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J Med Genet

Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3.

Olschwang S. Markie D. Seal S. Neale K. Phillips R. Cottrell S. Ellis I. Hodgson S. Zauber P. Spigelman A. Iwama T. Loff S. McKeown C. Marchese C. Sampson J. Davies S. Talbot I. Wyke J. Thomas G. Bodmer W. Hemminki A. Avizienyte E. de la Chapelle A. Aalto
INSERM U-434, CEPH, Paris, France.
A locus for Peutz-Jeghers syndrome (PJS) was recently mapped to chromosome 19p13.3. Each of 12 families studied was compatible with linkage to the marker D19S886. We have analysed 20 further families and found that the majority of these are consistent with a PJS gene on 19p13.3. Three families were, however, unlinked to 19p13.3 and none of the available PJS polyps from these families showed allele loss at D19S886. There were no obvious clinicopathological or ethnic differences between the 19p13.3 linked and unlinked families. There appears, therefore, to be a major PJS locus on chromosome 19p13.3 and the possibility exists of a minor locus (or loci) elsewhere.

Neonatal cholestasis and focal medullary dysplasia of the kidneys in a case of microcephalic osteodysplastic primordial dwarfism.

Berger A. Haschke N. Kohlhauser C. Amman G. Unterberger U. Weninger M.
University Children's Hospital Vienna, AKH, Department of Neonatology, Austria.
We report on a male infant who presented with intrauterine growth retardation, severe postnatal failure to thrive, microcephaly, facial dysmorphism, and skeletal dysplasia. The clinical and radiological findings are consistent with former descriptions of microcephalic osteodysplastic primordial dwarfism (MOPD) type I/III. In addition to previously published features, multiple fractures of the long bones, severe neonatal cholestasis, and histological dysplasia of the kidneys were found. The boy died at the age of 8 months. The new finding of focal renal medullary dysplasia further supports the hypothesis of a basic defect in tissue differentiation in the pathogenesis of this rare condition.

Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity.

Devriendt K. Standaert L. Van Hole C. Devlieger H. Fryns JP.
Centre for Human Genetics, University Hospital Leuven, Belgium.
We present a male infant with hypertelorism, severe myopia and sensorineural deafness, diaphragmatic hernia, and proteinuria. This patient combines features of two distinct genetic conditions, the syndrome of diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness (MIM 222448), and the facio-oculo-acoustico-renal syndrome (MIM 227290), which is characterised by similar anomalies, with the additional finding of proteinuria, but without diaphragmatic hernia. The present observations further suggest that these syndromes are the variable expression of a single autosomal recessive disorder.

P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population.

Year 1998
Gilfillan A. Warner JP. Kirk JM. Marshall T. Greening A. Ho LP. Hargreave T. Stack B. McIntyre D. Davidson R. Dean JC. Middleton W. Brock DJ.
Human Genetics Unit, University of Edinburgh, Western General Hospital, UK.
Only three mutant cystic fibrosis (CF) alleles have to date been established as conferring a dominant mild effect on affected subjects who are compound heterozygotes. We now add a fourth, P67L, which occurs on about 1.4% of Scottish CF chromosomes. Among 13 patients (12 unrelated) with this allele, the average age at diagnosis was 22.5 +/- 11.3 years. None of the cases had consistently raised sweat chloride concentrations, the average value being 57 +/- 9 mmol/l; 77% of the patients were pancreatic sufficient. When compared to three other established mild CF alleles, R117H, A455E, and 3849 + 10kb C-T, a compound heterozygote for P67L has minimal disease and clinical suspicions are unlikely to be confirmed other than by DNA typing.

Absence of mutations in the interspecies conserved regions of the CFTR promoter region in cystic fibrosis (CF) and CF related patients.

Year 1998
Verlingue C. Vuillaumier S. Mercier B. Le Gac M. Elion J. Ferec C. Denamur E.
Biochimie Genetique/INSERM U458, Hopital Robert Debre, Paris, France.
This study was aimed at testing if a 5.2 kb untranslated region on both sides of the first CFTR exon, shown to contain regulatory elements, could carry mutations responsible for cystic fibrosis (CF) or CF related phenotypes. Selection of the DNA segments studied within this region was based upon the identification of conserved sequences throughout evolution (phylogenetic footprints, PFs). Comparison of the CFTR sequences in eight species representing four orders of mammals (man, gibbon, rhesus monkey, squirrel, monkey, rabbit, cow, rat, and mouse) identified four clusters of PFs within the 3.9 kb of DNA sequence upstream from the initiation codon, as well as two nearby PFs at +1 kb within intron 1. Six DNA segments containing PFs were scanned for mutations by denaturing gradient gel electrophoresis (DGGE) in patients with CF (n = 29), congenital bilateral absence of the vas deferens (n = 143), or disseminated bronchiectasis (n = 33), for whom only one or no mutations had been identified despite extensive DGGE analysis of the 27 CFTR exons and exon/intron boundaries. Only one polymorphism (-966 T-->G) was identified with a frequency of 2.2% and no other sequence variations were found. This study reinforces the idea that the promoter region in the CFTR is not frequently mutated.

