Demographic Studies from a National Gaucher Disease Screening Program.

In May 1993, the National Gaucher Foundation initiated a nationwide Gaucher disease screening program in an attempt to promote recognition of the disease and to detect previously undiagnosed individuals. The program was based on self-selection by clinical symptoms of individuals who wanted to be tested for Gaucher disease. Information about symptoms, age, ancestry, gender, and family history was obtained via a self-report screening form completed by 700 individuals. Individuals designated at "high risk" for Gaucher disease were offered beta-glucocerebrosidase enzyme assay testing. Twenty-four of the respondents (3.4%) had Gaucher disease. The most commonly reported symptoms were fatigue (79.4%), bone pain (73.7%), and tendency to bruise (67.8%). The symptoms which showed a statistical difference between the "high risk" and "low risk" groups were liver enlargement (p < 0.005) and unexplained bone fractures (p < 0.03). The mean number of positive symptoms also showed a statistical difference between the groups (4.38 symptoms vs. 3.86 symptoms; p < 0.02). Due to the small sample size, no statistical comparisons were made on the symptomatology of affected vs. unaffected persons, but a descriptive analysis of these two groups is reported.

Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.

Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm.