X chromosome-linked immunodeficiency with hyper-IgM (HIGM1, MIM number 308230) is a rare disorder characterized by recurrent bacterial infections, very low or absent IgG, IgA and IgE, and normal to increased IgM and IgD serum levels. HIGM1 has been suggested to result from ineffective T-cell help for B cells. We and others have identified a novel, TNF-related activation protein (TRAP) that is exclusively expressed on the surface of stimulated T cells. TRAP, a type II transmembrane protein of M(r) 33,000, is the physiological ligand for CD40 (refs 5-8). Crosslinking of CD40 on B cells induces, in the presence of lymphokines, immunoglobulin class switching from IgM to IgG, IgA or IgE. Mapping of the TRAP gene to the X-chromosomal location q26.3-q27.1 (ref. 6) suggested a causal relationship to HIGM1, which had previously been assigned to Xq26 (refs 12-14). Here we present evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with HIGM1. The resultant failure of TRAP to interact with CD40 on functionally intact B cells is responsible for the observed immunoglobulin isotype defect in HIGM1.

Crouzon syndrome is an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis) and maps to chromosome 10q25-q26. We now present evidence that mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause Crouzon syndrome. We found SSCP variations in the B exon of FGFR2 in nine unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in three unrelated multigenerational families. In four sporadic cases, the normal parents did not have SSCP variation. Finally, direct sequencing has revealed specific mutations in the B exon in all nine sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in five patients.

Pfeiffer syndrome (PS) is one of the classic autosomal dominant craniosynostosis syndromes with craniofacial anomalies and characteristic broad thumbs and big toes. We have previously mapped one of the genes for PS to the centromeric region of chromosome 8 by linkage analysis. Here we present evidence that mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to 8p, cause one form of familial Pfeiffer syndrome. A C to G transversion in exon 5, predicting a proline to arginine substitution in the putative extracellular domain, was identified in all affected members of five unrelated PS families but not in any unaffected individuals. FGFR1 therefore becomes the third fibroblast growth factor receptor to be associated with an autosomal dominant skeletal disorder.

Clinical and electrophysiological investigations and nerve biopsies were carried out on 61 patients shown to have a chromosome 17p11.2 duplication (hereditary motor and sensory neuropathy-HMSN Ia). Of these, 50 showed a Charcot-Marie-Tooth (CMT) phenotype and eight could be classified as having the Roussy-Lévy syndrome. Of the patients with a CMT phenotype, three had associated pyramidal signs and of these one had 'complicated' HMSN and also signs of cerebellar and bulbar involvement. Diaphragmatic weakness was present in three severely affected cases, one of whom also had denervation of the anal sphincter associated with faecal incontinence. One unusual case presented in middle life with incapacitating muscle cramps associated with calf hypertrophy and only mild clinical signs of neuropathy. Prominent distal sensory loss was a consistent feature in one family, resulting in acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT and Roussy-Lévy phenotypes, in seven patients. Upper limb motor nerve conduction velocity was 19.9 m/s +/- 1.3 (SEM), range 5-34 m/s. This corresponds to values previously obtained for autosomal dominant HMSN I. This series consisted mainly of older patients with more advanced disease. In contrast to the findings in younger patients, in their nerve biopsies, myelin thickness tended to be relatively reduced for axon size, indicating remyelination and/or hypomyelination; there was also regression of the onion bulbs. It is concluded that the possession of two copies of the peripheral myelin protein 22 gene within the duplicated region on chromosome 17p gives rise to a range of phenotypes and not solely to a CMT syndrome, and that the pattern of histological change in the peripheral nerves alters with advance of the disease.

Background-Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. EVective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions. Methods-We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities. Results-Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly diVerent from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects. Conclusions-Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects. (J Med Genet 2001;38:145-150)