A new case of Myhre syndrome.

Myhre Syndrome is a rare condition associated with mental retardation, short stature, generalized muscle hypertrophy, cardiac defects and a distinct facial appearance. There have only been five reported cases and we now present a sixth, together with a review of the clinical features of this syndrome.

A case of Acro-renal-mandibular syndrome in an 18 week male fetus.

An 18 week male fetus is described with Acro-renal-mandibular syndrome. This third reported case of the syndrome is the first known male case and extends the phenotypic spectrum that characterizes the condition.

Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen.

Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.

Autosomal dominant spastic paraplegia: refined SPG8 locus and additional genetic heterogeneity.

OBJECTIVE: To map the gene responsible for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) in a large affected family. BACKGROUND: Autosomal dominant pure hereditary spastic paraplegia (ADPHSP) is genetically heterogeneous, and loci have been mapped at chromosomes 2p (SPG4), 14q (SPG3), 15q (SPG6), and recently, in a single family, at chromosome 8q24 (SPG8). METHODS: The authors carried out a genomewide linkage screen on a large family with ADPHSP, for which linkage to the chromosome 2, 14, and 15 loci was excluded. RESULTS: Analysis of markers on chromosome 8q24 gave a peak two-point lod score of 4.49 at marker D8S1799. Analysis of recombination events in this family and in the previously published SPG8-linked family narrowed the SPG8 locus from 6.2 cM to a 3.4-cM region between markers D8S1804 and D8S1179. In another four families, linkage to all four known ADPHSP loci was excluded. The SPG8-linked family had a significantly older mean age at onset of symptoms and had significantly more wheelchair-using patients than the four linkage-excluded families. CONCLUSIONS: These results contain the presence of an autosomal dominant pure hereditary spastic paraplegia (ADPHSP) locus at chromosome 8q24 and strongly suggest that there are at least five ADPHSP loci. The data provide additional evidence for locus-phenotype correlations in ADPHSP.

Towards earlier diagnosis of 22q11 deletions.

Over a 7 year period, 551 patients were investigated for the presence of a chromosome 22q11 deletion by fluorescence in situ hybridisation. Analysis of the presenting features of the 67 individuals with this chromosome deletion permitted us to devise guidelines to facilitate early diagnosis.

Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity.

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.

Paternal uniparental disomy for chromosome 6 causes transient neonatal diabetes.

We report an infant with intrauterine growth retardation and transient neonatal diabetes who has paternal uniparental disomy for chromosome 6. The infant was not dysmorphic and had no congenital anomalies. To our knowledge, this is the third case of paternal uniparental disomy occurring in an infant with transient neonatal diabetes, thus confirming the association.

Aetiopathology and genetic basis of neonatal diabetes.

A British Paediatric Association Surveillance Unit* study of neonatal diabetes determined a national incidence of 1 in 400,000 live births. Additional cases of transient neonatal diabetes were collected retrospectively. Most cases were of low birthweight at term: none had evidence of an autoimmune aetiopathogenesis. The median requirement for exogenous insulin treatment was three months. A significant number of cases developed type 2 diabetes in later life. Three of the 11 cases were found to have paternal uniparental isodisomy of chromosome 6. A further patient carried an unbalanced duplication of 6q 22-23, inherited from the father, which localised a potentially imprinted gene for diabetes to this region. The fact that low birthweight predisposes to type 2 diabetes in later life is well established, but a genetic defect that may relate both to intrauterine growth failure and the development of type 2 diabetes in later life has now been identified.

Holoprosencephaly in the west of Scotland 1975-1994.

Cases of holoprosencephaly which occurred in the west of Scotland over the past 20 years were ascertained from genetics, paediatric, and pathology department records. Fifty cases were identified of which 17 had an underlying cytogenetic abnormality. Of the remaining 33 cases, 26 were delivered after 28 weeks' gestation giving a birth prevalence of 1 in 26730. Twenty-one babies were liveborn and nine children are currently alive. All survivors are profoundly mentally retarded and most have seizures. Twenty-eight patients with non-chromosomal holoprosencephaly had a total of 23 sibs and three families were identified where there was either recurrence of holoprosencephaly (one family), a related cerebral malformation (one family), or mental handicap (one family) giving an overall recurrence risk for serious neurological disability of 12% (standard error 7%). We conclude that holoprosencephaly does not necessarily breed true and this observation should be taken into account when giving genetic counselling and attempting ultrasound prenatal diagnosis after the birth of an affected child.

