Antley-Bixler Syndrome Without Genital Anomalies Or Disordered Steroidogenesis

A number sign (#) is used with this entry because of evidence that the exclusively skeletal form of Antley-Bixler syndrome can be caused by heterozygous mutation in a fibroblast growth factor receptor gene, FGFR2 (176943), on chromosome 10q26.

A form of Antley-Bixler syndrome that includes disordered steroidogenesis (ABS1; 201750) is caused by mutation in the gene encoding cytochrome P450 oxidoreductase (POR; 124015).

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, including midface hypoplasia, choanal stenosis or atresia, and multiple joint contractures. 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

Antley and Bixler (1975) described a child with 'trapezoidocephaly,' midface hypoplasia, humeroradial synostosis, bowing of femora, fractures and other abnormalities. McGlaughlin et al. (2010) noted that Lacheretz et al. (1974) had reported features suggestive of the same disorder in a 10-year-old boy, issue of a consanguineous marriage.

DeLozier et al. (1980) described 2 unrelated female children with the same syndrome: craniosynostosis with midface hypoplasia resulting in typical facial appearance and ears; radiohumeral synostosis and bowing of the femora with neonatal femoral fractures. Although the differential diagnosis included campomelic syndrome (see 114290), osteogenesis imperfecta (see 166200), and certain of the acrocephalosyndactyly syndromes (see 101200), the disorder appeared to be unique. DeLozier et al. (1980) proposed the designation multisynostotic osteodysgenesis. DeLozier-Blanchet (1989) provided useful follow-up information on 1 of the patients reported by DeLozier et al. (1980). The patient's primary difficulties during the first decade of life resulted from joint limitations. Radiohumeral synostosis recurred after surgery at 6 months; eating and other everyday tasks were difficult. She had moderate camptodactyly of the hands, particularly at the metacarpal-phalangeal joints, and some restriction of knee movement. A pear-shaped nose was treated by plastic surgery. Intelligence was normal.

Schinzel et al. (1983) described 2 affected sisters: a newborn who died at 14 days of respiratory failure, and a fetus from a subsequent pregnancy in which the diagnosis was made in utero by ultrasonography. They described the features as craniosynostosis of coronal and lambdoidal sutures; brachycephaly; frontal bossing; severe midface hypoplasia with proptosis and choanal stenosis or atresia; humeroradial synostosis; medial bowing of ulnas; long, slender fingers with camptodactyly; narrow iliac wings; anterior bowing of femurs; and malformations of the heart and kidneys. Their proband did not have connatal fractures as did the first 2 cases but she did have vaginal atresia. Robinson et al. (1982) reported 3 sporadic cases. Yasui et al. (1983) reported an affected female with consanguineous parents. Suzuki et al. (1987) described this syndrome in a brother and sister with first-cousin parents.

Escobar et al. (1988) described a child followed over a period of 3 years. In addition to craniosynostosis, the patient had radiohumeral synostosis, femoral bowing, and multiple joint contractures. Escobar et al. (1988) provided a flow chart for management of patients with ABS.

Hassell and Butler (1994) reported a patient and reviewed 13 previously reported cases. The cardinal features included craniosynostosis, severe midface hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radiohumeral synostosis, long bone fractures and femoral bowing, and urogenital abnormalities. Early death, usually due to respiratory complications, occurred in 54% of reported cases. The oldest patient was 10 years old at the time of follow-up. Since some patients had normal intelligence, it is likely that brain development is normal if craniectomy is performed to treat sutural synostosis and if secondary factors, such as apnea, are avoided. Choanal stenting during infancy may be important to decrease airway obstruction.

Feigin et al. (1995) reported an infant, born to consanguineous parents, with the typical features of Antley-Bixler syndrome in addition to esophageal atresia and trisomy 21 (190685).

Crisponi et al. (1997) stated that since the first report by Antley and Bixler (1975) at least 23 cases had been reported. They reported an affected infant who died a few days after birth of respiratory failure. Unlike previously described cases, the elbow joint contracture was due to radioulnar synostosis rather than radiohumeral synostosis. The infant did not have long bone fractures, and the femurs were not markedly bowed.

Chabchoub et al. (1998) reported a female infant with bilateral coronal craniosynostosis, craniolacunia, profound midface hypoplasia, arachnodactyly and camptodactyly of fingers and toes, multiple joint contractures, and abnormal bowing of the radius and ulna without radiohumeral synostosis. The child died at 1 year of age after multiple respiratory infections, due to malnutrition and major neurologic deterioration.

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.

Prenatal Diagnosis

LeHeup et al. (1995) reported affected sibs. In the first case, renal agenesis was recognized prenatally when oligohydramnios led to the sonographic diagnosis of absent kidneys during the seventh month. Clinical features were recognized by ultrasonography at 21 weeks in the second case.

Molecular Genetics

Chun et al. (1998) reported a patient with clinical manifestations that they considered consistent with Antley-Bixler syndrome who carried an ser351-to-cys (S351C; 176943.0024) mutation on one allele of the FGFR2 gene. Chun et al. (1998) suggested that the Antley-Bixler syndrome is an autosomal dominant condition with possible gonadal mosaicism, or that alternatively, an autosomal dominant form and an autosomal recessive form of ABS may exist. They further suggested that FGFR mutations should be sought in other craniosynostosis patients with elbow synostosis. Gorlin (1999) and Gripp et al. (1999) refuted the clinical diagnosis of Antley-Bixler syndrome and suggested that the patient had a nonspecific craniosynostosis syndrome. Chitayat and Chun (1999) in response reiterated the importance of seeking a mutation in the FGFR2 gene, and expressed the wish that authors of previously reported cases of Antley-Bixler syndrome would perform DNA analysis of the FGFR2 gene and publish the results in order to clarify the inheritance of ABS.

In 3 patients with ABS, Reardon et al. (2000) identified the S351C substitution in the FGFR2 gene. The patients all had normal-appearing genitalia, and the steroid profile was normal in the 2 patients in whom it was carried out.

Huang et al. (2005) sequenced the cytochrome P450 reductase gene (POR; 124015) 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, who had previously been found to have a mutation 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. Huang et al. (2005) concluded that individuals with an ABS-phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct new disease: POR deficiency (201750). The existence of 2 distinct disorders was first suggested by Reardon et al. (2000).