Two patients with chromosome 22q11.2 deletion presenting with childhood obesity and hyperphagia.

Chromosome 22q11.2 deletion syndrome is a clinically heterogeneous condition of intellectual disability, parathyroid and thyroid hypoplasia, palatal abnormalities, cardiac malformations and psychiatric symptoms. Hyperphagia and childhood obesity is widely reported in Prader-Willi Syndrome (PWS) but there is only one previous report of this presentation in chromosome 22q11.2 deletion syndrome. We describe two further cases of chromosome 22q11.2 deletion syndrome in which hyperphagia and childhood obesity were the presenting features. This may be a manifestation of obsessive behaviour secondary to some of the psychiatric features commonly seen in chromosome 22q11.2 deletion syndrome. Serious complications may result from hyperphagia and childhood obesity therefore early recognition and intervention is crucial. Due to the similar clinical presentation of these two patients to patients with PWS, it is suggested that the hyperphagia seen here should be managed in a similar way to how it is managed in PWS.

MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome.

Kabuki syndrome (KS) is a rare multi-system disorder that can result in a variety of congenital malformations, typical dysmorphism and variable learning disability. It is caused by MLL2 point mutations in the majority of the cases and, rarely by deletions involving KDM6A. Nearly one third of cases remain unsolved. Here, we expand the known genetic basis of KS by presenting five typical patients with the condition, all of whom have novel MLL2 mutation types- two patients with mosaic small deletions, one with a mosaic whole-gene deletion, one with a multi-exon deletion and one with an intragenic multi-exon duplication. We recommend MLL2 dosage studies for all patients with typical KS, where traditional Sanger sequencing fails to identify mutations. The prevalence of such MLL2 mutations in KS may be comparable with deletions involving KDM6A. These findings may be helpful in understanding the mutational mechanism of MLL2 and the disease mechanism of KS.

Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q.

CONTEXT: Pseudohypoparathyroidism type 1b (PHP1b) is the result of end-organ resistance to PTH and other hormones such as TSH in the absence of any features of Albright's hereditary osteodystrophy. Patients with PHP1b show imprinting abnormalities at the complex GNAS locus. The molecular cause of autosomal dominant familial PHP1b has been well-defined with identification of microdeletions within the GNAS locus or the nearby STX16, but the molecular mechanism of the GNAS imprinting defects in sporadic PHP1b cases remains elusive. OBJECTIVE: We investigated the underlying molecular mechanism of GNAS imprinting defects in two patients with sporadic PHP1b. RESULTS: We identified paternal uniparental disomy of the long arm of chromosome 20 (patUPD20) in two unrelated patients with sporadic PHP1b. This provides an explanation for the patients' GNAS methylation abnormalities and hormone resistance. Our data and a review of the six published cases of patUPD20 suggest that high birth weight and/or early-onset obesity and macrocephaly may also represent features of patUPD20. CONCLUSION: We suggest that patUPD20 should be considered in the evaluation of patients with sporadic PHP1b.

Long-term outcome of Cavalier King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia.

The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (±14.3) months from diagnosis. At the end of the study, 36 dogs were still alive; five dogs died of an unrelated or unknown cause, and seven were euthanased due to severe clinical signs suggestive of NeP. During the follow-up period, the clinical signs of scratching, facial rubbing behaviour, vocalisation and exercise ability were evaluated. Nine out of 48 dogs stopped scratching (P<0.001), but there was no statistically significant change in the number of dogs exhibiting exercise intolerance, vocalisation or facial rubbing behaviour. The overall severity of clinical signs based on a visual analogue scale (VAS) (0 mm: no clinical signs 100 mm: severe clinical signs) increased (from median 75 mm (interquartile ranges (IQR) 68-84) to 84 mm (IQR 71.5-91), P<0.001). A quarter of the dogs were static or improved. In general, the majority of the owners felt that the quality of life of their dogs was acceptable. Medical treatments received were gabapentin or pregabalin and/or intermittently, carprofen. The owner's perception of their animal's progress, and progress based on VAS, had strong positive correlation (Spearman's rank correlation (s(r)) 0.74, P<0.001). Overall, this study suggests that clinical signs suggestive of NeP progress in three-quarters of CKCSs with CM and/or SM.

