| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p24.3 | Megalencephaly-polydactyly syndrome | 620748 | Autosomal dominant | 3 | MYCN | 164840 |
A number sign (#) is used with this entry because of evidence that megalencephaly-polydactyly syndrome (MPAPA) is caused by heterozygous mutation in the MYCN gene (164840) on chromosome 2p24.
Megalencephaly-polydactyly syndrome (MPAPA) is an autosomal dominant disorder characterized by megalencephaly, ventriculomegaly, postaxial polydactyly, and, notably, neuroblastoma during infancy (summary by Nishio et al., 2023).
Kato et al. (2019) reported a patient with macrocephaly and neurologic features including impaired intellectual development, megalencephaly, ventriculomegaly, and hypoplastic corpus callosum. Other clinical findings included postnatal growth retardation, postaxial polydactyly of the hands and feet, and dysmorphic facial features, including epicanthus, hypertelorism, high-arched palate, long philtrum, and prominent forehead. The boy had a neuroblastoma at 7 months of age, which was treated with surgery and chemotherapy.
Nishio et al. (2023) reported 2 patients with MPAPA. Patient 1 was a male fetus delivered at 31 weeks' gestation. A prenatal ultrasound in the second trimester showed ventriculomegaly and postaxial polydactyly, and a fetal brain MRI at 30 weeks' gestation demonstrated ventriculomegaly and macrocephaly. Postmortem examination showed postaxial polydactyly of both hands, hypertelorism, low-set ears, and retrognathia. Further findings included Meckel diverticulum and pyeloureteral dilatation. Patient 2 was an 8-month-old boy with megalencephaly, postaxial polydactyly, developmental delay, and facial dysmorphism. A brain MRI showed an enlarged ventricle and hypoplastic corpus callosum. At age 3 months, the boy was diagnosed with neuroblastoma, which responded well to chemotherapy and surgery.
The heterozygous mutations in the MYCN gene that were identified in patients with MPAPA by Kato et al. (2019) and Nishio et al. (2023) occurred de novo.
In a patient with MPAPA, Kato et al. (2019) identified a de novo heterozygous mutation in the MYCN gene (T58M; 164840.0008). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. Expression of MYCN with the T58M mutation in HEK293 cells demonstrated that the protein was hypophosphorylated compared to wildtype.
In 2 patients with MPAPA, Nishio et al. (2023) identified de novo heterozygous missense mutations in the MYCN gene: the previously identified T58M mutation and P60L (164840.0009). Expression of MYCN with each mutation in HEK293 cells resulted in decreased phosphorylation at T58 compared to wildtype. MYCN with the T58M mutation was also more stable compared to wildtype. Both mutants were able to activate transcription of downstream genes. Nishio et al. (2023) concluded that both of these mutations were gain-of-function. Based on the patients' phenotype, Nishio et al. (2023) concluded that these gain-of-function mutations in MYCN resulted in a mirror phenotype of Feingold syndrome-1 (164280), which results from loss of function of MYCN.
Kato, K., Miya, F., Hamada, N., Negishi, Y., Narumi-Kishimoto, Y., Ozawa, H., Ito, H., Hori, I., Hattori, A., Okamoto, N., Kato, M., Tsunoda, T., Kanemura, Y., Kosaki, K., Takahashi, Y., Nagata, K. I., Saitoh, S. MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome. J. Med. Genet. 56: 388-395, 2019. [PubMed: 30573562] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105487]
Nishio, Y., Kato, K., Mau-Them Frederic, T., Futagawa, H., Quelin, C., Masuda, S., Vitobello, A., Otsuji, S., Shawki, H. H., Oishi, H., Thauvin-Robinet, C., Takenouchi, T., Kosaki, K., Takahashi, Y., Saitoh, S. Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome. Hum. Genet. Genomics Adv. 4: 100238, 2023. [PubMed: 37710961] [Full Text: https://doi.org/10.1016/j.xhgg.2023.100238]