The portal for rare diseases and orphan drugs

Over 70 cases have been described in the literature.

Presentation at birth is with macrosomia, umbilical hernia and craniosynostosis which ranges from cloverleaf configuration to predominant involvement of the metopic ridge to craniofacial asymmetry. Cranial anomalies may lead to raised intercranial pressure, difficulty in articulation, frequent otitis media and resultant hearing loss. Typical abnormalities of the digits include brachydactyly, cutaneous syndactyly, preaxial polydactyly in the toes and postaxial polydactlyly in the hands with broad thumbs and absent middle phalanges. Characteristic facial features may include flat nasal bridge with epicanthal folds, down-slanting palpebral fissures, corneal anomalies, low-set, posteriorly rotated malformed ears, and an underdeveloped maxilla and mandible. Congenital cardiac malformations are frequent and may include ventricular septal defect, patent ductus arteriosus, pulmonic stenosis, tetralogy of Fallot, and transposition of great vessels. Intellectual disability is common (affecting 63-75% of cases). Males often have genital abnormalities such as hypogonadism and cryptorchidism. Small primary dentition is usual, teeth are short, undersized and widely spaced, appearing as small buds worn to the gingival margins and often there is prolonged retention of primary teeth. Growth is either slightly delayed or normal and many individuals have short stature. Persistent obesity, particularly truncal obesity, beginning in childhood is common. Additional skeletal abnormalities such as deformed hips, kyphoscoliosis, and genu valgum frequently occur. Situs inversus, dextrocardia, and polysplenia has been observed in a few patients.

The syndrome is caused by truncating, misssense and loss of function mutations in two different genes RAB23 gene (6p12.1) and less commonly MEGF8 gene (19q13.2). MEGF8 mutations are associated with defective lateralization and less severe craniosynostosis (usually involving only the metopic suture) in comparison with individuals with RAB23 gene mutations.

Clinical diagnosis is suspected on clinical presentation and confirmed by diagnostic molecular genetic screening firstly of RAB23 and then MEGF8.

Differential diagnosis includes other acrocephalosyndactyly disorders, as well as Gorlin syndrome, Apert syndrome and Greig cephalopolysyndactyly syndrome. Ciliopathy disorders also have overlapping features including the wide clinical variability and features such as obesity and polydactyly. Summitt syndrome and Goodman syndrome falls within the clinical spectrum of Carpenter syndrome.

Genetic prenatal diagnosis to screen for the causative familial mutations is possible where the mutation has previously been identified in a family member. Ultrasound may detect abnormal head shape, short and bowed femurs, flattened face, proptosis, heart defect, heterotaxy and digit anomalies.

Transmission is autosomal recessive. 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. Phenotypic expression varies considerably, even within the same family. Genetic counseling is recommended to affected families.

Multidisciplinary management and treatment is required. Most patients with this syndrome will undergo early craniofacial reconstruction to improve appearance and prevent intellectual disability. Surgery may be required for congenital heart defects and shunting may be required if there is raised intercranial pressure.

The prognosis is highly variable depending on the severity of the malformations and the degree of intellectual disability; some children grow up to become independent adults and others require more support due to intellectual disability or physical challenges. Life expectancy is shortened, mainly due to heart defects.