Alternative titles; symbols
SNOMEDCT: 763795006; ORPHA: 420179; DO: 0112102;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.13 | Malan syndrome | 614753 | Autosomal dominant | 3 | NFIX | 164005 |
A number sign (#) is used with this entry because of evidence that Malan syndrome (MALNS) is caused by heterozygous mutation in the NFIX gene (164005) on chromosome 19p13.
Marshall-Smith syndrome (MRSHSS; 602535) is also caused by heterozygous mutation in the NFIX gene.
Malan syndrome (MALNS) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present (summary by Martinez et al., 2015).
Malan et al. (2010) reported 3 unrelated patients with a similar phenotype consisting of postnatal overgrowth, macrocephaly, advanced bone age, long narrow face, high forehead, slender habitus, scoliosis, unusual behavior characterized especially by anxiety, and mental retardation. One of the patients had previously been diagnosed with a 'Sotos-like syndrome' (see Sotos syndrome, 117550).
Jezela-Stanek et al. (2016) reported 2 girls with overgrowth and psychomotor delay, 1 with a missense mutation in the NFIX gene and the other with a 19p13.2 deletion encompassing NFIX and several other genes. The patients shared dysmorphic features including high forehead, downslanting palpebral fissures, pointed chin, and abnormalities of the pinnae, as well as long tapered fingers and malformed toenails. Both exhibited aggressive self-injurious behavior. Noting that both patients had normal birth weights, the authors suggested that postnatal onset of weight gain and increased occipitofrontal circumference are noteworthy features of Malan syndrome, in contrast to Sotos syndrome, in which the overgrowth is usually prenatal and more significant.
Most reported cases of Malan syndrome have been sporadic and may represent new dominant mutations (Malan et al., 2010; Yoneda et al., 2012).
Malan et al. (2010) used a high-resolution array CGH in 18 patients with unexplained syndromic overgrowth and identified 2 patients with a de novo 19p13.1 monosomy. The deletions involved a single common gene, NFIX.
In a patient with MALNS, who had previously been diagnosed with a 'Sotos-like syndrome,' Malan et al. (2010) identified a heterozygous de novo nonsense mutation (Q190X; 164005.0001) in the NFIX gene. RT-PCR analysis in patient fibroblasts indicated that the phenotype was due to NFIX haploinsufficiency. The phenotype in this patient was similar to 2 patients found by Malan et al. (2010) to have a de novo 19p13.1 monosomy involving a deletion in the NFIX gene.
In 2 Japanese patients who had been diagnosed with Sotos syndrome and did not have mutations in the NSD1 gene (606681), Yoneda et al. (2012) identified different heterozygous splice site mutations (164005.0011-164005.0012). One mutation was de novo and the other was possibly inherited from the mother, who was not available for study. Both mutations were absent in 250 healthy Japanese controls.
Martinez et al. (2015) reported 5 de novo mutations in the NFIX gene, including 2 frameshift mutations and a recurrent splicing mutation (164005.0010) in 3 patients with MRSHSS (602535), and 2 missense mutations in the DNA-binding/dimerization domain in 2 patients with MALNS. The authors reviewed previously reported NFIX mutations and concluded that MRSHSS mutations are scattered through exons 6 to 10 of the gene, whereas most point mutations causing MALNS are clustered in exon 2. In addition, they stated that the most striking feature in both MALNS patients was a marfanoid habitus, with long and slender body, very low body mass index, long narrow face, and arachnodactyly. The authors proposed that the NFIX gene should be analyzed first in any patient exhibiting a phenotype intermediate between Sotos (117550) and Marfan (154700) syndromes.
Jezela-Stanek, A., Kucharczyk, M., Falana, K., Jurkiewicz, D., Mlynek, M., Wicher, D., Rydzanicz, M., Kugaudo, M., Cieslikowska, A., Ciara, E., Ploski, R., Krajewska-Walasek, M. Malan syndrome (Sotos syndrome 2) in two patients with 19p13.2 deletion encompassing NFIX gene and novel NFIX sequence variant. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 160: 161-167, 2016. [PubMed: 26927468] [Full Text: https://doi.org/10.5507/bp.2016.006]
Malan, V., Rajan, D., Thomas, S., Shaw, A. C., Louis dit Picard, H., Layet, V., Till, M., van Haeringen, A., Mortier, G., Nampoothiri, S., Puseljic, S., Legeai-Mallet, L., Carter, N. P., Vekemans, M., Munnich, A., Hennekam, R. C., Colleaux, L., Cormier-Daire, V. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am. J. Hum. Genet. 87: 189-198, 2010. [PubMed: 20673863] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.001]
Martinez, F., Marin-Reina, P., Sanchis-Calvo, A., Perez-Aytes, A., Oltra, S., Rosello, M., Mayo, S., Monfort, S., Pantoja, J., Orellana, C. Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes. Pediat. Res. 78: 533-539, 2015. [PubMed: 26200704] [Full Text: https://doi.org/10.1038/pr.2015.135]
Yoneda, Y., Saitsu, H., Touyama, M., Makita, Y., Miyamoto, A., Hamada, K., Kurotaki, N., Tomita, H., Nishiyama, K., Tsurusaki, Y., Doi, H., Miyake, N., Ogata, K., Naritomi, K., Matsumoto, N. Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features. J. Hum. Genet. 57: 207-211, 2012. [PubMed: 22301465] [Full Text: https://doi.org/10.1038/jhg.2012.7]