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.

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Thyrotoxicosis affects 0.2% of pregnant women and antithyroid drugs are the treatment of choice during pregnancy. Several case reports have suggested a relationship between the prenatal use of methimazole (MMI) and choanal atresia in the offspring. However, two epidemiological studies did not find an increased teratogenic risk for MMI. This multicenter case-control study compared the frequency of maternal hyperthyroidism treated with MMI during pregnancy, in children with choanal atresia (cases) and a control group randomly selected (three matched controls according to maternal age for each case). Mothers of cases (N = 61) and controls (N = 183) were interviewed for socio-demographic questions, obstetrical and genetic history, and exposure during pregnancy to different agents; specifically detailed information regarding hyperthyroidism and MMI intake was obtained. Prenatal exposure to maternal hyperthyroidism treated with MMI was identified in 10/61 cases (16.4%) compared to 2/183 (1.1%) in the control group (OR = 17.75; CI95% = 3.49-121.40). Cases and controls did not differ in their parental degree of education, paternal occupation, twinning, maternal parity, and other exposures during pregnancy. Facial features in exposed cases showed some similarities. Our data suggest that prenatal exposure to maternal hyperthyroidism treated with MMI is associated with choanal atresia. In addition, based on our cases and a critical literature review, we propose that the mother's disease might be the causal factor and not the MMI treatment.

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.