Growth Factors, Combined Defect Of

In 3 brothers born of healthy nonconsanguineous parents, Hoepffner et al. (1989) demonstrated a similar clinical phenotype with reduced subcutaneous fat on the limbs, lipodystrophy in the face and trunk, and reduced relative body weight. The neurocranium was relatively broad. The face was birdlike, with a beaked nose, moderate micrognathia, and a very narrow mouth. Other signs were contractures of joints, slight pectus excavatum, flat feet, and scleroderma-like changes in the skin, which was taut, thin, and atrophic, with moderate hyperkeratosis of the plantae surfaces and yellowish spotted discolorations with pigmented areas on the limbs and trunk. The eldest brother, born in 1965, showed insulin-resistant diabetes mellitus, amenable to diet, and type IV hyperlipoproteinemia (144600). The parents and the 2 younger brothers showed no disturbance in carbohydrate or fat metabolism. The microscopic changes in the skin were described by Mensing et al. (1982), who referred to the condition as a Werner-syndrome-like disorder. Biochemically, Hoepffner et al. (1989) demonstrated a combined defect in the action of 3 related peptides, insulin (176730), insulin-like growth factor I (147440) and epidermal growth factor (131530). Cultured fibroblasts showed a markedly reduced stimulation of RNA synthesis by the 3 growth factors and a decreased insulin stimulation of 2-deoxy-D-glucose uptake as compared with normal controls. Receptor binding of the 3 peptides occurred with normal capacity and affinity. Hoepffner et al. (1989) interpreted the findings as indicating that signal transfer of the different growth factors has a common denominator at the postreceptor level and that this is the site of the mutation. The defect may be located distal to the receptor-associated tyrosine kinases.