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling.

3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls. Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells. The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8. The GH-IGF axis evaluation could reflect a degree of GH resistance and/or IGF1 resistance. This is consistent with the signalling data in which the CUL7(-/-) cells showed impaired IGF1 signalling, CCDC8(-/-) cells showed impaired GH signalling and the OBSL1(-/-) cells showed impairment in both pathways. Dysregulation of the GH-IGF-IGF binding protein axis is a feature of 3-M syndrome.

Deletions in the VPS13B (COH1) gene as a cause of Cohen syndrome.

Cohen syndrome is an autosomal recessive disorder that is characterized by mental retardation, facial dysmorphism, microcephaly, retinal dystrophy, truncal obesity, joint laxity and intermittent neutropenia. Mutations in the VPS13B (COH1) gene underlie Cohen syndrome. In approximately 70% of the patients mutations in the gene are identified on both alleles, while in about 30% only a mutation in a single allele or no mutant allele is detected. The VPS13B locus was recently added to the growing list of benign copy number variants. We hypothesized that patients with unexplained Cohen syndrome would harbour deletions affecting the VPS13B locus. We screened 35 patients from 26 families with targeted array CGH and identified 7 copy number alterations: 2 homozygous and 5 heterozygous deletions. Our results show that deletions are an important cause of Cohen syndrome and screening for copy number alterations of VPS13B should be an integral part of the diagnostic work-up of these patients. These findings have important consequences for the diagnosis of patients with genetic disorders in general since, as we highlight, rare benign copy number variants can underly autosomal recessive disorders and lead to disease in homozygous state or in compound heterozygosity with another mutation.

Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models.

Repressor element-1 silencing transcription factor (REST) is a candidate modulator of gene expression during status epilepticus in the rodent. In such models, full-length REST and the truncated REST4 variant are induced and can potentially direct differential gene expression patterns. We have addressed the regulation of these REST variants in rodent hippocampal seizure models and correlated this with expression of the proconvulsant, substance P encoding, PPT-A gene. REST and REST4 were differentially regulated following kainic acid stimulus both in in vitro and in vivo models. REST4 was more tightly regulated than REST in both models and its transient expression correlated with that of the differential regulation of PPT-A. Consistent with this, overexpression of a truncated REST protein (HZ4, lacking the C-terminal repression domain) increased expression of the endogenous PPT-A gene. Similarly the proximal PPT-A promoter reporter gene construct was differentially regulated by the distinct REST isoforms in hippocampal cells with HZ4 being the major inducer of increased reporter expression. Furthermore, REST and REST4 proteins were differentially expressed and compartmentalized within rat hippocampal cells in vitro following noxious stimuli. This differential localization of the REST isoforms was confirmed in the CA1 region following perforant path and kainic acid induction of status epilepticus in vivo. We propose that the interplay between REST and REST4 alter the expression of proconvulsant genes, as exemplified by the PPT-A gene, and may therefore regulate the progression of epileptogenesis.

Leucodysplasia, microcephaly, cerebral malformation (LMC): a novel recessive disorder linked to 2p16.

We report three related and one unrelated child with an apparently novel neurodevelopmental disorder. The clinical course was very similar in all the four patients: congenital microcephaly with severe failure of post-natal brain growth, neonatal onset of intractable seizures associated with lack of developmental progression and death within the first 3 years of life. The appearance on cerebral neuroimaging was almost identical, with simplified gyration associated with a non-thickened cortex, severe hypoplasia of the corpus callosum, a small flattened brain stem, and specific cystic lesions in the white matter around the temporal and occipital horns. To our knowledge these patients represent a previously unreported, autosomal recessive syndrome. Homozygosity mapping in the consanguineous family has identified a candidate region on the chromosome 2p16.

