MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Exceptional manifestation of Madelung's disease after liver transplantation.

Unlike simple obesity, Madelung's disease (MD) is a rare disease characterized by symmetric accumulation of massive adipose tissue on the neck, the superior part of the trunk and limbs, leading to a pathognomonic cosmetic deformity. Here, we report an extremely rare case of MD associated with bilateral gynecomastia in a 61-year-old man, with a history of recent liver transplantation for alcoholic liver disease (ALD).

Cerebral cavernous malformation: new molecular and clinical insights.

Cerebral cavernous malformation (CCM) is a vascular malformation causing neurological problems, such as headaches, seizures, focal neurological deficits, and cerebral haemorrhages. CCMs can occur sporadically or as an autosomal dominant condition with variable expression and incomplete penetrance. Familial forms have been linked to three chromosomal loci, and loss of function mutations have been identified in the KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3 genes. Recently, many new pieces of data have been added to the CCM puzzle. It has been shown that the three CCM genes are expressed in neurones rather than in blood vessels. The interaction between CCM1 and CCM2, which was expected on the basis of their structure, has also been proven, suggesting a common functional pathway. Finally, in a large series of KRIT1 mutation carriers, clinical and neuroradiological features have been characterised. These data should lead to more appropriate follow up, treatment, and genetic counselling. The recent developments will also help to elucidate the precise pathogenic mechanisms leading to CCM, contributing to a better understanding of normal and pathological angiogenesis and to the development of targeted treatment.

Orofacial clefting: update on the role of genetics.

INTRODUCTION: Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects in the world. Prevalence varies between populations, with an average of 1/700. CL/P has a major clinical impact, requiring surgical, dental, orthodontic, speech, hearing and psychological management throughout childhood. The aetiology of CL/P is mostly unknown, and it is thought that both genetic and environmental factors play a role. Several causative genes for inherited syndromic forms of CL/P have been identified, and some recent studies have shown that these genes also contribute to the occurrence of isolated forms. Van der Woude syndrome (VWS) is one of the best models for non-syndromic CLP. It is an autosomal dominant disorder characterised by the presence of pits on the lower lip in addition to CL/P. Pits are the only feature distinguishing VWS from isolated clefts. Interestingly, in numerous VWS patients, the lip pits are very small and not readily diagnosed, thus mimicking isolated CL/P. Mutations in the IRF6 gene were shown to be the major genetic cause of VWS.' RESULTS: We performed direct sequence analysis of IRF6 on samples from a large European cohort and identified mutations in 27 (80%) families. This shows that IRF6 is the major causative gene of VWS in Europe also. Moreover, it is the gene to study when a seemingly isolated CL/P patient has minor signs, such as lip pits, since the identification of a mutation in IRF6 is associated with an increase in the risk of having a child with CL/P from 4-6%, the risk of transmission of an isolated cleft, to 50%, the risk of transmission of a dominant Mendelian disorder like VWS. Moreover, we studied the association of isolated CL/P with the IRF6 locus using two variants in a set of 195 patients from Belgium. As in an American study, a clear association was observed. This suggests that IRF6 also contributes to the occurrence of sporadic, isolated CL/P, even if no mutation in the gene can be identified in such patients. CONCLUSION: In conclusion, genes that are mutated in familial syndromic forms of CL/P may be predisposing genetic factors to sporadic isolated CL/P. Due to technological advances and the availability of the human genome sequence, we have now the opportunity to try and unravel the genetic factors behind the various forms of CL/P.

[Multiple bladder diverticula caused by occipital horn syndrome]. / Diverticulose vésicale liée à un syndrome de la corne occipitale.

We report on the case of a child who presented with recurrent, multiple, and voluminous bladder diverticula. Bladder diverticula are defined as a herniation of the mucosa through the bladder muscle or the detrusor. Causes are numerous and diverticula can be classified into primary congenital diverticula (para-ureteral - or Hutch diverticula - and posterolateral diverticula); secondary diverticula (resulting from chronic mechanical obstruction or from neurological disease; and diverticula secondary to connective tissue or muscle fragility. The latter is seen in disease entities such as prune belly syndrome, Ehlers-Danlos syndrome, cutis laxa syndrome, OHS (occipital horn syndrome), Menkes disease, and Williams-Beuren syndrome. In this patient, the cause of these diverticula was OHS, a genetic, recessive X-chromosome-linked syndrome, responsible for abnormal tissue caused by a disorder in copper metabolism. This case reminds us of the importance of pushing the diagnostic workup when presented with multiple and/or large bladder diverticula, and in particular to search for rare malformation syndromes after exclusion of an obstacle.

Genotypes and phenotypes of 162 families with a glomulin mutation.

A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling.

Germline Mutations in RASA1 Are Not Found in Patients with Klippel-Trenaunay Syndrome or Capillary Malformation with Limb Overgrowth.

The RASA1 gene encodes p120RASGAP, a multidomain cytoplasmic protein that acts as a negative regulator of the RAS signalling pathway. Heterozygous loss-of-function RASA1 mutations were identified in patients with Parkes Weber syndrome and multifocal capillary malformations. This syndrome is characterised by a capillary blush on an extremity, arteriovenous microfistulas, and bony and soft tissue hypertrophy. The aim of this study was to test RASA1 in 2 disorders characterised by asymmetric limb enlargement and vascular malformations, namely Klippel-Trenaunay syndrome and regional capillary malformation with overgrowth. We did not identify any clear pathogenic change in these patients. Thus, besides clinical and radiological criteria, RASA1 testing constitutes an additional tool to differentiate Parkes Weber syndrome of capillary malformation-arteriovenous malformation (CM-AVM) from overlapping disorders.