In 2 male infants of first-cousin parents, Borochowitz et al. (1991) observed a form of acute infantile spinal muscular atrophy (SMA type I; Werdnig-Hoffmann disease; 253300) in association with congenital bone fractures. The authors suggested autosomal recessive inheritance, ... In 2 male infants of first-cousin parents, Borochowitz et al. (1991) observed a form of acute infantile spinal muscular atrophy (SMA type I; Werdnig-Hoffmann disease; 253300) in association with congenital bone fractures. The authors suggested autosomal recessive inheritance, but noted that X-linked recessive inheritance could not be ruled out. Kelly et al. (1999) reported a boy with hypotonia, multiple joint contractures, generalized osteopenia, and congenital fractures whose sural nerve and muscle biopsies were consistent with a form of spinal muscular atrophy. There was also evidence for a sensory component. Molecular studies identified no abnormality of the SMN gene (600354) on chromosome 5q. Felderhoff-Mueser et al. (2002) reported a male infant with hypotonia, respiratory difficulty, decreased muscle mass, congenital fractures, and severe osteopenia. Contractures were not present. Muscle biopsy showed severe atrophy of type 1 and type 2 fibers, and postmortem examination revealed generalized muscle atrophy, normal bone structure on histology, marked depletion and atrophy of anterior horn cells, and astrogliosis in the anterior horn. Mutation analyses of the SMN gene and the IGHMBP2 gene (600502) were negative. Van Toorn et al. (2002) reported a male infant with severe hypotonia, congenital midshaft fractures of both femurs and a humerus, and dysmorphologic features, including long, thin digits, high-arched palate, pectus excavatum, and rocker-bottom feet. Postmortem examination showed very little skeletal muscle, severe loss of anterior horn cells, and normal bone histology. Van Toorn et al. (2002) noted that fetal immobility likely induced a decrease in mechanical use of bone, influencing bone remodeling and leading to reduced cortical thickness and fetal bone osteoporosis. Mutation analysis of the SMN gene was negative. The authors noted that all reported cases were male, suggesting X-linked recessive inheritance. Courtens et al. (2002) reported a case in a female infant born of consanguineous parents. She presented with neonatal hypotonia (requiring ventilation), fractures of the humerus and femur, and dislocated hips, and had no spontaneous movements. Additional features included generalized edema, accumulation of fat in the lower limbs, generalized hypertrichosis (which may have been familial), and congenital heart defect. Nerve and muscle studies were compatible with a severe and acute form of SMA. No mutations in the SMN gene were detected. Courtens et al. (2002) noted that all reported cases resulted in early death.