A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.

Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome.

Efficacy of Collagen Particles in Chronic Non Healing Ulcers.

INTRODUCTION: Chronic foot ulcers will lead to a significant and prolonged stress to the patients. Pain and discomfort that may be acute or continuous is the usual complaint in chronic non healing ulcers that may even exacerbate with change of the dressings. The end process in any wound healing is wound contracture and scar formation. Collagen plays an important role in this stage of wound healing. Collagen particles were used in chronic non healing ulcer management to prove their efficacy when compared with conventional dressing in a study conducted by us. OBJECTIVE: To compare the healing process in non healing ulcers using collagen particles with those of conventional method of dressing (betadine). MATERIALS AND METHODS: It was a non randomized, prospective study conducted for a period of October 2012 to October 2014 in hospitals belonging to Kasturba medical college. Non concurrent pre and post comparative study; between collagen group and conventional dressing group. A total of 110 patients with chronic ulcers were included; each group comprising 55 patients. RESULTS: There was a significant decrease in wound size with a mean difference of 37.29 in experimental group when compared to 14.29 in control group. CONCLUSION: Collagen dressing is effective in management of chronic non healing ulcers when compared to conventional betadine dressing. It heals by forming an early granulation tissue and thus reducing the length of hospital stay.

Update on Kleefstra Syndrome.

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

Cutaneous mucormycosis with necrotising fasciitis in a young immunocompetent individual.

Primary cutaneous mucormycosis is uncommon and is extremely rare in immunocompetent young individuals. Here we report a case of necrotising fasciitis due to mucormycosis in an immunocompetent young individual following minor trauma. Mucormycosis must be suspected in any wound that is worsening despite appropriate treatment even in immunocompetent individuals.

Sixteen New Cases Contributing to the Characterization of Patients with Distal 22q11.2 Microduplications.

The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E-H) to the commonly deleted/duplicated region. To date, 21 index cases with 'distal' 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit 'digenic' model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.

Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study.

PURPOSE: To determine the influence of epilepsy and its treatment on pregnancy and its outcome. DESIGN: Controlled, observational study. SETTING: National Health Service maternity hospitals in Liverpool and Manchester regions. POPULATION: 277 women with epilepsy (WWE) and 315 control women. METHODS: WWE were recruited from antenatal clinics. Controls were matched for age and parity but not gestational age. Information was obtained by interview and from clinical records. MAIN OUTCOME MEASURES: Obstetric complications, mode of delivery, condition of newborn. RESULTS: Distribution of epilepsy syndromes was similar to previous surveys. Most WWE (67%) received monotherapy with carbamazepine, sodium valproate or lamotrigine. Half WWE had no seizures during pregnancy but 34% had tonic clonic seizures. Seizure-related injuries were infrequent. Pregnancies with obstetric complications were increased in women with treated epilepsy (WWTE 45%, controls 33%; p=0.01). Most had normal vaginal delivery (WWTE 63%, controls 61%; p=0.65). Low birth weight was not increased (WWTE 6.2%, controls 5.2%; p=0.69). There were more major congenital malformations (MCM) (WWTE 6.6%, controls 2.1%; p=0.02) and fetal/infant deaths (WWTE 2.2%, controls 0.3%; p=0.09). Amongst monotherapies MCM prevalence was highest with valproate (11.3%; p=0.005). Lamotrigine (5.4%; p=0.23) and carbamazepine (3.0%; p=0.65) were closer to controls (2.1%). There was no association between MCM and dose of folic acid pre-conception. CONCLUSION: MCM were more prevalent in the babies of WWTE particularly amongst those receiving sodium valproate.

The behavioral consequences of exposure to antiepileptic drugs in utero.

The aim of the study was to examine the behavior of 242 children, aged between 6 and 16 years, born to mothers with epilepsy. Exposure to sodium valproate (VPA) in utero was associated with high levels of parental stress induced by the child's maladaptive behavior. These children were also poorer for daily living skills and skills relating to socialization. The outcomes on both measures were strongly affected by the Full Scale IQ (FSIQ) of the child; however, no significant differences were found between the groups and therefore this pattern of results cannot simply be attributed to a lower FSIQ. The results of this study suggest that exposure to VPA in utero and the presence of a lowered FSIQ are risk factors for the development of poorer adaptive behavior and a higher rate of maladaptive behaviors.

Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes.

