Malan syndrome in a patient with 19p13.2p13.12 deletion encompassing NFIX and CACNA1A genes: Case report and review of the literature

Abstract

Background: Malan syndrome is a recently introduced overgrowth disorder described in a limited number of individuals. Haploinsufficiency and also point mutations of NFIX gene have been proposed as its leading causative mechanism, however, due to the limited number of cases and different deletion sizes, genotype/phenotype correlations are still limited.

Methods: Here, we report the first Brazilian case of Malan syndrome caused by a 990 kb deletion in 19p13.2p13.12, focusing on clinical and behavioral aspects of the syndrome.

Results: The patient presented with macrocephaly, facial dysmorphisms, hypotonia, developmental delay, moderate thoracolumbar scoliosis, and seizures. The intellectual and behavioral assessments showed severe cognitive, language, and adaptive functions impairments. The 19p deleted region of our patient encompasses NFIX, CACNA1A, which seems to be related to a higher frequency of seizures among individuals with microdeletions in 19p13.2, and 15 other coding genes, including CC2D1A and NACC1, both known to be involved in neurobiological process and pathways.

Conclusion: Deletions involving NFIX gene should be considered in patients with overgrowth during childhood, macrocephaly, developmental delay, and seizures, as well as severe intellectual disability.

Keywords: CACNA1A; NFIX; 19p13.2 microdeletion; Malan syndrome; overgrowth disorder.

Figure 1

Patient at 19 years and 7 months of age showing macrocephaly, long face, frontal bossing, down‐slanting palpebral fissures, deep‐set eyes, long eyelashes, anteverted nares, open mouth appearance, and pointed chin

Figure 2

Genome map of the overlapping deletions of our patient (gray bar) and previously reported cases (black bars), and known genes in the chromosome 19p13 region. The patients` rearrangements were organized based on their initial deletion coordinates. Data were uploaded to UCSC genome browser, NCBI Build 37, February 2009, hg19 Assembly (http://www.genome.ucsc.edu)