Forsythe-Wakeling Syndrome

Clinical Features

Forsythe et al. (2009) reported 4 sibs, born of consanguineous Pakistani parents, with microcephaly, postnatal growth retardation, and global developmental delay with poor speech. All had similar dysmorphic features, including frontal bossing, sunken eyes, high nasal bridge, and large, prominent, low-set ears. During childhood, 3 patients developed persistent thrombocytopenia and steroid-nonresponsive nephrotic syndrome, resulting in death in 2 children. The fourth child had similar dysmorphic features and developmental delay, but did not have nephrotic syndrome or thrombocytopenia by age 25 months. The oldest child developed steroid-unresponsive nephrotic syndrome at age 7 years, with a renal biopsy showing glomerulosclerosis, tubular atrophy, interstitial fibrosis, and hyaline thickening of the arteriolar wall. He also had thrombocytopenia, generalized osteoporosis, and delayed bone age. There was no history of photosensitivity, poor vision, or deafness in any of the children, but 2 had keratinized, purple, nodular skin lesions. Studies of skin fibroblasts of 2 of the patients showed an intermediate recovery of RNA synthesis following UV irradiation. Forsythe et al. (2009) considered the dysmorphic features and fibroblast findings to be reminiscent of Cockayne syndrome (see, e.g., 133540).

Inheritance

The family reported by Forsythe et al. (2009) was consanguineous, suggesting autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a Pakistani family with an autosomal recessive disorder characterized by microcephaly, poor growth, developmental delay, dysmorphic features, nephrotic syndrome, and thrombocytopenia, Forsythe et al. (2009) identified a 27-Mb interval of shared homozygosity on chromosome 1p33-p31.1 between rs2354462 and rs718883 (maximum multipoint lod score of 2.4).