Further delineation of Malan syndrome

doi:10.1002/humu.23563

. 2018 Sep;39(9):1226-1237.

doi: 10.1002/humu.23563. Epub 2018 Jun 25.

Further delineation of Malan syndrome

Manuela Priolo¹, Denny Schanze², Katrin Tatton-Brown³, Paul A Mulder⁴, Jair Tenorio⁵, Kreepa Kooblall⁶, Inés Hernández Acero⁷, Fowzan S Alkuraya⁸, Pedro Arias⁵, Laura Bernardini⁹, Emilia K Bijlsma¹⁰, Trevor Cole¹¹, Christine Coubes¹², Irene Dapia⁵, Sally Davies¹³, Nataliya Di Donato¹⁴, Nursel H Elcioglu¹⁵, Jill A Fahrner¹⁶, Alison Foster¹⁷, Noelia García González¹⁸, Ilka Huber¹⁹, Maria Iascone²⁰, Ann-Sophie Kaiser²¹, Arveen Kamath¹³, Jan Liebelt²², Sally Ann Lynch²³, Saskia M Maas²⁴, Corrado Mammì¹, Inge B Mathijssen²⁴, Shane McKee²⁵, Leonie A Menke²⁶, Ghayda M Mirzaa²⁷, Tara Montgomery²⁸, Dorothee Neubauer², Thomas E Neumann²⁹, Letizia Pintomalli¹, Maria Antonietta Pisanti³⁰, Astrid S Plomp²⁴, Sue Price³¹, Claire Salter³², Fernando Santos-Simarro⁵, Pierre Sarda¹², Mabel Segovia³³, Charles Shaw-Smith³⁴, Sarah Smithson³⁵, Mohnish Suri³⁶, Rita Maria Valdez³⁷, Arie Van Haeringen¹⁰, Johanna M Van Hagen³⁸, Marcela Zollino³⁹, Pablo Lapunzina⁵, Rajesh V Thakker⁶, Martin Zenker², Raoul C Hennekam²⁶

Affiliations

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.

PMID: 29897170
PMCID: PMC6175110
DOI: 10.1002/humu.23563

Further delineation of Malan syndrome

Manuela Priolo et al. Hum Mutat. 2018 Sep.

. 2018 Sep;39(9):1226-1237.

doi: 10.1002/humu.23563. Epub 2018 Jun 25.

Authors

Affiliations

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.

PMID: 29897170
PMCID: PMC6175110
DOI: 10.1002/humu.23563

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.

PubMed Disclaimer

Figures

**Figure 1**
AP facial view of presently reported 42 individuals with Malan syndrome. Numbers of individuals in the panels correspond to numbers in the Tables. Ages are mentioned below each picture. For detailed descriptions please see Tables and text

**Figure 2**
*NFIX* cartoon with all reported variants in Malan (underneath the gene) and Marshall‐Smith (above the gene) syndrome. The color legend for missense, nonsense, ins/dels, splicing, and intragenic deletions is shown. Recurring variants are reported with additional circles. Exons and introns are in scale except introns 1 and 2. Blue: putative DNA binding and dimerization domain of the gene and inside it; green: MH1 (MAD homology 1) domain and the N‐terminal DNA binding (DNAbd) domain; orange: CAAT‐box transcription factor–nuclear factor I (CTF‐NFI) domain

See this image and copyright information in PMC

Cited by

Case Report: Novel pathogenic variant in NFIX in two sisters with Malan syndrome due to germline mosaicism.
Langley E, Farach LS, Mowrey K. Langley E, et al. Front Genet. 2022 Nov 9;13:1044660. doi: 10.3389/fgene.2022.1044660. eCollection 2022. Front Genet. 2022. PMID: 36437934 Free PMC article.
Profiling Cognitive and Social Functioning in a Small Cohort with Malan Syndrome.
Butti N, Urgesi C, Alfieri P, Priolo M, Montirosso R. Butti N, et al. Children (Basel). 2025 Jan 27;12(2):147. doi: 10.3390/children12020147. Children (Basel). 2025. PMID: 40003249 Free PMC article.
Quantifying neurobehavioral profiles across neurodevelopmental genetic syndromes and idiopathic neurodevelopmental disorders.
Frazier TW, Busch RM, Klaas P, Lachlan K, Loth E, Smith-Hicks C, Sahin M, Hardan AY, Uljarevic M; NET Development Project Team. Frazier TW, et al. Dev Med Child Neurol. 2025 May;67(5):618-629. doi: 10.1111/dmcn.16112. Epub 2024 Nov 11. Dev Med Child Neurol. 2025. PMID: 39526825 Free PMC article.
Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome.
Testa B, Conteduca G, Grasso M, Cecconi M, Lantieri F, Baldo C, Arado A, Andraghetti L, Malacarne M, Milani D, Coviello D, Sotos Collaborative Group. Testa B, et al. Genes (Basel). 2023 Jan 22;14(2):295. doi: 10.3390/genes14020295. Genes (Basel). 2023. PMID: 36833222 Free PMC article.
Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?
Harris JR, Gao CW, Britton JF, Applegate CD, Bjornsson HT, Fahrner JA. Harris JR, et al. Hum Genet. 2024 Apr;143(4):607-624. doi: 10.1007/s00439-023-02537-1. Epub 2023 Mar 23. Hum Genet. 2024. PMID: 36952035 Free PMC article.

