Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease.

The gene predisposing to neurofibromatosis type 2 (NF2) on human chromosome 22 has revealed a wide variety of different mutations in NF2 individuals. These patients display a marked variability in clinical presentation, ranging from very severe disease with numerous tumors at a young age to a relatively mild condition much later in life. To investigate whether this phenotypic heterogeneity is determined by the type of mutation in NF2, we have collected clinical information on 111 NF2 cases from 73 different families on whom we have performed mutation screening in this gene. Sixty-seven individuals (56.2%) from 41 of these kindreds revealed 36 different putative disease-causing mutations. These include 26 proposed protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), 6 splice-site mutations, 2 missense mutations, 1 base substitution in the 3' UTR of the NF2 cDNA, and a single 3-bp in-frame insertion. Seventeen of these mutations are novel, whereas the remaining 19 have been described previously in other NF2 individuals or sporadic tumors. When individuals harboring protein-truncating mutations are compared with cases with single codon alterations, a significant correlation (P < .001) with clinical outcome is observed. Twenty-four of 28 patients with mutations that cause premature truncation of the NF2 protein, schwannomin, present with severe phenotypes. In contrast, all 16 cases from three families with mutations that affect only a single amino acid have mild NF2. These data provide conclusive evidence that a phenotype/genotype correlation exists for certain NF2 mutations.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): clinical and radiological findings in a Guatemalan patient.

We report on a patient of Guatemalan descent whose physical and radiological findings are consistent with a diagnosis of spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL). This is a rare, autosomal recessive skeletal dysplasia with short limbs, severe scoliosis, high dorsal kyphoscoliosis, and joint hypermobility. Most described patients with SEMDJL are from the Afrikaans-speaking communities of South Africa. Patients with SEMDJL have an oval face, prominent eyes, and blue sclerae. Our patient's height and weight were below the fifth centile. She had prominent eyes with blue sclerae, a narrow, high-arched palate, pectus carinatum, severe scoliosis, and hyperextensibility and instability of most joints, with limited extension and supination of her elbows. A review of her roentgenograms showed severe scoliosis, poorly developed ischial, iliac, and pubic bones, a "bat-like" appearance of the iliac bones, "dysplastic" acetabulum, minimal metaphyseal and epiphyseal abnormalities at the knees, deformation of the proximal femoral metaphyses, and generalized brachydactyly of the hands and feet. This disorder may be more common than previously thought, and the diagnosis should be considered in any child with a dwarfing condition and joint laxity.