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.
Subject(s)
Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/physiopathology , Bone Diseases, Developmental/epidemiology , Bone Diseases, Developmental/physiopathology , Craniofacial Abnormalities/epidemiology , Craniofacial Abnormalities/physiopathology , Intellectual Disability/epidemiology , Intellectual Disability/physiopathology , Mental Disorders/epidemiology , Septo-Optic Dysplasia/epidemiology , Septo-Optic Dysplasia/physiopathology , Speech Disorders/epidemiology , Adaptation, Psychological , Adolescent , Adult , Child , Child, Preschool , Comorbidity , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Male , Mental Disorders/physiopathology , Netherlands/epidemiology , Phenotype , Speech Disorders/physiopathology , Syndrome , Young AdultABSTRACT
BACKGROUND AND OBJECTIVE: Megalencephaly (MEG) or enlarged brain occurs as a mild familial variant with normal brain structure, but otherwise is an uncommon human brain malformation that may be associated with significant developmental and neurological problems. It has been classified into anatomic and metabolic subtypes. The clinical findings associated with anatomic megalencephaly have been variable and few distinct subtypes have been described. We report five unrelated children with severe congenital MEG associated with polymicrogyria (PMG), postaxial polydactyly (POLY) and hydrocephalus (HYD). METHODS: The clinical records and brain MRI of five patients have been reviewed. RESULTS: All patients had striking MEG that was symmetric in three of the five patients, and mildly asymmetric in two. The birth OFC was between +2 and +4 SD. The gyral pattern was irregular with microgyri typical of PMG, which was most severe in the perisylvian region in all five patients. Four of the five had hydrocephalus treated with a shunt. Subsequently, one of the shunted patients had small ventricles while the others had mildly to moderately enlarged lateral ventricles. Three of the five patients had postaxial polydactyly of all four limbs. The corpus callosum was dysmorphic in one patient with a fused rostrum and genu, and intact although mildly thin in the others. None were abnormally thick. All patients had severe mental retardation; three had seizures and another had an epileptiform EEG. CONCLUSION: We believe this constellation of findings (MEG-PMG-POLY-HYD) comprises a new and distinct malformation syndrome that we designate the MPPH syndrome.