Neuropsychological assessment of a group of UK patients with Cohen syndrome.

Cohen syndrome is a rare autosomal recessive syndrome with a distinctive clinical phenotype that includes mental retardation and a characteristic sociable disposition. Variability in the level of learning disability and the behavioural phenotype is seen in the published literature. In a cohort of Finnish Cohen syndrome patients, severe mental retardation and non-maladaptive behaviour were described. Outside of Finland, autistic-spectrum behaviour has been reported in a few isolated Cohen syndrome patients but in a recent UK study was found to be highly prevalent. We report the results of neuropsychological studies in a group of 16 genetically heterogeneous patients, all with the characteristic clinical features of Cohen syndrome. Of the 9 patients who underwent formal neuropsychological testing, all but one was functioning in the severely mentally impaired range. Of the remaining patients, 3 were below the age of formal testing and 4 had such profound learning and behavioural problems that they were deemed unable to participate in testing. Mild maladaptive behaviour was observed in 13 patients and 3 were documented as having significant maladaptive behaviour. In contrast to the Finnish group of Cohen syndrome patients, this UK study identifies significant neuropsychological impairment combined with maladaptive behaviour as a characteristic of Cohen syndrome. Although autistic-type behaviour was observed, an increased prevalence of autism in Cohen syndrome was not confirmed.

Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome.

Cohen syndrome is a rare, recessively inherited condition associated with facial dysmorphism, developmental delay, and visual disability. A delay in making the diagnosis commonly occurs, contributed to by the lack of a definitive molecular test and the clinical variability of published case reports. A specific clinical phenotype has been delineated in a homogeneous cohort of Finnish Cohen syndrome patients, but the applicability of their diagnostic criteria to non-Finnish patients has been debated. Detailed delineation of Cohen syndrome in patients from outside Finland is therefore warranted. We report on the clinical features of 33 non-Finnish Cohen syndrome patients. Variability within the clinical spectrum is identified and the natural history of Cohen syndrome described. Diagnostic guidelines for facilitating accurate and early diagnosis are discussed. Results from molecular genetic analysis using markers located within the previously mapped COH1 critical region support allelic but not genetic heterogeneity in this UK cohort.

The ophthalmic findings in Cohen syndrome.

AIM: Cohen syndrome is an uncommon autosomal recessive condition comprising a characteristic facial appearance, mental retardation, benign neutropenia, and retinal dystrophy. This study aimed to identify patients with Cohen syndrome from across the United Kingdom in order to define the variability of ophthalmic manifestations. METHODS: Ophthalmic assessment was undertaken and past ophthalmic records reviewed in 22 patients with classic features of Cohen syndrome. RESULTS: All patients had visual problems which commonly started in the preschool years. 82% developed strabismus or refractive error during the first 5 years of life. 70% developed high myopia by the second decade. By contrast with the findings of others, early onset retinal dystrophy was common, occurring in 80% of study patients under age 5 years. 35% of patients were registered partially sighted or blind. CONCLUSION: The ophthalmic abnormalities associated with Cohen syndrome, including high myopia and a generalised, severe retinal dystrophy, are of early onset and frequently result in severe visual handicap. Cohen syndrome should be considered in the young, developmentally delayed child who presents with severe myopia and nyctalopia.

Age and causes of death in adult-onset myotonic dystrophy.

