De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the
DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in
Marshall-Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and
macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive
Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or
hypotonia have been reported in 30% of patients. Developmental delay/
learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including
strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include
pectus excavatum (40%) and
scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes
episodic ataxia type 2 or
familial hemiplegic migraine. One previous case had
episodic ataxia and one case we report has had
cyclical vomiting responsive to
pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later
neurological manifestations is important, although their penetrance is not yet clear.