Publications by authors named "Manuela Priolo"

26 Publications

  • Page 1 of 1

Pregnancy in a patient with Rothmund-Thomson type 2 syndrome.

Int J Gynaecol Obstet 2021 Jul 2;154(1):181-182. Epub 2021 Apr 2.

Cardiology Department, James Black Centre, King's College London, London, UK.

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http://dx.doi.org/10.1002/ijgo.13667DOI Listing
July 2021

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Am J Hum Genet 2021 03 16;108(3):502-516. Epub 2021 Feb 16.

Division of Medical Genetics, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008487PMC
March 2021

Variants in nuclear factor I genes influence growth and development.

Am J Med Genet C Semin Med Genet 2019 12 15;181(4):611-626. Epub 2019 Nov 15.

Department of Pediatrics, University of Amsterdam, Amsterdam, The Netherlands.

The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.
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http://dx.doi.org/10.1002/ajmg.c.31747DOI Listing
December 2019

Maturity Onset Diabetes of the Young is Not Necessarily Associated with Autosomal Inheritance: Case Description of a De Novo HFN1A Mutation.

Diabetes Ther 2019 Aug 16;10(4):1543-1548. Epub 2019 May 16.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Via Consolare Valeria 1, 98124, Messina, Italy.

Maturity onset diabetes of the young (MODY) accounts for up to 4% of all cases of diabetes in pediatric patients. MODY is usually characterized by autosomal dominant inheritance, impaired insulin secretion, and an average age at diagnosis of 18-26 years. Mutations in the hepatocyte nuclear factor 1-alpha (HNF1A), glucokinase, hepatocyte nuclear factor 4-alpha, and hepatocyte nuclear factor 1-beta genes are the mutations most frequently observed in cases of MODY. We herein report a case of HNF1A-MODY characterized by an early onset of diabetes. Genetic investigations revealed a de novo heterozygous substitution, N237D (HNF1A c.709A>G), in exon 3 of the HNF1A gene. Our case supports the hypothesis that de novo mutations are more frequent than expected. This recent evidence may suggest that conventional clinical diagnostic criteria for MODY should be revised and personalized according to the individual patient.
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http://dx.doi.org/10.1007/s13300-019-0633-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612332PMC
August 2019

Nuclear Factor One X Mice model for Malan syndrome: the less the better.

Authors:
Manuela Priolo

EBioMedicine 2019 Jan 7;39:15-16. Epub 2018 Dec 7.

Operative Unite of Medical Genetics, Great Metropolitan Hospital Bianchi-Melacrino-Morelli, Reggio Calabria, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2018.11.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355653PMC
January 2019

Further delineation of Malan syndrome.

Hum Mutat 2018 09 25;39(9):1226-1237. Epub 2018 Jun 25.

Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern Ireland.

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.
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http://dx.doi.org/10.1002/humu.23563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175110PMC
September 2018

Genetic risk of prediabetes and diabetes development in chronic myeloid leukemia patients treated with nilotinib.

Exp Hematol 2017 11 28;55:71-75. Epub 2017 Jul 28.

Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. Electronic address:

Impaired fasting glucose and type 2 diabetes represent adverse events in patients with chronic myeloid leukemia (CML) treated with the second generation tyrosine kinase inhibitor nilotinib. An unweighted genetic risk score (uGRS) for the prediction of insulin resistance, consisting of 10 multiple single-nucleotide polymorphisms, has been proposed. We evaluated uGRS predictivity in 61 CML patients treated with nilotinib. Patients were genotyped for IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes. The uGRS was based on the sum of the risk alleles within the set of selected single-nucleotide polymorphisms. Molecular response (MR) and MR were achieved in 90% and 79% of patients, respectively. Before treatment, none of the patients had abnormal blood glucose. During treatment and subsequent follow-up at 80.2 months (range: 1-298), seven patients (11.5%) had developed diabetes that required oral treatment, a median of 14 months (range: 3-98) after starting nilotinib treatment. Twelve patients (19.7%) had developed prediabetes. Prediabetes/diabetes-free survival was significantly higher in patients with a uGRS <10 than in those with higher scores (100% vs. 22.8 ± 12.4%, p <0.001). Each increment of one unit in the uGRS caused a 42% increase in the prediabetes/diabetes risk (hazard ratio = 1.42, confidence interval: 1.04-1.94, p = 0.026). The presence of more than 10 allelic variants associated with insulin secretion, processing, sensitivity, and clearance is predictive of prediabetes/diabetes development in CML patients treated with nilotinib. In clinical practice, uGRS could help tailor the best tyrosine kinase inhibitor therapy.
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http://dx.doi.org/10.1016/j.exphem.2017.07.007DOI Listing
November 2017

