Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode b-and c-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancerpredisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.

We have studied the neurodevelopmental outcome of 104 consecutive unselected children who underwent open-heart surgery from 1987 through 1989. Survivors had formal neurologic and psychometric examinations after 2 years of age. Mean IQ was 90, and 78% had scores above 70. Cerebral palsy occurred in 22%. Deep hypothermia for longer than 45 minutes was associated with IQ less than 85 (P < .001) and later cerebral palsy (P = .02). Those less than 1 month old at operation had a median IQ of 96, and 25% had cerebral palsy. Median IQ for survivors of hypoplastic left heart syndrome was 66, only one had an IQ above 70, and 57% had cerebral palsy. Median IQ for transposition of great arteries was 109, only one was less than 85, and all had normal neurologic examinations. Those between 1 and 6 months of age at operation had a median IQ of 93, with 64% above 85, and 5% had cerebral palsy. Those older than 6 months had a median IQ of 99, with 70% above 85, and 13% had cerebral palsy. For infants less than 1 month old at operation, a strong association existed between outcome, type of lesion, and duration of deep hypothermia (P < .01), although not in all cases. In those older than 1 month at operation, no association existed between outcome and any study variable. Although the majority of children have an uneventful outcome after open-heart surgery, a significant morbidity exists. This is related to several factors, including type of lesion and duration of hypothermia, particularly in neonates; preoperative congenital and acquired lesions; and possible perioperative cerebrovascular events.

We describe 2 children with severe ptosis, trigonocephaly, broad nasal bridge, and major brain malformation. A total of 8 children have been reported who share most of these findings. Two of the individuals have had identical pericentric inversions involving chromosome 2p12-q14. These cases appear to represent a unique malformation syndrome.

Five matings to a dir ins (6;2)(q16;q31q33) carrier have produced a high frequency (42%) of offspring with unbalanced karyotypes. Five children have the derivative chromosome 2 resulting in del (2)(q31q33) and one individual received the derivative chromosome 6 leading to dup (2)(q31q33). The findings associated with the deletion include pre- and postnatal growth retardation, developmental delay, minor facial anomalies, seizures, complex structural heart defects, and limb deficiency. Autopsy of one individual showed complex brain malformations including hydrocephalus secondary to obstruction of the foramina of Monro, extensive heterotopias and polymicrogyria, and an unusual form of total anomalous pulmonary venous return. We compare the findings in these children to those of previously reported cases and construct an overview of the range of anomalies. Apparently, no other individual with dup (2)(q31q33) has been described. We compare the physical peculiarities of our patient with those of individuals with duplications of overlapping regions of 2q.