hypoplasia, choanal stenosis or atresia, multiple joint contractures, visceral anomalies (particularly of the genitourinary system), and impaired steroidogenesis (present only in patients with POR mutations). Mortality has been reported to be as high as 80% in the neonatal period, primarily due to airway compromise, and prognosis improves with increasing age (summary by McGlaughlin et al., 2010).

Clinical Features

Miller (2008) considered the phenotypic overlap between ABS caused by POR mutations and ABS caused by FGFR2 mutations (ABS2; 207410) impressive. Aside from genital anomalies and disordered pattern of steroidogenesis present in patients with POR mutations, no dysmorphic feature appears to distinguish the 2 groups.

Reardon et al. (2000) was impressed with the occurrence of genital abnormalities in patients, especially females, who had been diagnosed as having Antley-Bixler syndrome. They reported abnormalities of steroid biogenesis in 7 of 16 patients with an Antley-Bixler phenotype. Reardon et al. (2000) suggested that ABS with disordered steroidogenesis might be a distinct genetic entity.

Diagnosis

McGlaughlin et al. (2010) noted that craniosynostosis and radiohumeral synostosis present from the perinatal period are generally considered to be the minimum criteria for a diagnosis of Antley-Bixler syndrome.

Clinical Management

Huang et al. (2005) noted that it is clinically important to distinguish patients with an ABS phenotype and disordered steroidogenesis from those with ABS and normal steroidogenesis, not only because of differences in inheritance patterns, but also because patients with POR deficiency are vulnerable to different risk factors and require different management and different teams of physicians. Some patients with POR mutations have died unexpectedly without a clear explanation, and Reardon et al. (2000) noted that patients may require steroid hormone supplementation. Patients with POR mutations may be at risk for adrenal insufficiency and Addisonian crisis, especially at times of severe febrile illness or major surgery.

Biochemical Features

In the absence of POR, environmental toxins and drugs that are usually metabolized to benign products by hepatic P450 enzymes may achieve teratogenic concentrations. Fluconazole, which acts on a fungal cytochrome P450 system, has been implicated in this fashion (Aleck and Bartley, 1997). Because fluconazole is a strong inhibitor of lanosterol 14-alpha-demethylase (CYP51A1; 601637), Kelley et al. (2002) evaluated sterol metabolism in lymphoblast cell lines from a patient diagnosed as having Antley-Bixler syndrome with ambiguous genitalia but without an FGFR2 mutation. When grown in the absence of cholesterol to stimulate cholesterol biosynthesis, cells from this patient accumulated markedly increased levels of lanosterol and dihydrolanosterol. Mutation analysis of CYP51A1, however, disclosed no obvious pathogenic mutation.

Shackleton et al. (2004) studied steroid excretion in 8 patients diagnosed with ABS and 1 patient with a milder but related phenotype without skeletal or genital abnormalities. The steroid excretion pattern was consistent and distinctive in all 9 patients, and was significantly different from that measured in controls (p less than 0.01). A high ratio of metabolites of the primary adrenal steroid precursors pregnenolone and progesterone to cortisol metabolites was the most characteristic feature for diagnosis. The authors stated that pregnanediol could be considered a hallmark analyte since it is essentially absent from the urine of normal individuals or those with other defects in steroid biosynthesis. Shackleton et al. (2004) proposed the use of this distinctive steroid metabolic profile as the primary biochemical parameter for the diagnosis of the ABS-like phenotype not associated with FGFR2 mutations.

Molecular Genetics

In individuals with disordered steroidogenesis with bony features of Antley-Bixler syndrome, including the patient reported by Kelley et al. (2002), Fluck et al. (2004) demonstrated mutations in the POR gene (e.g., 124015.0001). Fluck et al. (2004) proposed that severe mutations in POR without associated disorders of FGF receptors are sufficient to cause the ABS-like phenotype. The grossly dysmorphic embryonic lethal phenotype of POR knockout mice, with neural tube, cardiac, eye, and limb anomalies, suggests that severe disorders of POR may be sufficient to account for the skeletal findings in some individuals with an ABS phenotype (Shen et al., 2002; Otto et al., 2003). By contrast, milder mutations in POR may manifest as mild disorders of steroid synthesis.

Huang et al. (2005) sequenced the cytochrome P450 reductase gene and exons 8 and 10 of the FGFR2 gene in 29 individuals diagnosed with Antley-Bixler syndrome with or without hormonal findings suggesting POR deficiency and found that POR and FGFR2 mutations segregated completely. In 15 patients, POR mutations were found on both alleles; in 4, mutations were found on only 1 allele; 6 carried FGFR2 mutations; and 4 patients carried no mutations. One patient, a male infant with an Antley-Bixler syndrome skeletal phenotype and abnormal steroids and genitalia, who had previously been found to carry a missense mutation of unclear significance in the FGFR1 gene (136350.0011) by Hurley et al. (2004), was found to be a compound heterozygote for mutations in the POR gene as well (124015.0015 and 124015.0016). The 34 affected POR alleles included 10 with ala287-to-pro (124015.0002), all from whites, and 7 with arg457-to-his (124015.0005), including 4 Japanese, 1 African, and 2 Caucasians; 17 of the 34 carried 16 'private' mutations, including 9 missense and 7 frameshift mutations. Huang et al. (2005) recreated these 11 missense mutations, plus 10 others found in databases or reported elsewhere, by site-directed mutagenesis and assessed them by 4 assays: assays that were based on cytochrome c, which is not a physiologic substrate for POR, correlated poorly with clinical phenotype, but assays that were based on POR's support of catalysis by P450c17 (the enzyme most closely associated with the hormonal phenotype) provided an excellent genotype/phenotype correlation. Huang et al. (2005) concluded that individuals with an ABS skeletal phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct disease: POR deficiency.