Antley-Bixler syndrome (ORPHA:83)
A rare syndromic craniosynostosis characterized by craniosynostosis with midface hypoplasia, radiohumeral synostosis, femoral bowing and joint contractures.
Epidemiology
Antley-Bixler syndrome (ABS) has been described in more than 100 patients. The relative prevalence of the two main etiologies is unknown but cases due to FGFR2 variants seem rarer than those due to POR variants.
Clinical description
Children present with characteristic facial features, including a large domed forehead, flat nose, and midface hypoplasia with proptosis and dysplastic ears. The types of craniosynostosis may include trigonocephaly (due to early metopic synostosis) or brachycephhaly but also severe pansynostosis with cloverleaf skull. Characteristic skeletal features include the radio-humeral synostosis, femora bowing (with possible fractures). Arachnodactyly and/or camptodactyly, choanal atresia and cleft palate have also been reported. A diverse range of malformations (cardiac, renal, anal or vertebral) are often associated. Urogenital anomalies with sexual ambiguity due to impaired steroidogenesis can occur. Intellectual development is variable.
Etiology
Two genetically distinct forms are observed: type 1 Antley-Bixler syndrome is associated with heterozygous mutations in the FGFR2 gene (10q26) without impairment of steroidogenesis, whereas type 2 Antley-Bixler is associated with homozygous mutations in the POR gene (7q11.2), encoding cytochrome P450 oxidoreductase (POR), which plays a direct role in steroidogenesis. Type 2 Antley-Bixler can thus be accompanied by sexual ambiguity, but this is not a compulsory finding.
Diagnostic methods
The diagnosis is usually suspected by imaging features and confirmed by molecular screening: next generation sequencing panels, whole exome sequencing and whole genome sequencing.
Differential diagnosis
A similar clinical picture is observed due to in utero environmental exposure to 1) fluconazole, a lanosterol 14 alpha-demethylase inhibitor and 2) methotrexate. A similar phenotype has been reported associated with biallelic CYP26B1 variants.
Antenatal diagnosis
ABS may be evoked in case of syndromic craniosynostosis including radio-humeral synostosis, femora bowing, choanal atresia and other visceral malformations.
Genetic counseling
Inheritance depends on the gene involved. ABS due to FGFR2 is autosomal dominant, and most cases are de novo. Affected families should be informed that it is associated with a low recurrence risk (the residual risk is due to germinal mosaicism risk, estimated to approximately 1%). ABS due to POR variants is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is symptomatic, and includes early neurosurgical as well as pulmonary and orthopedic management. This disorder is associated with a high risk of pediatric complications.
Prognosis
The prognosis is poor with the majority of reported patients dying during infancy due to respiratory and medullary complications.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Geneviève BAUJAT | ITHACA*


                                * European Reference Network