Radioulnar Synostosis With Microcephaly, Short Stature, Scoliosis, And Mental Retardation

Clinical Features

Tsukahara et al. (1995) reported the case of a 9-year-old boy with radioulnar synostosis, short stature, microcephaly, clinodactyly of the fifth fingers, partial webbing, scoliosis, and mental retardation. Tsukahara et al. (1995) considered the disorder in their patient to be different from that in the patients described by Giuffre et al. (1994).

Giuffre et al. (1994) described 7 affected individuals from 2 unrelated families with microcephaly and radioulnar synostosis; 6 had short stature and 1 was at the 50th centile for height. In the first family, clinodactyly of the fifth finger and partial webbing was also present; in the second family, 1 patient had submucous cleft palate. There was slight psychomotor impairment in the male patients of each family that was not reported in the female subjects. Inheritance was consistent with an autosomal dominant pattern.

Udler et al. (1998) described an 8-year-old Israeli Arab girl who appeared to have the same condition as the patient of Tsukahara et al. (1995). Her parents were first cousins, raising the possibility of autosomal recessive inheritance. Limited supination of the elbow joints was noted at delivery and x-ray studies showed radioulnar synostosis. This was repaired at 2.5 years, but recurred between 4 and 6 years. At 6 years, right-sided thoracic scoliosis was diagnosed; radiologic examination showed no signs of skeletal dysplasia. Development, especially of speech, was delayed, although no delay of motor development was observed. At the age of 8 years, she was unable to read or write. Occipitofrontal head circumference was 31.5 cm at birth, and microcephaly as well as short stature had been present throughout.

Selicorni et al. (2005) reported a 3-year-old boy with microcephaly, radioulnar synostosis, and mental retardation. His height was at the 50th centile and there was no scoliosis. Selicorni et al. (2005) commented that the facial dysmorphism differed among their patient and those reported by Giuffre et al. (1994), Tsukahara et al. (1995), and Udler et al. (1998). They suggested the existence of a common phenotype characterized by the association of microcephaly and radioulnar synostosis, accompanied variably by growth and/or psychomotor delay.

Gaspar et al. (2008) reported a mother and son with apparent X-linked semidominant inheritance of Giuffre-Tsukahara syndrome. The son was referred at age 7 years because of developmental delay, learning disability, and attention deficit and hyperactivity disorder. Dysmorphic features were apparent, including microcephaly, dysmorphic ears with unusually shaped antihelix, hypotelorism, a prominent nose, and a thin upper lip. He had dorsal kyphosis, right hydrocele, and inguinal hernia. The forearms had limited supination, and there was partial syndactyly of fingers and clinodactyly and brachymesophalangy of the fifth fingers. Radiographs showed radioulnar synostosis with luxation of the radial head on the right side and fibrous synostosis of radius and ulna on the left side. The 36-year-old mother of the patient reportedly had bilateral radioulnar deformity with limited supination of both forearms. She showed mild mental retardation and learning disability with an IQ below the normal range. X-inactivation studies in the mother showed a strongly skewed and nonrandom pattern. Further studies showed that the affected son inherited the allele that was mostly inactivated in his mother, whereas a healthy brother inherited the mother's activated allele. These findings supported X-linked semidominant inheritance, with the mother having a milder phenotype. Gaspar et al. (2008) postulated that the gene defect mapped to chromosome Xp22.13-q21.33 within the inactivated maternal allele. The authors concluded that Giuffre-Tsukahara syndrome is a single genetic entity characterized by the association of microcephaly and radioulnar synostosis and mental retardation, but without characteristic facies.

Dalal et al. (2010) reported a girl, born of consanguineous Indian parents, with apparent Giuffre-Tsukahara syndrome. She presented at age 6 years with global developmental delay, poor speech, microcephaly, short stature, and limited elbow movement. She had pectus excavatum, limited movement of forearms, brachydactyly, clinodactyly, scoliosis, and joint laxity of the fingers and knees. Radiologic evaluation showed bilateral proximal radioulnar synostosis. She also had dysmorphic facial features, including prominent eyes, hypotelorism, flat malar region, simple ears, thick lips, and bilateral myopia. Molecular studies showed no evidence of skewed X inactivation. There was no family history of a similar disorder. Dalal et al. (2010) postulated X-linked dominant inheritance, but noted that autosomal recessive inheritance could not be excluded.

Nomenclature

The syndrome described here was designated 'Tsukahara syndrome' by Udler et al. (1998). This syndrome is distinct from the 'Tsukahara syndrome' involving type A1 brachydactyly, short stature, scoliosis, microcephaly, ptosis, hearing loss, and mental retardation (613627).