ORPHA: 592574;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q13.2 | Menke-Hennekam syndrome 2 | 618333 | Autosomal dominant | 3 | EP300 | 602700 |
A number sign (#) is used with this entry because of evidence that Menke-Hennekam syndrome-2 (MKHK2) is caused by heterozygous mutations in exon 30 or 31 of the EP300 gene (602700) on chromosome 22q13.
Menke-Hennekam syndrome-2 (MKHK2) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, and hearing impairment are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-2 (RSTS2; 613684), patients with MKHK1 do not resemble the striking phenotype of RSTS2.
For a discussion of genetic heterogeneity of Menke-Hennekam syndrome, see MKHK1 (618332).
Menke et al. (2018) described a 17-year-old girl from the UK (patient E1) who had presented as a neonate as floppy, with very lax joints, and who developed feeding problems including difficulty swallowing necessitating a percutaneous gastrostomy (PEG). She had recurrent otitis media, airway infections, urinary tract infections, and was found to have very low immunoglobulins. She had strabismus and bilateral moderate sensorineural hearing loss. In her teens she had duodenal ulcers that suggested Crohn disease (IBD1; 266600), but biopsies were inconclusive. She was diagnosed with autism spectrum disorder, showed hyperactive behaviors, and suffered insomnia. This patient had been reported as patient 6 by Hamilton et al. (2016), who noted motor and speech delay, with walking achieved at 2.5 years and speech at age 5. Menke et al. (2018) also described a 14-year-old girl from the Netherlands (E2) who had slept unusually much during infancy and did not seem to notice feelings of hunger and had no suck reflex. At age 13 she still did not seem to notice feelings of hunger and preferred pureed food. At age 4, speech therapy was started both for speech delay and for swallowing problems, and at age 5 physiotherapy was started because of delay in fine motor skills. She was found to have an IQ of 91 (verbal 101, performance 82). Autism spectrum disorder was also diagnosed. At age 13 she continued to have recurrent otitis and a decrease in muscle strength of the hands, and had developed a progressive contracture of the fifth fingers. Both girls were born at term at average gestational size. At last evaluation the patients were still of average size with normal head circumference. Patient E1 had large halluces with fibular deviation, and E2 had normal halluces. Both had normal thumbs.
In both patients with MKHK2 reported by Menke et al. (2018), one of whom had been reported by Hamilton et al. (2016), the mutations in EP300 were shown to have arisen de novo.
In 2 patients with MKHK2, Menke et al. (2018) identified 2 heterozygous de novo mutations in EP300 (602700.0012, 602700.0013).
Hamilton, M. J., Newbury-Ecob, R., Holder-Espinasse, M., Yau, S., Lillis, S., Hurst, J. A., Clement, E., Reardon, W., Joss, S., Hobson, E., Blyth, M., Al-Shehhi, M., Lynch, S. A., DDD study, Suri, M. Rubinstein-Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum. Clin. Dysmorph. 25: 135-147, 2016. [PubMed: 27465822] [Full Text: https://doi.org/10.1097/MCD.0000000000000143]
Menke, L. A., DDD Study, Gardeitchik, T., Hammond, P., Heimdal, K. R., Houge, G., Hufnagel, S. B., Ji, J., Johansson, S., Kant, S. G., Kinning, E., Leon, E. L., and 14 others. Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome. Am. J. Med. Genet. 176: 862-876, 2018. [PubMed: 29460469] [Full Text: https://doi.org/10.1002/ajmg.a.38626]