Kosaki Overgrowth Syndrome

A number sign (#) is used with this entry because of evidence that Kosaki overgrowth syndrome (KOGS) is caused by heterozygous mutation in the PDGFRB gene (173410) on chromosome 5q32.

Description

Kosaki overgrowth syndrome is characterized by a facial gestalt involving prominent forehead, proptosis, downslanting palpebral fissures, wide nasal bridge, thin upper lip, and pointed chin. Affected individuals are tall, with an elongated lower segment, hands, and feet. Skin is hyperelastic and fragile, and there is progressive neurologic deterioration with white matter lesions on brain imaging (Takenouchi et al., 2015).

Clinical Features

Takenouchi et al. (2015) described 2 unrelated Japanese girls with an overgrowth syndrome who exhibited strikingly similar facial features as well as hyperelastic, fragile skin, scoliosis, white matter lesions, and neurologic deterioration. The first girl had normal psychomotor development in childhood but exhibited accelerated linear growth. At age 8 years, she developed a 3-cm mandibular tumor that was removed surgically; pathology was consistent with myofibroma. At age 14, her height, lower-segment, hand, and foot length were all more than +4 SD. Facial features included prominent forehead and supraorbital ridge, mild proptosis, ptosis, downslanting palpebral fissures, wide nasal bridge, high columella insertion, thin upper lip, and pointed chin. Her skin was hyperelastic, thin, and fragile. In early adolescence, she began to have recurrent episodes of depression and anxiety as well as schizophrenic symptoms, including auditory hallucinations. The second girl, who had been reported by Watanabe et al. (2011) under a presumptive diagnosis of Shprintzen-Goldberg syndrome (see 182212) but who was negative for mutation in the SKI gene (164780), had normal psychomotor development in infancy and Stanford-Binet IQ of 73 at age 6 years, but her IQ was measured at less than 40 at age 13. She had distinctive facial features that were strikingly similar to those of the first girl, with a prominent forehead, proptosis, downslanting palpebral fissures, xanthoma on bilateral upper eyelids, wide and depressed nasal bridge, thin upper lip, and pointed chin. Both girls had thoracolumbar scoliosis, and both also exhibited an abnormal cranial shape with protrusion of the posterior fossa and a diffuse granular pattern on x-ray. Brain MRI showed extensive periventricular white matter lesions in both patients, but there was no evidence of intracranial calcification on CT scan. Family history was noncontributory in both cases.

Molecular Genetics

In a Japanese girl with overgrowth, facial dysmorphism, hyperelastic fragile skin, scoliosis, and neurologic deterioration, who was negative for mutation in 6 known overgrowth-associated genes, Takenouchi et al. (2015) performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in the PDGFRB gene (P584R; 173410.0005). Sequencing of the PDGFRB gene in an unrelated but similarly affected Japanese girl revealed heterozygosity for the same de novo mutation.