Diseases title

Baraitser-Winter syndrome )

Orpha Number: 2995
Cerebrofrontofacial syndrome type 3, Iris coloboma-ptosis-intellectual deficit syndrome

Baraitser-Winter syndrome (BWS) is a malformation syndrome, characterized by facial dysmorphism (hypertelorism with ptosis, broad bulbous nose, ridged metopic suture, arched eyebrows, progressive coarsening of the face), ocular coloboma, pachygyria and/or band heterotopias with antero-posterior gradient, progressive joint stiffening, and intellectual deficit of variable severity, often with severe epilepsy. Fryns -Aftimos (FA) corresponds to the appearance of BWS in elderly patients.BWS and FA were initially considered separate entities. They were reported collectively in approximatively 30 unrelated patients so far.The clinical picture includes striking dysmorphism, hypertelorism, metopic ridging giving a trigonocephalic appearance to the skull, wide palpebral fissures, long downslanted palpebral fissures, congenital ptosis, broad nose with large bulbous or flat tip, prominent nasal root, long philtrum, mild micrognathia and highly arched eyebrows. Facial characteristics get coarser in late infancy and adolescence, with marked nasogenian folds. Cleft lip and palate may be present. Ocular anomalies such as iris and/or retinal coloboma with or without microphthalmos are frequent. Most patients present with some degree of cortical dysplasia, pachygyria (often more marked in the frontal area) and subcortical band heterotopias. In most severe cases, the brain has a lissencephalic aspect, but some patients have a normal MRI. Head circumference tends to evolve to microcephaly during infancy. Growth is mildly delayed, and final stature is below normal. Patients have been reported with hydronephrosis, but, visceral malformations are rare. Intellectual deficiency ranges from mild to profound and correlates with the severity of brain anomalies and the presence of seizures which may be drug-resistant. Limitation of movement in large joints (knee, shoulder, elbow) become apparent in adolescence, and affect walking abilities in adulthood. Kyphoscoliosis may also develop. In infancy, neurological problems are prominent and facial dysmorphism less obvious.BWS is a genetically heterogeneous disorder, caused by a heterozygous mutation in one of the 2 genes coding for ubiquitously expressed actins: ACTB, located to 7p22-p12 (BRWS1) and ACTG1 on 17q25.3 (BRWS2). All mutations are missense and probably act by a gain of function mechanism, as deletions of the same genes do not result in BWS phenotype.Diagnosis is confirmed by DNA sequencing of ACTG1 and ACTB.In infancy, BWS may resemble Noonan syndrome (see this term). Teebi Type Hypertelorism (see this term) has similar palpebral appearance. CHARGE syndrome, Norman-Roberts type lissencephaly syndrome and other syndromes with lissencephaly/pachygyria as a major feature (see these terms) are partially overlapping.Abnormal gyration pattern may be detected prenatally. Recurrence risk is probably All molecularly confirmed cases are sporadic, with, in theory, an autosomal dominant transmission, but effective transmission has never been reported.Developmental delay is managed by appropriate educative measures. Epilepsy management is difficult, as in other forms of pachygyria, some patients are drug resistant, even with polytherapies. Orthopedic monitoring is mandatory, considering progressive joint limitations that could lead to loss of autonomous ambulation.Early prognosis may be poor in those with severe brain anomalies, but most patients with milder CNS anomalies can reach adulthood, although most patients will never be autonomous.
source: Orphanet