From Whole Gene Deletion to Point Mutations of EP300-Positive Rubinstein-Taybi Patients: New Insights into the Mutational Spectrum and Peculiar Clinical Hallmarks.

Hum Mutat 2016 Feb 4;37(2):175-83. Epub 2015 Nov 4.

Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italia.

Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by growth deficiency, skeletal abnormalities, dysmorphic features, and intellectual disability. Causative mutations in CREBBP and EP300 genes have been identified in ∼55% and ∼8% of affected individuals. To date, only 28 EP300 alterations in 29 RSTS clinically described patients have been reported. EP300 analysis of 22 CREBBP-negative RSTS patients from our cohort led us to identify six novel mutations: a 376-kb deletion depleting EP300 gene; an exons 17-19 deletion (c.(3141+1_3142-1)_(3590+1_3591-1)del/p.(Ile1047Serfs*30)); two stop mutations, (c.3829A>T/p.(Lys1277*) and c.4585C>T/p.(Arg1529*)); a splicing mutation (c.1878-12A>G/p.(Ala627Glnfs*11)), and a duplication (c.4640dupA/p.(Asn1547Lysfs*3)). All EP300-mutated individuals show a mild RSTS phenotype and peculiar findings including maternal gestosis, skin manifestation, especially nevi or keloids, back malformations, and a behavior predisposing to anxiety. Furthermore, the patient carrying the complete EP300 deletion does not show a markedly severe clinical picture, even if a more composite phenotype was noticed. By characterizing six novel EP300-mutated patients, this study provides further insights into the EP300-specific clinical presentation and expands the mutational repertoire including the first case of a whole gene deletion. These new data will enhance EP300-mutated cases identification highlighting distinctive features and will improve the clinical practice allowing a better genotype-phenotype correlation.
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http://dx.doi.org/10.1002/humu.22922DOI Listing
February 2016

Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients.

J Med Genet 2015 Dec 30;52(12):804-14. Epub 2015 Sep 30.

Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.

Background: The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified.

Methods: We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported.

Results: The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations.

Conclusions: In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.
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http://dx.doi.org/10.1136/jmedgenet-2015-103184DOI Listing
December 2015

NFIX mutations affecting the DNA-binding domain cause a peculiar overgrowth syndrome (Malan syndrome): a new patients series.

Eur J Med Genet 2015 Sep 17;58(9):488-91. Epub 2015 Jul 17.

UO Genetica Medica, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmg.2015.06.009DOI Listing
September 2015

Ear nose throat manifestations in hypoidrotic ectodermal dysplasia.

Int J Pediatr Otorhinolaryngol 2013 Nov 13;77(11):1801-4. Epub 2013 Sep 13.

Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy. Electronic address:

The ectodermal dysplasias (EDs) are a large and complex group of inherited disorders. In various combinations, they all share anomalies in ectodermal derived structures: hair, teeth, nails and sweat gland function. Clinical overlap is present among EDs. Few causative genes have been identified, to date. Altered gene expression is not limited to the ectoderm but a concomitant effect on developing mesenchymal structures, with modification of ectodermal-mesenchymal signaling, takes place. The two major categories of ED include the hidrotic and hypohidrotic form, the latter more frequent; they differentiate each other for the presence or absence of sweat glands. We report Ear Nose Throat manifestations of ED, linked to the reduction of mucous glands in the nasal fossae with reduced ciliar function, and decrease salivary glands function. Often patients report an increased rate of infections of the upper respiratory tract and of the ear. Nasal obstruction due to the presence of nasal crusting, hearing loss and throat hoarseness are the most represented symptoms. Environmental measures, including a correct air temperature and humidification, is mandatory above all in subjects affected by hypohidrotic form.
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http://dx.doi.org/10.1016/j.ijporl.2013.09.004DOI Listing
November 2013

A peculiar mutation in the DNA-binding/dimerization domain of NFIX causes Sotos-like overgrowth syndrome: a new case.

Gene 2012 Dec 13;511(1):103-5. Epub 2012 Sep 13.

Unità Operativa di Genetica medica, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.

The Nuclear Factor I-X (NFIX) is a member of the nuclear factor I (NFI) family proteins, which are implicated as site-specific DNA-binding proteins and is deleted or mutated in a subset of patients with Sotos-like overgrowth syndrome and in patients with Marshall-Smith syndrome. We evaluated an additional patient with clinical features of Sotos-like syndrome by sequencing analysis of the NFIX gene and identified a 21 nucleotide in frame deletion predicting loss of 7 amino acids in the DNA-binding/dimerization domain of the NFIX protein. The deleted residues are all evolutionally conserved amino acids. The present report further confirms that mutations in DNA-binding/dimerization domain cause haploinsufficiency of the NFIX protein and strongly suggests that in individuals with Sotos-like features unrelated to NSD1 changes genetic testing of NFIX should be considered.
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http://dx.doi.org/10.1016/j.gene.2012.08.040DOI Listing
December 2012

Absence of deletion and duplication of MLL2 and KDM6A genes in a large cohort of patients with Kabuki syndrome.

Mol Genet Metab 2012 Nov 6;107(3):627-9. Epub 2012 Jul 6.

Unita' Operativa di Genetica Medica, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.

Kabuki syndrome is a rare, multiple congenital anomaly/mental retardation syndrome caused by MLL2 point mutations and KDM6A microdeletions. We screened a large cohort of MLL2 mutation-negative patients for MLL2 and KDM6A exon(s) microdeletion and microduplication. Our assays failed to detect such rearrangements in MLL2 as well as in KDM6A gene. These results show that these genomic events are extremely rare in the Kabuki syndrome, substantiating its genetic heterogeneity and the search for additional causative gene(s).
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http://dx.doi.org/10.1016/j.ymgme.2012.06.019DOI Listing
November 2012

Clinical and molecular cytogenetic studies in ring chromosome 5: report of a child with congenital abnormalities.

Eur J Med Genet 2012 Feb 2;55(2):112-6. Epub 2011 Dec 2.

Laboratoire d'Histologie, Cytologie et Cytogénétique, Faculté de Médecine et des Sciences de Santé, Université de Bretagne Occidentale, 22, Avenue Camille Desmoulins, CS 93837, F-29238 Brest cedex 3, France.

We report here a child with a ring chromosome 5 (r(5)) associated with facial dysmorphology and multiple congenital abnormalities. Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones was performed to determine the breakpoints involved in the r(5). The 5p deletion extended from 5p13.2-3 to 5pter and measured 34.61 Mb (range: 33.7-35.52 Mb) while the 5q deletion extended from 5q35.3 to 5qter and measured 2.44 Mb (range: 2.31-2.57 Mb). The patient presented signs such as microcephaly, hypertelorism, micrognathia and epicanthal folds, partially recalling those of a deletion of the short arm of chromosome 5 and the "cri-du-chat" syndrome. The most striking phenotypic features were the congenital heart abnormalities which have been frequently reported in deletions of the distal part of the long arm of chromosome 5 and in rings leading to a 5q35-5qter deletion. However, the NKX2-5 gene, which has been related to congenital heart defects, was not deleted in our patient, nor presumably to some other patients with 5q35.3-5qter deletion. We propose that VEGFR3, deleted in our patient, could be a candidate gene for the congenital heart abnormalities observed.
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http://dx.doi.org/10.1016/j.ejmg.2011.11.005DOI Listing
February 2012

Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients.

