Further delineation of Malan syndrome

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 compa...

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Published in:	Human mutation Vol. 39; no. 9; pp. 1226 - 1237
Main Authors:	Priolo, Manuela, Schanze, Denny, Tatton‐Brown, Katrin, Mulder, Paul A., Tenorio, Jair, Kooblall, Kreepa, Acero, Inés Hernández, Alkuraya, Fowzan S., Arias, Pedro, Bernardini, Laura, Bijlsma, Emilia K., Cole, Trevor, Coubes, Christine, Dapia, Irene, Davies, Sally, Di Donato, Nataliya, Elcioglu, Nursel H., Fahrner, Jill A., Foster, Alison, González, Noelia García, Huber, Ilka, Iascone, Maria, Kaiser, Ann‐Sophie, Kamath, Arveen, Liebelt, Jan, Lynch, Sally Ann, Maas, Saskia M., Mammì, Corrado, Mathijssen, Inge B., McKee, Shane, Menke, Leonie A., Mirzaa, Ghayda M., Montgomery, Tara, Neubauer, Dorothee, Neumann, Thomas E., Pintomalli, Letizia, Pisanti, Maria Antonietta, Plomp, Astrid S., Price, Sue, Salter, Claire, Santos‐Simarro, Fernando, Sarda, Pierre, Segovia, Mabel, Shaw‐Smith, Charles, Smithson, Sarah, Suri, Mohnish, Valdez, Rita Maria, Haeringen, Arie, Hagen, Johanna M., Zollino, Marcela, Lapunzina, Pablo, Thakker, Rajesh V., Zenker, Martin, Hennekam, Raoul C.
Format:	Journal Article
Language:	English
Published:	United States Hindawi Limited 01-09-2018 Wiley John Wiley and Sons Inc
Subjects:	Abnormalities, Multiple - genetics Abnormalities, Multiple - physiopathology Adolescent Adult Anxiety Body height Bone Diseases, Developmental - genetics Bone Diseases, Developmental - physiopathology Child Child, Preschool Children Chromosome Deletion Congenital Hypothyroidism - genetics Congenital Hypothyroidism - physiopathology Craniofacial Abnormalities - genetics Craniofacial Abnormalities - physiopathology Developmental Disabilities - genetics Developmental Disabilities - physiopathology Epilepsy Exons - genetics Female Genotypes Hand Deformities, Congenital - genetics Hand Deformities, Congenital - physiopathology Humans Intellectual Disability - genetics Intellectual Disability - physiopathology Life Sciences Macrocephaly Malan syndrome Male Marshall‐Smith syndrome Megalencephaly - genetics Megalencephaly - physiopathology Mutation, Missense - genetics NFI Transcription Factors - genetics NFIX Phenotype Phenotypes phenotype‐genotype Septo-Optic Dysplasia - genetics Septo-Optic Dysplasia - physiopathology Sotos syndrome Sotos Syndrome - genetics Sotos Syndrome - physiopathology Stop codon Weaver syndrome Young Adult phenotype phenotype-genotype NFIX Sotos syndrome Malan syndrome Weaver syndrome Marshall-Smith syndrome Bone Diseases Developmental Developmental Disabilities Exons Humans Male Hand Deformities Young Adult Female Adult Craniofacial Abnormalities Septo-Optic Dysplasia Child Intellectual Disability Chromosome Deletion Multiple Congenital Abnormalities Preschool NFI Transcription Factors Congenital Hypothyroidism Megalencephaly Adolescent Mutation Missense Sotos Syndrome
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Summary:	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. Malan is an overgrowth syndrome caused by NFIX variants, likely as frequent as other overgrowth syndromes. The overgrowth is present at birth but no longer evident in half of the adults. Facial characteristics are different from Sotos syndrome, clinical evaluation in itself allows differentiation of the two entities, and the designation “Sotos type 2” is no longer acceptable. NFIX variants can also cause Marshall‐Smith syndrome, but with a different site of the stop codon, which explains the differences in phenotypes.
Bibliography:	These authors contributed equally to the manuscript. Communicating Editor: Stephen Robertson PMCID: PMC6175110
ISSN:	1059-7794 1098-1004
DOI:	10.1002/humu.23563