Brain malformations-musculoskeletal abnormalities-facial dysmorphism-intellectual disability syndrome (ORPHA:500150)
A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, intellectual disability and mild to moderate facial dysmorphism in association with variable brain malformations (including abnormal gyration patterns, ventriculomegaly, white matter abnormalities, hypoplasia of the corpus callosum and cerebellar hemispheres), musculoskeletal abnormalities (including hemivertebrae, scoliosis or kyphosis, contractures, and joint laxity), ocular involvement (strabismus, hypermetropia and cortical visual impairment) and hypotonia. Additional clinical manifestations may include seizures, short stature urogenital malformations, heart defects and gastrointestinal malformations.
Epidemiology
To date, approximately 30 patients with this syndrome has been described.
Clinical description
All affected individuals have mild to moderate facial dysmorphisms, including facial asymmetry, midface retraction, low-set ears, downslanting palpebral fissures, deep-set eyes, horizontal eyebrows, a broad and/or depressed nasal bridge, and a short philtrum. Developmental delay and intellectual disability are observed in all affected individuals, whilst other manifestations are variably present. Significant brain abnormalities are observed in the majority of individuals scanned and may include abnormal gyration patterns, ventriculomegaly, white matter abnormalities, hypoplasia of the corpus callosum and cerebellar hemispheres. Musculoskeletal involvement is observed in over three-quarters of individuals and may include joint laxity, scoliosis, or kyphosis, hemivertebrae, cubitus valgus, contractures, small hands and feet, and/or abnormal ribs. Eye and/or vision abnormalities are observed in approximately 70% of patients; whilst strabismus is commonly observed, other features may include hyperopia, cortical visual impairment, and optic atrophy. Short stature is observed in half of individuals. Congenital malformations are less frequently present (≤ 30% of individuals) and may include heart defects (ventricular/atrial septal defect and patent ductus arteriosus), urogenital malformations (single kidney, horseshoe kidney, and kidney dysplasia), intestinal atresia, high-arched or cleft palate, and craniosynostosis. Immunoglobulin deficiency and abnormal coagulation has been reported in several patients. Neurological features include hypotonia (75% of individuals) and seizures (55%).
Etiology
The disorder is due to a heterozygous de novo SON mutation (21q22.11), which encodes for a protein required for proper RNA splicing.
Diagnostic methods
Diagnosis is with whole exome sequencing.
Differential diagnosis
As the clinical phenotype is heterogeneous, the differential diagnosis include the whole group of multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay and intellectual disability associated with brain malformations.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Whilst the disease is autosomal dominant, all reported cases have occurred sporadically.
Management and treatment
A multidisciplinary team approach should be considered, including a pediatrician, clinical geneticist, and psychiatrist. Referral to other specialists (e.g. orthopedic surgeon, ophthalmologist, neurologist) is indicated when specific problems are suspected. Screening of congenital defects (urogenital and heart defects) is recommended after diagnosis. Seizures should be treated according to standard procedures.
Prognosis
The eldest described patient was 34 years of age.

                            Last update: 
                            February 2021


                            - Expert reviewer(s): 
                            Dr J.M.T. [Jos] DRAAISMA | ITHACA*


                                * European Reference Network