Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing.

OBJECTIVE: Diagnostic molecular genetic testing for multiple endocrine neoplasia type 1 (MEN1) has been available since the identification of the MEN1 gene in 1997. Mutation screening of the MEN1 gene has been recommended for patients who meet clinical criteria for MEN1 (at least two of the following: parathyroid hyperplasia, pancreatic endocrine tumour or pituitary adenoma) and those in whom a diagnosis of MEN1 is suspected. We examined the appropriateness of these clinical criteria. PATIENTS AND METHODS: A total of 292 patients were referred for diagnostic testing. The coding region of the MEN1 gene was sequenced in 186 index cases and mutation testing was requested for 106 subjects, including 83 asymptomatic relatives. RESULTS: MEN1 gene mutations were identified in 68/186 index cases (37%). Twenty-nine of the 60 MEN1 mutations reported are novel. The likelihood of finding a mutation was correlated with the number of MEN1-related tumours (mutation detection rate of 79%, 37% and 15% in patients with three, two and one main MEN1-related tumours; P < or = 0.00001) and increased in the presence of a family history (mutation detection rate of 91%, 69% and 29%vs. 69%, 23% and 0% in sporadic cases with three, two or one main MEN1-related tumours, respectively; P < or = 0.00001). The pick-up rate in the 83% of subjects who met proposed criteria for diagnostic testing was 42%, but in those who did not meet these criteria this fell to 0%. CONCLUSIONS: The likelihood of finding an MEN1 mutation depends on the clinical features of the patient and their family. This large series supports present referral criteria for diagnostic mutation screening, but suggests that patients with sporadic isolated tumours rarely have MEN1 mutations.

A locus for isolated cleft palate, located on human chromosome 2q32.

We present evidence for the existence of a novel chromosome 2q32 locus involved in the pathogenesis of isolated cleft palate. We have studied two unrelated patients with strikingly similar clinical features, in whom there are apparently balanced, de novo cytogenetic rearrangements involving the same region of chromosome 2q. Both children have cleft palate, facial dysmorphism, and mild learning disability. Their karyotypes were originally reported as 46, XX, t(2;7)(q33;p21) and 46, XX, t(2;11)(q33;p14). However, our molecular cytogenetic analyses localize both translocation breakpoints to a small region between markers D2S311 and D2S116. This suggests that the true location of these breakpoints is 2q32 rather than 2q33. To obtain independent support for the existence of a cleft-palate locus in 2q32, we performed a detailed statistical analysis for all cases in the human cytogenetics database of nonmosaic, single, contiguous autosomal deletions associated with orofacial clefting. This revealed 2q32 to be one of only three chromosomal regions in which haploinsufficiency is significantly associated with isolated cleft palate. In combination, our data provide strong evidence for the location at 2q32 of a gene that is critical to the development of the secondary palate. The close proximity of these two translocation breakpoints should also allow rapid progress toward the positional cloning of this cleft-palate gene.

Beckwith-Wiedemann syndrome in a child with chromosome 18q deletion.

Molecular genetic investigation of a female infant with Beckwith-Wiedemann syndrome (BWS) showed loss of IGF2 imprinting but no evidence of uniparental disomy. In addition, a deletion of chromosome 18q22.1 was identified in this infant without clinical features of 18q-syndrome (microcephaly, short stature, hypotonia). The association of a chromosome 18 deletion and BWS may be coincidental or may indicate the location of a trans activating regulator element for maintenance of IGF2 imprinting.

Genomic instability associated with limb defects: case report and review of the literature.

We report a child in whom we observed markedly increased genome-wide spontaneous chromosomal breakage in both leucocytes and fibroblasts associated with severe growth retardation, radial aplasia, leucopenia, mild hydrocephalus and an unusual trichodystrophy. Exposure to DNA cross-linking agents diepoxybutane, mitomycin-C and mustine hydrochloride in this case did not result in the increased chromosome breakage seen in Fanconi anaemia. It may be that this child has a defect in postreplicative DNA repair interacting with the protein components deficient in FA.

X-linked hydrocephalus masquerading as spina bifida and destructive porencephaly in successive generations in one family.

The authors report a case of X-linked hydrocephalus which presented as a destructive porencephaly. There was asymmetric dilatation of the ventricles of prenatal onset, and neuro-imagining studies were suggestive of infection or haemorrhage. The child was profoundly handicapped but did not have adducted thumbs. Two of his mother's brothers had been stillborn, and postmortem reports revealed that the diagnosis had been isolated hydrocephalus and not spina bifida as reported by the family. Despite serial ultrasound scans, recurrence of X-linked hydrocephalus in the mother's subsequent pregnancy was not detected until 26 weeks gestation, when the ventricles became grossly dilated. The diagnosis was confirmed in this family by identification of a mutation within the LICAM gene.

X-linked hydrocephalus masquerading as spina bifida and destructive porencephaly in successive generations in one family.

The authors report a case of X-linked hydrocephalus which presented as a destructive porencephaly. There was asymmetric dilatation of the ventricles of prenatal onset, and neuro-imagining studies were suggestive of infection or haemorrhage. The child was profoundly handicapped but did not have adducted thumbs. Two of his mother's brothers had been stillborn, and postmortem reports revealed that the diagnosis had been isolated hydrocephalus and not spina bifida as reported by the family. Despite serial ultrasound scans, recurrence of X-linked hydrocephalus in the mother's subsequent pregnancy was not detected until 26 weeks gestation, when the ventricles became grossly dilated. The diagnosis was confirmed in this family by identification of mutation within the L1CAM gene.

Clinical and molecular cytogenetic (FISH) diagnosis of Williams syndrome.

Sixteen children and adolescents with a firm clinical diagnosis of Williams syndrome were investigated with the chromosome fluorescence in situ hybridisation (FISH) technique employing the elastin gene probe. In each case there was a fluorescent signal on one chromosome 7 homologue only, indicating elastin gene deletion. No deletion was demonstrated in another child in whom an earlier diagnosis of Williams syndrome was judged doubtful at review. Firm clinical diagnosis correlates with elastin gene deletion in 16/16 cases of Williams syndrome and detection of such hemizygosity by FISH constitutes a useful confirmatory diagnostic test.

Effects of topical baclofen on C fibre-evoked neuronal activity in the rat dorsal horn.

Baclofen appears to be an agonist for the bicuculline-insensitive gamma-aminobutyrateB receptors associated with C fibre terminals in the dorsal horn of the spinal cord. We have tested the effect of baclofen (applied intrathecally onto the spinal cord) on the A and C fibre-evoked responses of convergent/multireceptive neurones in the halothane-anaesthetized rat. L-Baclofen produced a dose-dependent inhibition of the C fibre- and pinch-evoked activity of these neurones which persisted for 2 h whilst the A fibre and tactile activities were little changed. The C fibre-evoked (X 3 threshold) responses were markedly or completely inhibited 10 min after doses of between 0.25 and 30 micrograms of L-baclofen (n = 21) with 0.05 micrograms causing a 48% (n = 3) and 0.01 micrograms a 28% inhibition (n = 3). D-Baclofen (30 micrograms), the inactive isomer, produced no significant changes in activity (n = 10). Bicuculline (60 micrograms) applied intrathecally before (n = 7) or after (n = 8) L-baclofen did not reverse the inhibitions. Intravenous baclofen (1-3 mg/kg) also produced neuronal inhibitions similar to the effects of intrathecal injection. The results suggest that gamma-aminobutyrateB receptors may exert a presynaptic control of C fibre afferents in the dorsal horn following intrathecal administration in the rat.