BACKGROUND: In utero exposure to antiepileptic drugs (AEDs) can result in several different teratogenic effects including major malformations, dysmorphic facial features, and learning and behavioural problems. It is estimated that there is a 2-3-fold increase in the risk of malformations compared with the general population. The risk of cognitive impairment and behavioural problems is less clear. OBJECTIVE: To report the frequency and specificity of individual dysmorphic features and to relate the dysmorphic facial phenotype to developmental outcome. METHODS: A retrospective study of 375 children born to 219 mothers with epilepsy. The age of the study group ranged from 6 months to 16 years. Each child underwent a physical examination and a battery of neuropsychological tests. Dysmorphic features were scored from photographs on a blind basis by a panel of dysmorphologists. RESULTS: A total of 274 children were exposed to AEDs (63 to valproate, 94 to carbamazepine, 26 to phenytoin, 15 to other monotherapies, and 76 to polytherapy). Major malformations were identified in 14% of children exposed to valproate in utero, 5% exposed to carbamazepine, and 4% in the non-exposed group. Overall, 47% of exposed children were correctly identified as having been exposed to AEDs in utero. There was a significant correlation between verbal intelligence quotient and dysmorphic facial features in the valproate exposed children only. CONCLUSION: Children exposed to valproate have more distinctive facial features, but a subtle and distinctive facial phenotype is also seen in children exposed to carbamazepine. Nearly half (45%) of unexposed children had some of the facial features associated with AED exposure, showing that many of these features may be seen as part of normal variation and that the diagnosis of the fetal anticonvulsant syndrome is difficult to make on the basis of facial gestalt alone. Developmental surveillance should be offered to children with prenatal exposure to AEDs, particularly those with exposure to high doses of valproate.

Neuropsychological effects of exposure to anticonvulsant medication in utero.

OBJECTIVE: To investigate the long-term differential drug effects on cognitive functioning in school-aged children exposed to antiepileptic drugs (AEDs) in utero. METHODS: Mothers with epilepsy were recruited from specialist epilepsy clinics and obstetric clinics from the Liverpool and Manchester region. The mothers and their children were recruited without prior knowledge of their AED treatment during pregnancy or the health of the offspring. A battery of neuropsychological tests was applied to each mother-child pair in order to obtain a neuropsychological profile for each child. RESULTS: Neuropsychological investigation was performed on 249 children between the ages of 6 and 16. Children exposed to sodium valproate had a significantly lower verbal IQ when compared to children exposed to other antiepileptic drugs or not exposed at all. The same children were more likely to have an IQ below 69 and more likely to have memory impairment when compared to the other groups. The mothers' IQ, exposure to sodium valproate, and the number of tonic-clonic seizures during pregnancy were significant predictors of verbal IQ in this population. CONCLUSIONS: This retrospective study highlights the potential harmful effects of sodium valproate exposure in utero on neuropsychological development.

The longer term outcome of children born to mothers with epilepsy.

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.

Angioleiomyoma in the tonsil: an uncommon tumour in a rare site.

An angioleiomyoma was excised from the palatine tonsil in a 30-year-old woman who complained of a painless swelling in the region of the tonsil. The mucosa covering the lesion showed prominent dilated blood vessels, necessitating vascular laboratory investigations to exclude any possibility of an aneurysm arising from the carotid system. The mass was excised with little blood loss. This was an uncommon tumour in an unusual site and required radio-imaging and angiographic studies of the great vessels of the head and neck before any operation was attempted. To the best of our knowledge, this is the first case reported in English.

Rhinosporidiosis of the parotid duct cyst: cytomorphological diagnosis of an unusual extranasal presentation.

This cytology report highlights a case of rhinosporidiosis of the parotid duct cyst not associated with nasal manifestations. In an endemic area, one should be familiar with its morphologic features in fine-needle aspiration cytology even on scanty material, for it could be one of the investigations in the initial workup of a case.

Hirschsprung's disease, associated rare congenital anomalies.

OBJECTIVE: Hirschsprung's disease may be associated with a number of congenital anomalies of which Down's syndrome and intestinal atresias are commonly encountered. The study aimed to assess the impact of rare associated anomalies on the diagnosis and management of Hirschsprung's disease. METHODS: A retrospective review of the clinical presentation, diagnosis and outcome of thirty five consecutive newly diagnosed cases of Hirschsprung's disease encountered over two years was performed. RESULTS: Besides Down's syndrome (two), intestinal atresia (one) and pigmentary ocular defects (two), three rare anomalies (Occipital meningocele, Calcific meconium cyst with anal stenosis, Malrotation) were encountered in four of thirty five cases. The clinical features, radiologic anatomy and gross morphology of the bowel were unconventional and the diagnosis was supported by intraoperative acetylcholinesterase staining of biopsies. Though the diagnosis was relatively delayed in these cases, the outcome has been comparable to the rest. The dilemma in their diagnosis and management and their possible pathoembryology is discussed. CONCLUSION: Awareness of such associations and a specific investigative protocol is imperative for timely diagnosis and minimal morbidity in complex presentations of Hirschsprung's disease.

Neural hypertrophy in carcinoma stomach.

Neural hypertrophy with hyperplastic Schwann cells in the wall of the stomach along with enterochromaffin cell hyperplasia was incidentally observed at histology in the gastrectomy specimen of a 43-year-old man with carcinoma stomach who had presented with upper abdominal pain of one year duration. The patient had no previous abdominal surgery or evidence of gastrointestinal obstructive pathology. The significance of this neural hypertrophy is not known.