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Approximatively 80 patients have been reported in the literature to date.

Malan syndrome is an overgrowth disorder characterized by postnatal overgrowth (in infancy and childhood), developmental delay, moderate to severe intellectual disability and unusual behavior (i.e. anxieties, noise sensitivity, hetero/auto-aggressive behavior). It is worth noting that overgrowth is less marked in adulthood. The most characteristic facial features include macrocephaly, long, triangular face, prominent forehead, depressed nasal bridge, deeply set eyes, downslanting palpebral fissures, short nose with anteverted nares, small mouth with an everted lower lip and a prominent chin. Additional variable manifestations comprise musculoskeletal abnormalities with slender habitus, scoliosis and pectus excavatum as well as long hands. Visual problems are frequent, especially strabismus, myopia, hypermetropia, nystagmus and underdeveloped optic nerves. Structural brain imaging abnormalities (i.e. enlarged ventricles, hypoplasia of the corpus callosum, cortical dysplasia and periventricular nodular heterotopia) have also been reported. Some patients have seizures and/or electroencephalogram abnormalities. The increased prevalence of epilepsy in individuals with deletions of NFIX may be explained by the presence of a contiguous gene disorder.

NFIX (Nuclear factor I X) haploinsufficiency is responsible for this syndrome and may be the result of heterozygous loss-of-function variants in the NFIX (Nuclear Factor I X (19p13.13) gene or 19p13 microdeletions encompassing the gene NFIX.

Malan syndrome is a clinically recognizable overgrowth syndrome. The diagnosis is based on the major clinical findings including postnatal overgrowth, facial dysmorphism with macrocephaly, intellectual disability and behaviorally anxiety. The genetic diagnosis is established by identification of a heterozygous pathogenic variant in NFIX or a deletion encompassing this gene. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and/or comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing).

The differential diagnoses include Sotos syndrome, Weaver syndrome and Marfan or Marfan-like syndromes. In case of large 19p13 deletions, other clinical signs are reported corresponding to the 19p13.13 microdeletion syndrome.

Prenatal diagnosis is possible if the disease-causing variant has been identified in the family. The recent implementation of prenatal whole exome sequencing could lead to molecular diagnostics during pregnancy.

Malan syndrome is inherited in an autosomal dominant manner. In the majority of cases, the pathogenic variants or deletions occur de novo. In this situation, the risk to sibs of the proband is very low due to a possible germinal mosaicism (<1%). In the rare familial cases, there is a 50% risk of transmitting the disease from an affected individual to offspring.

Management of Malan syndrome requires a multidisciplinary approach with appropriate medical specialists for intellectual disability, seizures, musculoskeletal and ocular abnormalities. Special education training along with behavioral intervention therapy may also be required.

Malan syndrome has significant impact on quality of life.