Myotonic dystrophy is a relatively common type of muscular dystrophy, associated with a variety of systemic complications. Long term follow-up is difficult because of the slow progression. The objective of this study was to determine survival, age at death and causes of death in patients with the adult-onset type of myotonic dystrophy. A register of myotonic dystrophy patients was set up in Southern Limburg (the Netherlands), using data longitudinally collected over a 47-year period (1950-97). Survival for 180 patients (from the register) with adult-onset type myotonic dystrophy was established by the Kaplan-Meier method. The median survival was 60 years for males and 59 years for females. Survival of the patients was also estimated from the age of 15 years to the ages of 25, 45 and 65 years and compared with the expected survival of age- and sex-matched birth cohorts from the normal Dutch population. The observed survival to the ages of 25, 45 and 65 years was 99%, 88% and 18% compared with an expected survival of 99%, 95% and 78%, respectively. Thus, survival to the age of 65 in patients with adult-onset myotonic dystrophy is markedly reduced. A weak positive correlation between the CTG repeat length and younger age at death was found in the 13 patients studied (r = 0.50, P = 0.08). The cause of death could be determined in 70 of the 83 deceased patients. Pneumonia and cardiac arrhythmias were the most frequent primary causes of death, each occurring in approximately 30%, which was far more than expected for the general Dutch population. In addition, we assessed mobility in the years before death in a subgroup of 18 patients, as a reflection of the long-term physical handicap in myotonic dystrophy patients. Half of the patients studied were either partially or totally wheelchair-bound shortly before their death.

Severe feeding problems and congenital laryngostenosis in a patient with 3q23 deletion.

UNLABELLED: Common clinical features of patients with 3q23 deletion include the phenotype of BPES (blepharophimosis, ptosis, epicanthus inversus and telecanthus syndrome), growth and mental retardation, microcephaly ear and nose dysmorphism and joint and digit abnormalities. We report on a 3-year-old girl with the phenotype of BPES, mental retardation, facial dysmorphism and camptodactyly. In addition, she had a congenitally small larynx and severe, chronic feeding difficulties. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q23-q25). CONCLUSION: Congenital laryngostenosis and severe feeding problems may be part of the clinical syndrome caused by chromosome 3q23 deletion.

Laparoscopic cholecystectomy in biliary pancreatitis.

Laparoscopic cholecystectomy has emerged as the treatment of choice for uncomplicated cholelithiasis. Despite early concerns, many surgeons have applied this new technique to more complicated biliary tract disease states, including biliary pancreatitis. To evaluate the safety of laparoscopic cholecystectomy in this setting, we retrospectively reviewed 29 patients with clinical and laboratory evidence of biliary pancreatitis who underwent this procedure between March 1990 and December 1992. The severity of pancreatitis was determined by Ranson's criteria. Two patients had a Ranson's score of 6, one of 5, one of 4, five scored 3, nine scored 2, nine also scored 1, and two patients scored 0. The mean serum amylase level on admission was 1,610 (range 148 to 7680). All patients underwent laparoscopic cholecystectomy during the same hospital admission for biliary pancreatitis, with the mean time of operation being 5.5 days from admission. Operative time averaged 123 minutes (range 60-220 minutes). Intraoperative cholangiography was obtained in 76 per cent of patients. Three patients had choledocholithiasis on intraoperative cholangiography and were treated with choledochoscopy, laparoscopic common bile duct exploration, and saline flushing of the duct. The mean length of hospital stay was 11 days (range 5-32 days). There were seven postoperative complications requiring prolonged hospitalization with all but one treated non-operatively. One patient with a preoperative Ranson score of 6 developed necrotizing pancreatitis and subsequently required operative pancreatic debridement and drainage. There were no deaths in this series and no postoperative wound infections. The average recovery period for return to work was 2 weeks. These statistics compare favorably with literature reports for open cholecystectomy in biliary pancreatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Video thoracoscopic dorsal sympathectomy: a new approach.

With the recent popularization of video laparoscopic cholecystectomy comes a renewed interest in thoracoscopy and its clinical applications in intrathoracic disease. Successful video thoracoscopic dorsal sympathectomy was accomplished in a patient with causalgia of the right upper extremity with immediate and complete resolution of pain and vasomotor symptoms. Standard operative approaches to dorsal sympathectomy are technically difficult, having risks of major nerve injury and Horner's syndrome. Video thoracoscopic dorsal sympathectomy obviates these risks and should become the procedure of choice in the future.