Antley–Bixler syndrome

Overview

Antley–Bixler Syndrome (ABS) is a rare genetic disorder that affects multiple parts of the body, including the skull, face, skeleton, and genitalia. It is primarily characterized by craniosynostosis (premature fusion of skull bones), skeletal abnormalities, joint contractures, midface hypoplasia, and, in some cases, abnormalities of the genital and urinary tracts.

ABS is a complex condition with variable severity. It can be life-threatening in infancy due to respiratory complications or cranial pressure if left untreated. Two forms of ABS are recognized, each associated with different genetic mutations and inheritance patterns.

Causes

Antley–Bixler Syndrome can be caused by mutations in two different genes:

• FGFR2 gene: Associated with autosomal dominant inheritance. Mutations in this gene affect fibroblast growth factor receptor 2, important in bone development.

• POR gene: Associated with autosomal recessive inheritance. POR mutations cause defects in cytochrome P450 oxidoreductase, affecting steroid metabolism and leading to genital and adrenal abnormalities.

The two forms may present differently, with the POR-related form showing more hormonal and genital anomalies, and the FGFR2-related form focusing on skeletal features.

Symptoms

Clinical features of Antley–Bixler Syndrome vary, but common symptoms include:

Craniofacial Abnormalities:

• Craniosynostosis (abnormal skull shape)

• Midface hypoplasia (underdeveloped upper jaw)

• Low-set ears

• Proptosis (bulging eyes)

Skeletal and Limb Anomalies:

• Radiohumeral synostosis (fusion of arm bones)

• Joint contractures (stiff or fixed joints)

• Bow-shaped femurs or tibias

• Fractures or fragile bones

Genital and Hormonal Abnormalities (especially with POR mutations):

• Ambiguous genitalia or genital hypoplasia

• Adrenal insufficiency

• Disorders of steroid hormone synthesis

Other Possible Features:

• Breathing difficulties due to facial and tracheal abnormalities

• Hydrocephalus (fluid buildup in the brain)

• Intellectual disability (in some cases)

Diagnosis

Diagnosis is based on clinical findings and confirmed through genetic testing. Diagnostic steps include:

• Physical examination: Identifies craniofacial and skeletal abnormalities

• Radiologic imaging: CT or X-rays to assess skull sutures and bone structure

• Hormonal testing: Especially in suspected POR-related cases, to evaluate adrenal and gonadal function

• Genetic testing: Confirms mutations in FGFR2 or POR genes

• Prenatal diagnosis: Possible through ultrasound and molecular testing in families with known mutations

Treatment

Treatment of Antley–Bixler Syndrome is multidisciplinary and tailored to the individual’s symptoms. It typically includes:

Surgical Interventions:

• Cranial surgery: To correct craniosynostosis and prevent increased intracranial pressure

• Orthopedic surgery: To address limb deformities or joint fusions

• Tracheostomy or airway surgery: In cases of respiratory obstruction

Hormonal and Endocrine Management (POR-related form):

• Glucocorticoid and mineralocorticoid replacement for adrenal insufficiency

• Sex hormone therapy in cases of ambiguous genitalia or delayed puberty

Supportive Therapies:

• Physical therapy to improve mobility

• Speech and occupational therapy for developmental support

• Hearing and vision evaluations

Prognosis

The prognosis of Antley–Bixler Syndrome varies based on the severity of symptoms and the presence of life-threatening complications. Key points include:

• Infants with severe craniofacial or respiratory issues may face early life-threatening complications

• With timely surgical correction and hormonal management, many individuals can live into adulthood

• Developmental outcomes vary; some individuals may experience learning or physical disabilities

Ongoing care from a coordinated medical team is essential for improving quality of life and preventing complications.