Bainbridge-Ropers syndrome (ORPHA:352577)
A rare, genetic, syndromic intellectual disability disorder with a variable phenotypic presentation typically characterized by microcephaly, severe feeding difficulties, failure to thrive, severe global development delay that frequently results in absent/poor speech, moderate to severe intellectual disability and hypotonia. Distinctive craniofacial features include prominent forehead, high-arched, thin eyebrows, hypertelorism, downslanting palpebral fissures, long, tubular nose with broad tip and prominent nasal bridge and wide mouth with full, everted lower lip. Joint laxity and ulnar deviation of wrists are also frequently observed.
Epidemiology
Less than 100 cases have been reported in literature and databases to date.
Clinical description
Presentation is usually in the first months of life; however, intrauterine growth retardation has been reported in some cases. Symptoms of global development delay include hypotonia, delay in achieving independent sitting and walking, and marked language delay. Intellectual disability ranges from moderate to severe. Affected individuals may also display autistic features. Feeding difficulties requiring support are frequent. Other frequent gastrointestinal features include gastroesophageal reflux and constipation. Distinct facial features include highly arched or delineated eyebrows and also synophrys, and frequently a highly arched palate. Patients may exhibited skeletal anomalies including scoliotic attitude, joint laxity, pectus excavatum or carinatum and ulnar deviation of wrists.
Etiology
The disorder is due to loss of function mutations in ASXL3 gene (18q12.1).
Diagnostic methods
Diagnosis is based on presentation of clinical features, and can be confirmed by genetic testing. Most of the patients described so far had been confirmed by next generation sequencing techniques.
Differential diagnosis
Differential diagnosis includes other syndromes with moderate-severe intellectual disability and poor language. In some reported cases Cornelia de Lange syndrome was suspected due to feeding difficulties, developmental delay and eyebrow characteristics.
Antenatal diagnosis
There is no definitive antenatal diagnosis available, however ultrasound may show intrauterine growth retardation which should be investigated further. As germline mosaicism has been described, prenatal diagnosis may be considered where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant; however, no familial transmission has been observed so far. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that, for each pregnancy, there is 50% risk of passing the mutation to offspring. It is also important to counsel affected families about the possibility of recurrence due to germline mosaicism.
Management and treatment
Given the multisystemic involvement, multidisciplinary follow-up is needed and should include neurological follow up, developmental assessments, physiotherapy (particularly for joint laxity and musculoskeletal issues), feeding interventions for those with persistent feeding issues, and ophthalmologic follow up for patients with strabismus and/or refractive error.
Prognosis
Quality of life and the functional consequences depends on the severity of the developmental delay and intellectual disability.

                            Last update: 
                            March 2021


                            - Expert reviewer(s): 
                            Dr Irene VALENZUELA PALAFOLL | ITHACA*


                                * European Reference Network