A patient with Simpson-Golabi-Behmel syndrome and hepatocellular carcinoma.

Year 1998
Lapunzina P. Badia I. Galoppo C. De Matteo E. Silberman P. Tello A. Grichener J. Hughes-Benzie R.
Department of Paediatrics, Hospital de Ninos de Buenos Aires, University of Buenos Aires, Argentina.
Simpson-Golabi-Behmel syndrome (SGBS) is an X linked disorder characterised by pre- and postnatal overgrowth, coarse facial features, and visceral and skeletal abnormalities. Like other overgrowth syndromes, in the SGBS there is an increased risk for developing neoplasia, mainly embryonic, such as Wilms tumour. We report a 3 year old male patient with SGBS and hepatocellular carcinoma, a previously undescribed tumour associated with the syndrome.

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

Year 1998
Brewer CM. Lam WW. Hayward C. Grace E. Maher ER. FitzPatrick DR.
Human Genetics Unit, Western General Hospital, Edinburgh, UK.
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.

Evidence of linkage of the inflammatory bowel disease susceptibility locus on chromosome 16 (IBD1) to ulcerative colitis.

Year 1998
Mirza MM. Lee J. Teare D. Hugot JP. Laurent-Puig P. Colombel JF. Hodgson SV. Thomas G. Easton DF. Lennard-Jones JE. Mathew CG.
Division of Medical & Molecular Genetics, UMDS, Guy's Hospital, London, UK.
Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) of unknown aetiology which are characterised by chronic inflammation of the gastrointestinal tract. Epidemiological studies suggest the presence of a genetic component in the aetiology of both CD and UC. A susceptibility gene for Crohn's disease has recently been mapped to the pericentromeric region of chromosome 16 (IBD1), and this finding has been replicated in two subsequent studies. Although CD and UC are distinct clinical entities, the fact that both disorders occur in a significant proportion of families with multiple cases of IBD suggests that overlapping sets of susceptibility genes may be involved. We have addressed this question for IBD1 by typing eight microsatellite markers from the locus in 70 kindreds affected with either UC only or with both UC and CD and analysing the data for linkage by both non-parametric and parametric methods. Evidence for linkage was detected in families affected with only UC, with a mean proportion of 0.70 affected sib pairs sharing alleles identical by descent at D16S3136 (p=0.01), and a peak non-parametric linkage score of 2.02 at D16S3120 with the GENEHUNTER program (p=0.02). The estimated sib relative risk attributable to IBD1 in these families was 1.46. Surprisingly, no evidence of linkage was detected in the families affected with both UC and CD (p>0.2). The data suggest that IBD1 may also contribute to susceptibility to ulcerative colitis, and that it is likely to be located in the 12 cM interval between D16S419 and D16S409.

Molecular basis of variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene.

Year 1998
Frank J. Lam H. Zaider E. Poh-Fitzpatrick M. Christiano AM.
Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Variegate porphyria (VP) is an autosomal dominant disorder characterised by a partial defect in the activity of protoporphyrinogen oxidase (PPO), and has recently been genetically linked to the PPO gene on chromosome 1q22-23 (Z=6.62). In this study, we identified a mutation in the PPO gene in a patient with VP and two unaffected family members. The mutation consisted of a previously unreported T to C transition in exon 13 of the PPO gene, resulting in the substitution of a polar serine by a non-polar proline (S450P). This serine residue is evolutionarily highly conserved in man, mouse, and Bacillus subtilis, attesting to the importance of this residue. Interestingly, the gene for Gardner's syndrome (FAP) also segregates in this family, independently of the VP mutation. Gardner's syndrome or familial adenomatous polyposis (FAP) is also an autosomal dominantly inherited genodermatosis, and typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. The specific gene on chromosome 5 that is the site of the mutation in this disorder is known as APC (adenomatous polyposis coli), and the gene has been genetically linked to the region of 5q22.

Pancreatic exocrine dysfunction associated with mitochondrial tRNA(Leu)(UUR) mutation.

Year 1998
Onishi H. Hanihara T. Sugiyama N. Kawanishi C. Iseki E. Maruyama Y. Yamada Y. Kosaka K. Yagishita S. Sekihara H. Satoh S.
Department of Psychiatry, Yokohama City University School of Medicine, Kanagawa, Japan.
We report on pancreatic exocrine dysfunction in families that have the mitochondrial tRNA(Leu)(UUR) gene mutation. These families exhibited maternally inherited diabetes mellitus (DM) and an A to G substitution at nt 3243 of the mitochondrial tRNA(Leu)(UUR) gene (A3243G mutation). Pancreatic necropsy samples from one proband showed accumulation of degenerated mitochondria in pancreatic acinar cells. Pancreatic exocrine dysfunction was recognised by a functional pancreatic study. This study indicates that exocrine pancreatic dysfunction may be associated with the A3243G mutation.

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