Orphanet J Rare Dis 2011 Jun 9;6:38. Epub 2011 Jun 9.

Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, Italy.

Background: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause.

Methods: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools.

Results: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site.

Conclusions: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.
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http://dx.doi.org/10.1186/1750-1172-6-38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141365PMC
June 2011

The metabotropic glutamate receptor 1, GRM1: evaluation as a candidate gene for inherited forms of cerebellar ataxia.

J Neurol 2010 Apr 19;257(4):598-602. Epub 2009 Nov 19.

Laboratory of Molecular Genetics, G. Gaslini Institute, Largo G. Gaslini 5, 16148, Genoa, Italy.

The metabotropic glutamate (mGlu) 1 receptor, coded by the GRM1 gene, is involved in synaptic activities, learning and neuroprotection. Eleven different mouse Grm1 mutations, either induced or spontaneously occurring, have been reported, including one from our group. All the mutations result in a complex phenotype with ataxia and intention tremor in mice. Moreover, autoantibodies against mGlu1 receptor have been associated with paraneoplastic cerebellar ataxia in humans. In spite of the large clinical and genetic heterogeneity displayed by the inherited forms of cerebellar ataxia, forms remain with a yet unknown molecular definition. With the evidence coming out from mouse models and from paraneoplastic ataxia, it seems that GRM1 represents a good candidate gene for early-onset ataxia forms, though no GRM1 mutations have thus far been looked for. The aim of this study was to investigate the possible involvement of GRM1 in early-onset or familial forms of ataxia. We searched for gene mutations in a panel of patients with early-onset ataxia as yet molecularly undefined. No causative mutations were found, though we detected synonymous variants in the exons and changes in flanking intronic sequences which are unlikely to alter correct splicing upon bioinformatics prediction. As for other known forms of inherited ataxias, absence of mutations in GRM1 seems to suggest a relatively low frequency in cerebellar ataxias.
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http://dx.doi.org/10.1007/s00415-009-5380-3DOI Listing
April 2010

Approach towards a new classification for ectodermal dysplasias: integration of the clinical and molecular knowledge.

Am J Med Genet A 2009 Sep;149A(9):2068-70

Division of Dermatopharmacology, Department of Dermatology, The Warren Alpert School of Medicine of Brown University, 593 Eddy Street, Providence, RI 02903, USA.

Rapid advances in new basic knowledge have led to a greater understanding of the genetic, embryologic, molecular biologic, and functional mechanisms underlying the ectodermal dysplasias. Scientists, researchers, and clinicians from diverse fields desire a classification that meets the needs of these rapidly changing concepts which, in addition to being clinically useful, can help further advances in understanding the basic underlying mechanisms, and can also spur the development of new therapies. The currently used classification was designed for clinical utility and has not easily integrated with the new concepts. Various users have suggested that a new classification should be based on underlying genetic and molecular abnormality, functional mechanism, embryology, or clinical features. The goal of this conference was to advance towards a consensus and this manuscript is a summary of a workshop focused on an approach towards the development of a classification that integrates the clinical and molecular knowledge.
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http://dx.doi.org/10.1002/ajmg.a.32961DOI Listing
September 2009

Ectodermal dysplasias: an overview and update of clinical and molecular-functional mechanisms.

Authors:
Manuela Priolo

Am J Med Genet A 2009 Sep;149A(9):2003-13

Operative Unit of Medical Genetics Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy.

