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.

No abstract

List of key featuresTriphalangeal thumb Bifid thumb Dysplastic ears with over-folded helix Hearing loss Imperforate anus Renal hypoplasia/agenesis Clinical summaryA 3-year 4-month-old boy was referred to the genetic clinic with dysplastic ears, thumb anomaly, and developmental delay. He was delivered at 30 weeks of gestation by Cesarean section. His birth weight was 1320 g (25th centile), length 43 cm (∼50th centile). He was operated on for an imperforate anus on the first day of his life. Examination in the genetic clinic indicated a weight of 10 kg (less than third centile), occipital-frontal circumference of 45 cm (less than third centile), dysplastic ears with hypoplastic ear lobules, bilateral triphalangeal thumbs together with a bifid thumb on the right, spasticity and flexion contractures in his lower extremities, flat feet, and overlapping toes (Fig. 1). He had moderate hearing loss and chronic renal failure. He had mental retardation. Urinary system ultrasonography showed bilateral small kidneys with grade-2 parenchymal echogenicity. Intraparenchymal hemorrhage was detected on cranial ultrasonography, and it was subsequently confirmed by MRI. Echocardiography was normal. Radiography of the hands indicated bilateral triphalangeal thumbs with a rudimentary middle phalanx on the left and a double distal phalanx on the right. He was the first child of a G2P1 29-year-old mother and a nonconsanguineous 31-year-old father. His mother was hospitalized repeatedly in pregnancy because of increased urea, creatinine levels, and hypertension. On physical examination, she also had bilateral dysplastic ears with over-folded helices, bilateral triphalangeal thumbs together with loss of flexion on the second interphalangeal joints, and a medial deviation of the distal phalanges (Fig. 1). Renal scintigraphy showed renal agenesis on the left and grade-2 parenchymal echogenicity on the right. She was diagnosed with chronic renal failure and hypertension. In addition, she had mild hearing loss. She had undergone anorectal repair for an imperforate anus as a neonate and several preauricular skin tags had been removed in childhood. Neither the mother nor the child had any cardiac or spinal abnormalities. Both had normal karyotypes. Molecular studies were not possible, but on the basis of these clinical findings, we diagnosed Townes-Brocks syndrome (TBS).

No abstract

No abstract