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Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only. This article is protected by copyright.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion.METHODS: We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry.RESULTS: We defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys.CONCLUSIONS: Our results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.

ClC-7 is a chloride-proton antiporter of the CLC protein family. In complex with its accessory protein Ostm-1, ClC-7 localizes to lysosomes and to the osteoclasts' ruffled border, where it plays a critical role in acidifying the resorption lacuna during bone resorption. Gene inactivation in mice causes severe osteopetrosis, neurodegeneration, and lysosomal storage disease. Mutations in the human CLCN7 gene are associated with diverse forms of osteopetrosis. The functional evaluation of ClC-7 variants might be informative with respect to their pathogenicity, but the cellular localization of the protein hampers this analysis. Here we investigated the functional effects of 13 CLCN7 mutations identified in 13 new patients with severe or mild osteopetrosis and a known ADO2 mutation. We mapped the mutated amino acid residues in the homology model of ClC-7 protein, assessed the lysosomal colocalization of ClC-7 mutants and Ostm1 through confocal microscopy, and performed patch-clamp recordings on plasma-membrane-targeted mutant ClC-7. Finally, we analyzed these results together with the patients' clinical features and suggested a correlation between the lack of ClC-7/Ostm1 in lysosomes and severe neurodegeneration. © 2020 American Society for Bone and Mineral Research (ASBMR).

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

PurposeMowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221. ispartof: Genetics in Medicine vol:20 issue:9 pages:965-975 ispartof: location:United States status: published

5q11.2 Deletion is a very rare genomic disorder, and its clinical phenotype has not yet been characterized. This report describes a patient with an 8.6 Mb deletion, showing hypotonia, mild developmental delay, short stature, and distinctive dysmorphic features (frontal bossing, square face, deep-set eyes, prominent columella, long philtrum, thin lips). © 2016 Wiley Periodicals, Inc.

The Nuclear Factor I-X (NFIX) is a member of the nuclear factor I (NFI) protein family and is deleted or mutated in a subset of patients with a peculiar overgrowth condition resembling Sotos Syndrome as well as in patients with Marshall-Smith syndrome. We identified three additional patients with this phenotype each carrying a different new mutation affecting the DNA-binding/dimerization domain of the NFIX protein. The present report further adds weight to the hypothesis that mutations in DNA-binding/dimerization domain are likely to cause haploinsufficiency of the NFIX protein and confirms that NFIX is the second gene that should be tested in individuals with overgrowth conditions resembling Sotos syndrome, previously tested negative for NSD1 mutations. We then propose to consider this overgrowth syndrome (namely Malan syndrome) and Marshall-Smith syndrome NFIX-related diseases.

Brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Genetic causes of this anomaly are heterogeneous and only partially characterized. In this report we describe an Italian family in which four subjects share brachydactyly type E and a 3 Mb microduplication in region 6p25. The duplication involves the gene FOXC1, expressed during the osteoblast differentiation, which appears a potential candidate gene for brachydactyly.

The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6Mb. Here, we describe a case of a child with macrocephaly, overgrowth with advanced bone age, attention deficits, evidence of mild mental retardation and dysmorphic features. An array-CGH analysis detected a 252 Kb duplication at the 22q11.2 region inherited from mother and 142 Kb duplication at 8q22.1 region inherited from father. Both parents show mild dysmorphic features. The duplicated genes in chromosomes 22q and 8q are TOP3B and PGCP, respectively. We describe for the first time a patient carrying the smaller atypical 22q11.2 duplication who also presents with mild mental retardation and generalized overgrowth. This patient has an additional duplication in 8q22.1 which may act as a genomic modifier of its clinical phenotype.

Objective: To evaluate an in vivo pro-oxidant state in patients with ataxia telangiectasia (AT). Methods: A set of oxidative stress endpoints were measured in 9 AT homozygotes, 16 AT heterozygotes (parents) and 83 controls (grouped in age ranges as for patients and parents, respectively). The following analytes were measured: (a) leukocyte 8-hydroxy-2-deoxyguanosine (8-OHdG); (b) blood glutathione (GSSG and GSH); and (c) plasma levels of glyoxal (Glx) and methylglyoxal (MGlx). Results: AT patients displayed a significant decrease in blood GSSG (p=0.012) and in MGlx plasma concentrations (P=0.012). A nonsignificant decrease in the GSSG:GSH ratio (p = 0.1) and a non-significant increase in 8-OHdG and Glx levels were observed in AT patients vs. young controls (age range 4-35 years). AT heterozygotes failed to display any significant changes vs. adult controls (age range 36-68 years). Conclusion: No significant increase in oxidative stress biomarkers was detected in blood from AT patients. The decrease in GSSG and MGlx levels in AT patients may suggest an adaptive response to a pro-oxidant state in AT-related target organs. (c) 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Oxidative stress has been associated with Down syndrome (DS) and with its major phenotypic features, such as early ageing. In order to evaluate an in vivo pro-oxidant state, the following analytes were measured in a group of DS patients aged 2 months to 57 years: (a) leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG); (b) blood glutathione; (c) plasma levels of: glyoxal (Glx) and methylglyoxal (MGlx); some antioxidants (uric acid, UA, ascorbic acid, AA and Vitamin E), and xanthine oxidase (XO) activity. A significant 1.5-fold increase in 8-OHdG levels was observed in 28 DS patients vs. 63 controls, with a sharper increase in DS patients aged up to 30 years. The GSSG:GSHx100 ratio was significantly higher in young DS patients (< 15 years), in contrast to DS patients aged >= 15 years that showed a significant decrease in the GSSG:GSHx100 ratio ratio vs. controls of the respective age groups. Plasma Glx levels were significantly higher in young DS patients, whereas no significant difference was detected in DS patients aged >= 15 years. Unlike Glx, the plasma levels of MGlx were found to be significantly lower in DS patients vs. controls. A significant increase was observed in plasma levels of UA in DS patients that could be related to an increased plasma XO activity in DS patients. The plasma concentrations of AA were also increased in young (< 15 years) DS patients, but not in older patients vs. controls in the same age range. The levels of Vitamin E in DS patients did not differ from the values determined in control donors. The evidence for a multiple pro-oxidant state in young DS patients supports the role of oxidative stress in DS phenotype, with relevant distinctions according to patients' ages.