The ectodermal dysplasias (EDs) are a large and complex group of disorders. In various combinations, they all share anomalies in hair, teeth, nails, and sweat gland function. The anomalies affecting the epidermis and epidermal appendages are extremely variable. Many are associated with malformations in other organs and systems. Clinical overlap is present among EDs. Few causative genes have been identified, to date. Most of the EDs present multisystem involvement with abnormal development of structures also derived from mesoderm. In the last few years, it has become evident that gene expression in the EDs is not limited to the ectoderm and that there is a concomitant effect on developing mesenchymal structures, with modification or abolition of ectodermal-mesenchymal signaling. It is possible to approach this group of diseases basing on functional and molecular findings and to begin to explain the complex clinical consequences of mutations affecting specific developmental pathways. We have reviewed the molecular basis of ectodermal dysplasias applying this new clinical-functional classification. For each subset of the identified ED, we will now describe the genes and related proteins involved in terms of: (1) structure of the genes and their role in differentiation of the epidermis and the ectodermal derivatives; (2) genotype-phenotype correlation.
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http://dx.doi.org/10.1002/ajmg.a.32804DOI Listing
September 2009

Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11.

Am J Hum Genet 2008 Jul 19;83(1):106-11. Epub 2008 Jun 19.

Program in Genetics & Genomic Biology and The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.
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http://dx.doi.org/10.1016/j.ajhg.2008.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443840PMC
July 2008

Erratum to: Clinical and molecular characterization of Italian patients affected by Cohen syndrome.

J Hum Genet 2008 Mar;53(3):285

Medical Genetics, Department of Molecular Biology, University of Siena, V. Le Bracci 2, 53100, Siena, Italy.

The complete affiliations of two authors appeared incorrectly. The affiliations of A. Selicorni and D. Milani should be given as.
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http://dx.doi.org/10.1007/s10038-007-0239-xDOI Listing
March 2008

MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment.

Eur J Hum Genet 2008 May 23;16(5):565-71. Epub 2008 Jan 23.

Operative Unit of Medical Genetics, Hospital of Reggio Calabria Az. Ospedaliera Bianchi-Melacrino-Morelli, V Petrara Reggio Calabria, Reggio Calabria, Italy.

Human chromosome 11p15.5 harbours a large cluster of imprinted genes. Different epigenetic defects at this locus have been associated with both Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). Multiple techniques (Southern blotting, COBRA and microsatellite analysis) have been used so far to detect various DNA methylation abnormalities, uniparental disomies and copy number variations, which are characteristics of these two diseases. We have now evaluated a methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) for the molecular diagnosis of BWS and SRS. Seventy-three samples derived from BWS- and SRS-affected individuals and 20 controls were analysed by conventional tests and MS-MLPA in blind. All cases that were found positive with conventional methods were also identified by MS-MLPA. These included cases with paternal UPD11, hyper- or hypo-methylation at the Imprinting Centre 1 or Imprinting Centre 2 and rare 11p15.5 duplications. In summary, this MS-MLPA assay can detect both copy number variations and methylation defects of the 11p15.5 critical region within one single experiment and represents an easy, low cost and reliable system for the molecular diagnostics of BWS and SRS.
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http://dx.doi.org/10.1038/sj.ejhg.5202001DOI Listing
May 2008

Expanding the phenotype of 22q11 deletion syndrome: the MURCS association.

Clin Dysmorphol 2008 Jan;17(1):13-7

Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy.