Outcome of Burkholderia (Pseudomonas) cepacia colonisation in children with cystic fibrosis following a hospital outbreak.

BACKGROUND: While there are reports on the outcome in adults and teenagers with cystic fibrosis of colonisation with Burkholderia (Pseudomonas) cepacia, there is little information in children. METHODS: In December 1991 only one of 115 children with cystic fibrosis attending a paediatric centre was colonised with B cepacia. Over the next 12 months there was a rapid increase with 23 (20%) becoming colonised; eighteen (79%) of these became colonised in hospital at a time that overlapped with the admission of a B cepacia positive child. Three different bacteriocin types were isolated, with one type (S22/PO) being present in 17 (74%) patients. The outcome for children who became colonised with B cepacia was compared with that in 33 children who continued to be colonised with Pseudomonas aeruginosa alone. RESULTS: Children colonised with B cepacia were older and more poorly nourished than those colonised with P aeruginosa, but did not have poorer pulmonary function. After colonisation, the forced expiratory volume in one second (FEV1) deteriorated between consecutive annual tests, with the average deterioration being greater in those with higher initial levels. Five children with B cepacia died from respiratory failure although none showed a fulminant deterioration. Introduction of segregation measures within hospital led to a dramatic decrease in the number of newly colonised patients. CONCLUSIONS: This study provides further evidence for person-to-person spread of B cepacia and confirms the effectiveness of simple isolation measures in interrupting spread. Colonisation with B cepacia and P aeruginosa in children is associated with a more rapid decline in lung function and a significantly increased mortality compared with cases colonised with P aeruginosa alone.

Uniparental isodisomy for chromosome 16 in a growth-retarded infant with congenital heart disease.

We report a growth-retarded infant with congenital heart disease and maternal isodisomy for chromosome 16. Non-mosaic trisomy 16 was detected at mid-trimester chorionic villus sampling, performed because biochemical screening indicated an increased Down's syndrome risk. Further karyotyping analysis of the placenta, after delivery, showed a 50 per cent mosaic trisomy 16. The infant had an atrioventricular (A-V) canal defect, scoliosis, and several minor dysmorphic features. Although uniparental disomy for chromosome 16 has been reported previously, to our knowledge this is the first case of uniparental isodisomy for chromosome 16 which has been investigated with multiple DNA probes.

The regulation of membrane 125I- and 86Rb+ permeability in a virally transformed cell line (NCL-SG3) derived from the human sweat gland epithelium.

We have explored the factors that may regulate membrane permeability in a cell line (NCL-SG3) derived from the human sweat gland epithelium. Ionomycin increased the rate of 125I-efflux from preloaded cells and this action appeared to be due to an increase in intracellular free calcium ([Ca2+]i). The ionomycin-evoked increase in 125I- efflux was reduced in cells that were exposed either to barium or to valinomycin in the presence of a high concentration of external potassium. It thus appears that a fraction of the ionomycin-evoked increase in 125I- efflux is due to the activation of potassium channels and experiments using 86Rb+ also suggested that ionomycin increased the rate of potassium efflux, an effect which was totally abolished by barium. Blockade of Na(+)-K(+)-2Cl- cotransport and of Cl- -HCO3- exchange reduced the basal rate of 125I- efflux and the ionomycin-evoked increase in 125I-efflux from control cells and from cells depolarized by valinomycin. These transport systems thus contribute to anion efflux, although [Ca2+]i-dependent chloride channels also appear to be present. Acetylcholine increases [Ca2+]i in the secretory cells of human sweat glands, but this neurotransmitter did not increase [Ca2+]i in NCL-SG3 cells and so membrane permeability was not under cholinergic control. Adrenaline did not increase [Ca2+]i, but this hormone did evoke cyclic-3',5'-adenosine monophosphate (cyclic AMP) production. However, membrane permeability was not under adrenergic control, as the cells did not appear to express functional, cyclic AMP-dependent anion channels. This may be because they were not fully differentiated under the culture conditions. ATP consistently evoked a dose-dependent increase in anion efflux that appeared to be mediated by [Ca2+]i. The increase in [Ca2+]i was initiated by the release of calcium from a limited internal store and was subsequently sustained by calcium influx. UTP and ADP also increased [Ca2+]i, whereas adenosine, AMP and alpha,beta-methylene ATP were without effect. These data thus suggest that a subclass of type 2 purine receptor, which is functionally coupled to phosphoinositidase C, is present in these cells.