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Hum Mutat. 2018 Sep;39(9):1226-1237. doi: 10.1002/humu.23563. Epub 2018 Jun 25.

Further delineation of Malan syndrome.

Author information

1
Unità Operativa di Genetica Medica, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.
2
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
3
Division of Genetics and Epidemiology, Institute of Cancer Research, London and South West Thames Regional Genetics Service, St. George's University Hospitals NHS Foundation Trust, London, UK.
4
Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health, Lentis Psychiatric Institute, Groningen, The Netherlands.
5
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, and CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
6
Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
7
Genetics Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
8
Saudi Human Genome Project, King Abdulaziz City for Science and Technology, and Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
9
Cytogenetics Unit, Casa Sollievo della Sofferenza Foundation, San Giovanni Rotondo, Italy.
10
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
11
Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
12
Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
13
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
14
Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
15
Department of Pediatric Genetics, Marmara University Medical School, Istanbul, and Eastern Mediterranean University, Mersin, Turkey.
16
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
17
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
18
Unit Hospital Universitario Central de Asturias, Oviedo, Spain.
19
Sørland Hospital, Kristiansand, Norway.
20
Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
21
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
22
South Australian Clinical Genetics Services, SA Pathology, North Adelaide, Australia.
23
UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, and Clinical Genetics, Temple Street Children's University Hospital, Dublin, Ireland.
24
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
25
Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern Ireland.
26
Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
27
Center for Integrative Brain Research, Seattle Children's Research Institute, and Department of Human Genetics, University of Washington, Seattle, Washington.
28
Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK.
29
Mitteldeutscher Praxisverbund Humangenetik, Halle, Germany.
30
Medical Genetic and Laboratory Unit, "Antonio Cardarelli" Hospital, Naples, Italy.
31
Department of Clinical Genetics, Northampton General Hospital NHS Trust, Northampton, UK.
32
Wessex Clinical Genetics Service, Princess Ann Hospital, Southampton, UK.
33
CENAGEM, Centro Nacional de Genética, Buenos Aires, Argentina.
34
Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
35
University Hospitals Bristol NHS Trust, Bristol, UK.
36
Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
37
Genetics Unit, Hospital Militar Central "Cirujano Mayor Dr. Cosme Argerich,", Buenos Aires, Argentina.
38
Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
39
Department of Laboratory Medicine, Institute of Medical Genetics, Catholic University, Rome, Italy.

Abstract

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.

KEYWORDS:

Malan syndrome; Marshall-Smith syndrome; NFIX; Sotos syndrome; Weaver syndrome; phenotype; phenotype-genotype

PMID:
29897170
PMCID:
PMC6175110
DOI:
10.1002/humu.23563
[Indexed for MEDLINE]
Free PMC Article

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