The MURCS association [Müllerian Duct aplasia or hypoplasia (M), unilateral renal agenesis (UR) and cervicothoracic somite dysplasia (CS)] manifests itself as Müllerian Duct aplasia or hypoplasia, unilateral renal agenesis and cervicothoracic somite dysplasia. We report on a 22-year-old woman with bicornuate uterus, right renal agenesis, C2-C3 vertebral fusion (MURCS association) and 22q11.2 deletion. Angio-MRI revealed the aberrant origin of arch arteries. Hashimoto thyroiditis, micropolycystic ovaries with a dermoid cyst in the right ovary and mild osteoporosis were also diagnosed. Accurate revision of radiographs enabled us also to identify thoracolumbar and lumbosacral vertebral-differentiation defects. Audiometry and echocardiogram were normal. Bone densitometry showed osteoporosis. As per our evaluation, the patient had short stature, obesity (BMI 30.7) and facial features suggestive of the 22q11 deletion syndrome. Multiplex ligation-dependent probe amplification analysis showed a de-novo 22q11.2 deletion confirmed by array-comparative genomic hybridization analysis. We discuss whether this is a casual association or whether it is an additional syndrome owing to the well known phenotype extensive variability of the 22q11 deletion syndrome.
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http://dx.doi.org/10.1097/MCD.0b013e3282ef97eeDOI Listing
January 2008

Clinical and molecular characterization of Italian patients affected by Cohen syndrome.

J Hum Genet 2007 8;52(12):1011-1017. Epub 2007 Nov 8.

Medical Genetics, Department of Molecular Biology, University of Siena, V. Le Bracci 2, 53100, Siena, Italy.

Cohen syndrome is an autosomal recessive disorder with variability in the clinical manifestations, characterized by developmental delay, visual disability, facial dysmorphisms and intermittent neutropenia. We described a cohort of 10 patients affected by Cohen syndrome from nine Italian families ranging from 5 to 52 years at assessment. Characteristic age related facial changes were well documented. Visual anomalies, namely retinopathy and myopia, were present in 9/10 patients (retinopathy in 9/10 and myopia in 8/10). Truncal obesity has been described in all patients older than 6 years (8/8). DNA samples from all patients were analyzed for mutations in COH1 by DHPLC. We detected 15 COH1 alterations most of them were truncating mutations, only one being a missense change. Partial gene deletions have been found in two families. Most mutations were private. Two were already reported in the literature just once. A single base deletion leading to p.T3708fs3769, never reported before, was found in three apparently unrelated families deriving from a restricted area of the Veneto's lowland, between Padova town and Tagliamento river, in heterozygous state. Given the geographical conformation of this region, which is neither geographically or culturally isolated, a recent origin of the mutation could be hypothesized.
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http://dx.doi.org/10.1007/s10038-007-0208-4DOI Listing
February 2008

Malpuech syndrome: broadening the clinical spectrum and molecular analysis by array-CGH.

Eur J Med Genet 2007 Mar-Apr;50(2):139-43. Epub 2006 Oct 28.

Operative Unit of Medical Genetics, Hospital of Reggio Calabria Az. Ospedaliera Bianchi-Melacrino-Morelli, V Petrara Reggio Calabria, 89100 Reggio Calabria, RC, Italy.

We report on a patient with mental and growth retardation, bilateral cleft lip and palate, hypertelorism, ptosis, hearing loss and mild epispadias, suggestive of Malpuech syndrome. High-resolution karyotype and microarray-CGH using an oligonucleotide array with 75Kb oligo's were normal, excluding Wolf-Hirschhorn syndrome. Long-term follow-up revealed psychiatric manifestations starting at young age.
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http://dx.doi.org/10.1016/j.ejmg.2006.10.004DOI Listing
May 2007

Pulmonary agenesis/hypoplasia, microphthalmia, and diaphragmatic defects: report of an additional case.

Clin Dysmorphol 2004 Jan;13(1):45-6

Diaphragmatic defects with associated pulmonary hypoplasia/agenesis and anophthalmia/microphthalmia have been reported as part of a complex syndromic phenotype. We report a case with the combination of these malformations.
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http://dx.doi.org/10.1097/00019605-200401000-00013DOI Listing
January 2004

How wide is the ocular spectrum of Delleman syndrome?

Clin Dysmorphol 2004 Jan;13(1):33-4

We describe a patient with cerebral and cutaneous features typical of oculocerebrocutaneous syndrome. The ocular anomalies observed have not been previously reported in patients affected with this syndrome.
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http://dx.doi.org/10.1097/00019605-200401000-00009DOI Listing
January 2004