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.

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.

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.

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.

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.

Noninvasive measurement of pulsatile blood volume changes. Its usefulness in peripheral vascular disease.

A clinical trial was made of a new noninvasive technic for the measurement of arterial blood volume changes in a limb segment. The instrument employed is small, portable, provides a digital display in cc/min, is readily calibrated, gives reproducible values of the segmental phen be used to screen patients with peripheral vascular disease and to assess postoperative results.

Ruptured submucosal gastric artery microaneurysm.

A patient with massive upper gastrointestinal hemorrhage from a ruptured submucosal gastric artery microaneurysm is described. Intraoperative diagnosis was made and wedge resection of the lesion resulted in survival of the patient. Forty-two cases in this entity have been reported in the literature, with nonoperative therapy being uniformly fatal; there were only four cases of successful surgical management. An increased awareness of this entity in cases of unexplained gastrointestinal hemorrhage is the key to diagnosis and successful management.

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)

Laparoscopic inguinal herniorrhaphy in a swine model. Third place winner of the Conrad Jobst Award in the Gold Medal paper competition.

A simplified method of laparoscopic inguinal herniorrhaphy using prosthetic materials was evaluated in a swine hernia model. The goals of this study were to determine 1) effectiveness of repair in a rapidly growing animal, 2) effectiveness and extent of adhesion formation of different prosthetic materials, 3) the effect of repair on testicular growth, and 4) histologic effects on the hernia site and surrounding structures. In a prospective randomized study, 30 juvenile male swine (average, 23 kg) with 35 congenital indirect inguinal hernias underwent laparoscopic herniorrhaphy using one of three prosthetic materials: Group 1 (polytetrafluoroethylene/Gore-Tex), N = 10; Group 2 (polypropylene mesh/Marlex), N = 10; Group 3 (polypropylene mesh/Prolene), N = 10. A standardized laparoscopic herniorrhaphy technique consisting of stapling prosthetic material over the hernia defect without peritoneal dissection was employed. During the 3-month postoperative period, animals were sequentially examined for normal growth and development, normal testicular development, and signs of hernia recurrence. Clinically apparent complications related to herniorrhaphy occurred in five animals (17%) during the observation period (one with repair failure, one with testicular torsion, two with repair failure and bowel obstruction, and one with intestinal obstruction secondary to adhesions). All three animals with bowel obstruction died. At 90 days after surgery all remaining animals (N = 27) were euthanized (Group 1 = 9, Group 2 = 8, Group 3 = 10). Average weight was 84 kg. Necropsy findings included no additional hernia recurrences, and one mesh erosion into the urinary bladder.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety, efficacy, cost, and morbidity of laparoscopic versus open cholecystectomy: a prospective analysis of 228 consecutive patients.

Laparoscopic cholecystectomy has become the procedure of choice in most hospitals for the resolution of surgically treatable gallbladder disease. Few reports address the results of laparoscopic cholecystectomy in comparison to open cholecystectomy during the same time interval within the same institution. One hundred ninety-six laparoscopic cholecystectomies were performed from April 1990 through February 1991. Initial patient selection was restricted to elective procedures for chronic cholecystitis with expanded indications as experience was gained. Of the 196 cases, 11 required conversion to open cholecystectomy, leaving 185 laparoscopic cholecystectomies for comparison. During the same period, 82 open cholecystectomies were performed. Thirty-nine of these were complicated cases and would not have been considered for laparoscopic cholecystectomy early in the study, leaving 43 routine open cholecystectomies for comparative purposes. In the laparoscopic group, 1.1 per cent of the patients had major operative complications as opposed to the open group, which had none. There were no common bile duct injuries in either group. To provide a true cost-benefit analysis, a group of patients was identified that would qualify for elective, same-day admission for either an open or laparoscopic procedure. Laparoscopic cholecystectomy (LC) was performed on 70 patients, and open cholecystectomy (OC) was performed on 26 patients. A comparison of data from these groups showed no significant difference in age or sex. Hospitalization costs averaged $5,390 for the LC group versus $5,392 for the OC group. Postoperative hospital stay averaged 1.3 days for the LC group versus 3.7 days for the OC group (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Laparoscopic hernia repair: a preliminary report.

Advances in laparoscopic technique have provided the opportunity to perform preperitoneal herniorrhaphy and potentially avoid the morbidity associated with open techniques. From January 1991 to May 1992, two primary surgeons repaired 63 inguinal hernias (42 indirect, 20 direct, 1 femoral) on 48 patients using a standardized laparoscopic technique. The hernia defect was visualized laparoscopically, and the peritoneum anterior to the defect was incised. The hernia sac was dissected from the inguinal canal. The hernia defect was then loosely packed with rolled 1 x 6-inch polypropylene mesh (average number of rolls used was 3.4). A sheet of polypropylene mesh (average 5 x 8 cm) was then placed over the mesh rolls and the hernia defect and anchored with an endostapler. The peritoneum was closed over the mesh sheet with standard laparoscopic clips. There were 44 males and 4 females in the study group. The mean age was 55 years (range, 17-89 years). The mean follow-up was 5.8 months (range, 1-12 months). Thirty-three patients underwent unilateral hernia repair, and 15 patients underwent bilateral hernia repair. Clinically unsuspected contralateral hernias were identified at the time of laparoscopy in seven patients. The mean duration of surgery was 118 minutes (range, 80-165 minutes) for bilateral hernia repair, and 70 minutes (range, 45-100 minutes) for unilateral hernia repair. All patients with laparoscopic hernia repairs were treated on a same-day or less-than-24-hour in-hospital stay. Complications were designated as minor, moderate, or severe. There were 14 minor complications, which included subcutaneous hematomas at the trocar site, scrotal ecchymosis, groin swelling emphysema, and testicular asymmetry.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.