Development, behaviour and sensory processing in Marshall–Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes
Paul A. Mulder, Ingrid D. C. van Balkom, Annemiek Landlust, Manuela Priolo, Leonie A. Menke, Inés Hernández Acero, Fowzan S. Alkuraya, Pedro Arias, Laura Bernardini, Emilia K. Bijlsma, Tim Cole, Christine Coubes, Irene Dapía, Sally Davies, Nataliya Di Donato, Nursel Elçioğlu, Jill A. Fahrner, Alison Foster, Noelia García González, Ilka Huber, Maria Iascone, Ann-Sophie Kaiser, Arveen Kamath, Kreepa Kooblall, Pablo Lapunzina, Jan Liebelt, Sally Ann Lynch, Saskia M. Maas, Corrado Mammì, Inge B. Mathijssen, Shane McKee, Ghayda Mirzaa, Tara Montgomery, D. Neubauer, Thomas Neumann, Letizia Pintomalli, Maria Antonietta Pisanti, Astrid S. Plomp, Sue Price, Claire Salter, Fernando Santos‐Simarro, P. Sardá, Denny Schanze, Mabel Segovia, Charles Shaw‐Smith, Sarah Smithson, Mohnish Suri, Katrin Tatton-Brown, Jair Tenorio, Rajesh V. Thakker, Rita Valdéz, Arie van Haeringen, Johanna M. van Hagen, Martin Zenker, Marcella Zollino, Winifred Wiese Dunn, Sigrid Piening, Raoul C. M. Hennekam
Abstract
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.