Development of lentigines within naevoid hypopigmentation.
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Child, Preschool↗
Biomedical subjects
S Huson
Publications and source records attributed to S Huson.
Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.
The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.
Chromosome Mapping↗
Del(18p) shown to be a cryptic translocation using a multiprobe FISH assay for subtelomeric chromosome rearrangements.
We have previously described a fluorescence in situ hybridisation (FISH) assay for the simultaneous analysis of all human subtelomeric regions using a single microscope slide. Here we report the use of this multiprobe FISH assay in the study of a patient whose karyotype was reported by G banding analysis as 46,XX,del(18)(p11.2). Although the proband had some features suggestive of a chromosomal abnormality, relatively few of the specific features of del(18p) were present. She was a 37 year old female with mild distal spinal muscular atrophy (SMA), arthritis of the hands, an abnormal chest shape (pectus excavatum), and an unusual skin condition (keratosis pilaris). Reverse chromosome painting with degenerate oligonucleotide primer-polymerase chain reaction (DOP-PCR) amplified del(18p) chromosomes as a probe confirmed the abnormality as del(18p), with no evidence of any other chromosome involvement. Subsequently, the multiprobe FISH assay confirmed deletion of 18p subtelomeric sequence. However, the assay also showed that sequences corresponding to the 2p subtelomeric probe were present on the tip of the shortened 18p. The patient is therefore monosomic for 18p11.2-pter and trisomic for 2p25-pter, and the revised karyotype is 46,XX,der(18)t(2;18)(p25; p11.2). We believe that a proportion of all cases reported as telomeric deletions may be cryptic translocations involving other chromosome subtelomeric regions. Further studies such as this are necessary to define accurately the clinical characteristics associated with pure monosomy in chromosomal deletion syndromes.
Adult↗
A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map.
Karyotypic analysis in a patient with Peutz-Jeghers' syndrome demonstrated a pericentric inversion on chromosome 6. Further investigation was undertaken using fluorescence in situ hybridisation (FISH) with yeast artificial chromosome clones selected to contain genetic markers from chromosome 6, and a probe for the centromeric alphoid repeat array. This analysis located one inversion breakpoint within the alphoid array, in a 1-cM interval between D6S257 and D6S402, and the other in a 4-cM interval between D6S403 and D6S311. The oestrogen receptor gene locus (ESR) is excluded from the latter interval.
Adult↗
A 90 kb DNA deletion associated with neurofibromatosis type 1.
A deletion of 90 kb of DNA has been identified in a patient with neurofibromatosis type 1, using pulsed field gel electrophoresis. The deletion lies between probes 17L1A and AC5 in the critical region of chromosome 17 and represents the only molecular alteration found by PFGE in a series of 90 unrelated patients. The subject showing the deletion is an isolated case, shows typical clinical features, and represents one of the first examples of a molecular deletion to be found in this disorder.
Chromosome Deletion↗
Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene.
von Recklinghausen neurofibromatosis (VRNF) is one of the most common inherited disorders affecting the human nervous system. VRNF is transmitted as an autosomal dominant defect with high penetrance but variable expressivity. The disorder is characterized clinically by hyperpigmented patches of skin (café au lait macules, axillary freckles) and by multiple tumors of peripheral nerve, spinal nerve roots, and brain (neurofibromas, optic gliomas). These tumors can cause disfigurement, paralysis, blindness, and death. We have determined the chromosomal location of the VRNF gene by genetic linkage analysis using DNA markers. The VRNF gene is genetically linked to the locus encoding nerve growth factor receptor, located on the long arm of chromosome 17 in the region 17q12----17q22. However, crossovers with the VRNF locus suggest that a mutation in the nerve growth factor receptor gene itself is unlikely to be the fundamental defect responsible for the VRNF phenotype.
Chromosome Mapping↗
Common pathogenetic mechanism for three tumor types in bilateral acoustic neurofibromatosis.
Bilateral acoustic neurofibromatosis (BANF) is a genetic defect associated with multiple tumors of neural crest origin. Specific loss of alleles from chromosome 22 was detected with polymorphic DNA markers in two acoustic neuromas, two neurofibromas, and one meningioma from BANF patients. This indicates a common pathogenetic mechanism for all three tumor types. The two neurofibromas were among three taken from the same patient, and both showed loss of identical alleles demonstrating that the same chromosome suffered deletion in both tumors. The third neurofibroma from this patient showed no detectable loss of heterozygosity, which suggests the possibility of a more subtle mutational event that affects chromosome 22. In the two acoustic neuromas, only a portion of chromosome 22 was deleted, narrowing the possible chromosomal location of the gene that causes BANF to the region distal to the D22S9 locus in band 22q11. The identification of progressively smaller deletions on chromosome 22 in these tumor types may well provide a means to clone and characterize the defect.
Alleles↗
Ophthalmic manifestations of neurofibromatosis.
The eyes of 64 patients known to have neurofibromatosis were examined. Lisch nodules were the commonest manifestation of the disease and were present in 95% of all patients (100% of those aged 16 years or older).
Adolescent↗
Von Recklinghausen neurofibromatosis: a linkage study of candidate and random marker genes.
Genotyping, using plasma proteins or DNA polymorphisms or both, was carried out on 30 families selected through probands with Von Recklinghausen disease. The data provide additional evidence for the exclusion of loci on chromosomes 3 and 5, and chromosome arms 1q, 2p, 4p, 4q, 6q, 7p, 9q, 11p, 11q, and 14q. There was no evidence for genetic heterogeneity at D1S1 (DNF15S2) on chromosome arm 3p, using the Morton test for heterogeneity.
Blood Proteins↗
DNA linkage analysis in Von Recklinghausen neurofibromatosis.
We have used DNA linkage analysis in 11 families with Von Recklinghausen neurofibromatosis (VRNF) in order to search for the chromosomal localisation of the defective gene causing this serious neurological disorder. Three groups of polymorphic DNA markers were used: (1) markers for chromosome 22, because of possible allelic genetic heterogeneity between VRNF and bilateral acoustic neurofibromatosis; (2) markers near the centromere of chromosome 4, since there was preliminary evidence for linkage between the VRNF gene and Gc; and (3) oncogenes and growth factors as possible candidate genes for VRNF. Our data exclude close linkage between any of these markers and the gene for VRNF.
DNA↗
Gene mapping and myotonic dystrophy.
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Base Sequence↗
Childhood vulval lichen sclerosus in a patient with ectodermal dysplasia and uncombable hair.
An 11-year-old girl was diagnosed as having ectodermal dysplasia, with abnormalities of her nails, teeth, and hair noted from infancy. Her hair was unruly and investigations confirmed the changes seen in "cheveux incoiffables"-the uncombable hair syndrome. She also had atopy requiring treatment to control asthma and eczema. When she was 8 years old she developed vulval lichen sclerosus, which was controlled easily with early treatment. The coexistence of these conditions is discussed.
Asthma↗