Oculocerebrofacial syndrome, Kaufman type (ORPHA:2707)
A rare, genetic, syndromic intellectual disability characterized by severe intellectual disability, distinctive craniofacial features and variable multiple congenital anomalies including ocular, brain, urogenital and skeletal abnormalities.
Epidemiology
To date, 19 molecularly diagnosed cases have been described in the scientific and medical literature.
Clinical description
The most prominent clinical findings are severe intellectual disability, pre-and postnatal growth retardation, microcephaly, and typical craniofacial features which include non-progressive microcephaly of prenatal onset, prominence of the zygomatic region of the face, full cheeks, prominent frontal tubers, sparse and arched eyebrows, blepharophimosis with epicanthal folds, upslanted palpebral fissures, preauricular skin tags, underdeveloped and abnormally folded ears, wide nasal base, low nasal bridge, anteverted nares, long and flat philtrum and retrognathia. Hypotonia, feeding difficulties, failure to thrive and poor speech development are universal findings. Many patients require tube-feeding. Perceptive language is better than expressive, some patients acquire a few words and basic ambulation skills such as eating and dressing independently. Brain abnormalities may include absent or hypoplastic corpus callosum and changes in white matter signal intensity on MRI, but major structural brain malformations are absent. Epilepsy may occur. Ocular abnormalities include short and narrow palpebral fissures, microcornea/microphtalmos, refractive errors and strabismus. Other less frequently observed congenital anomalies include hearing loss, urogenital abnormalities (hypoplastic external genitals, hypospadias, vesicoureteral reflux, duplicated renal pelvis), skeletal abnormalities (including clinodactyly, hypoplastic or absent distal phalanges of some digits, pectus carinatum, coxa valga, pes talus varus and scoliosis). Ectodermal anomalies include thin, sparse hair, and light colored, fine skin. Gastroesophageal reflux is a frequent problem. Congenital heart malformations and breathing problems (tracheo/laryngomalacia, subglottic stenosis) are frequent. About half of patients have abnormal cholesterol levels (low total HDL/LDL levels). Patients have an overall friendly disposition.
Etiology
The syndrome is caused by biallelic inactivating mutations in the UBE3B gene (12q24.11), which encodes ubiquitin protein ligase E3B, a putative calmodulin-regulated mitochondria-associated enzyme involved in the protein ubiquitination pathway.
Diagnostic methods
Diagnosis is established in a proband with developmental delay/intellectual disability, characteristic craniofacial anomalies and biallelic UBE3B pathogenic variants.
Differential diagnosis
Differential diagnosis principally includes other syndromes featuring association of blepharophimosis and intellectual disability (e.g. blepharophimosis-intellectual disability syndrome, Maat-Kievit Brunner type), as well as Toriello-Carey syndrome, Smith-Lemli-Opitz syndrome, and DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and Seizures) if digital anomalies are present.
Antenatal diagnosis
Prenatal testing for at risk pregnancies is possible where the UBE3B pathogenic variants have been identified previously in a family member.
Genetic counseling
Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Full multisystem evaluation should be performed following the diagnosis, and growth, developmental progress, vision, hearing and contractures/scoliosis should be regularly followed up. Educational intervention and speech therapy should start as early as possible. Intervention for feeding problems may be needed. Treatment of the encountered congenital and functional anomalies is standard.
Prognosis
Prognosis depends on the severity of symptoms; however, data is limited.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Dr Katalin SZAKSZON | ITHACA*


                                * European Reference Network