See all "Cited by" articles

References

1. Aggarwal, A. , Nguyen, J. , Rivera‐Davila, M. , & Rodriguez‐Buritica, D. (2017). Marshall‐Smith syndrome: Novel pathogenic variant and previously unreported associations with precocious puberty and aortic root dilatation. European Journal of Medical Genetics, 60, 391–394. 10.1016/j.ejmg.2017.04.01 - DOI - PubMed
1. Auvin, S. , Holder‐Espinasse, M. , Lamblin, M. D. , & Andrieux, J. (2009). Array‐CGH detection of a de novo 0.7‐Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms. Epilepsia, 50, 2501–2503. 10.1111/j.1528-1167.2009.02189.x - DOI - PubMed
1. Bonaglia, M. C. , Marelli, S. , Novara, F. , Commodaro, S. , Borgatti, R. , Minardo, G. , … Zuffardi, O. (2010). Genotype‐phenotype relationship in three cases with overlapping 19p13.12 microdeletions. European Journal of Human Genetics, 18, 1302–1309. 10.1038/ejhg.2010.115 - DOI - PMC - PubMed
1. Dolan, M. , Mendelsohn, N. J. , Pierpont, M. E. , Schimmenti, L. A. , Berry, S. A. , & Hirsch, B. (2010). A novel microdeletion/microduplication syndrome of 19p13.13. Genetics in Medicine, 212, 503–511. 10.1097/GIM.0b013e3181e59291 - DOI - PubMed
1. Dong, H. Y. , Zeng, H. , Hu, Y. Q. , Xie, L. , Wang, J. , Wang, X. Y. , … Tan, Z. P. (2016). 19p13.2 Microdeletion including NFIX associated with overgrowth and intellectual disability suggestive of Malan syndrome. Molecular Cytogenetics, 22, 71 10.1186/s13039-016-0282-4 - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Supplementary concepts

Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information

[1] Aggarwal, A. , Nguyen, J. , Rivera‐Davila, M. , & Rodriguez‐Buritica, D. (2017). Marshall‐Smith syndrome: Novel pathogenic variant and previously unreported associations with precocious puberty and aortic root dilatation. European Journal of Medical Genetics, 60, 391–394. 10.1016/j.ejmg.2017.04.01 - DOI - PubMed

[2] Aggarwal, A. , Nguyen, J. , Rivera‐Davila, M. , & Rodriguez‐Buritica, D. (2017). Marshall‐Smith syndrome: Novel pathogenic variant and previously unreported associations with precocious puberty and aortic root dilatation. European Journal of Medical Genetics, 60, 391–394. 10.1016/j.ejmg.2017.04.01 - DOI - PubMed

[3] Auvin, S. , Holder‐Espinasse, M. , Lamblin, M. D. , & Andrieux, J. (2009). Array‐CGH detection of a de novo 0.7‐Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms. Epilepsia, 50, 2501–2503. 10.1111/j.1528-1167.2009.02189.x - DOI - PubMed

[4] Auvin, S. , Holder‐Espinasse, M. , Lamblin, M. D. , & Andrieux, J. (2009). Array‐CGH detection of a de novo 0.7‐Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms. Epilepsia, 50, 2501–2503. 10.1111/j.1528-1167.2009.02189.x - DOI - PubMed

[5] Bonaglia, M. C. , Marelli, S. , Novara, F. , Commodaro, S. , Borgatti, R. , Minardo, G. , … Zuffardi, O. (2010). Genotype‐phenotype relationship in three cases with overlapping 19p13.12 microdeletions. European Journal of Human Genetics, 18, 1302–1309. 10.1038/ejhg.2010.115 - DOI - PMC - PubMed

[6] Bonaglia, M. C. , Marelli, S. , Novara, F. , Commodaro, S. , Borgatti, R. , Minardo, G. , … Zuffardi, O. (2010). Genotype‐phenotype relationship in three cases with overlapping 19p13.12 microdeletions. European Journal of Human Genetics, 18, 1302–1309. 10.1038/ejhg.2010.115 - DOI - PMC - PubMed

[7] Dolan, M. , Mendelsohn, N. J. , Pierpont, M. E. , Schimmenti, L. A. , Berry, S. A. , & Hirsch, B. (2010). A novel microdeletion/microduplication syndrome of 19p13.13. Genetics in Medicine, 212, 503–511. 10.1097/GIM.0b013e3181e59291 - DOI - PubMed

[8] Dolan, M. , Mendelsohn, N. J. , Pierpont, M. E. , Schimmenti, L. A. , Berry, S. A. , & Hirsch, B. (2010). A novel microdeletion/microduplication syndrome of 19p13.13. Genetics in Medicine, 212, 503–511. 10.1097/GIM.0b013e3181e59291 - DOI - PubMed

[9] Dong, H. Y. , Zeng, H. , Hu, Y. Q. , Xie, L. , Wang, J. , Wang, X. Y. , … Tan, Z. P. (2016). 19p13.2 Microdeletion including NFIX associated with overgrowth and intellectual disability suggestive of Malan syndrome. Molecular Cytogenetics, 22, 71 10.1186/s13039-016-0282-4 - DOI - PMC - PubMed

[10] Dong, H. Y. , Zeng, H. , Hu, Y. Q. , Xie, L. , Wang, J. , Wang, X. Y. , … Tan, Z. P. (2016). 19p13.2 Microdeletion including NFIX associated with overgrowth and intellectual disability suggestive of Malan syndrome. Molecular Cytogenetics, 22, 71 10.1186/s13039-016-0282-4 - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Further delineation of Malan syndrome

Affiliations

Further delineation of Malan syndrome

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Supplementary concepts

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical