Menke-Hennekam Syndrome 1

A number sign (#) is used with this entry because of evidence that Menke-Hennekam syndrome-1 (MKHK1) is caused by heterozygous mutation in exon 30 or 31 of the CREBBP gene (600140) on chromosome 16p13. Mutation elsewhere in the CREBBP gene results in Rubinstein-Taybi syndrome-1 (RSTS1; 180849), which is phenotypically distinct.

Description

Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-1 (RSTS1; 180849), patients with MKHK1 do not resemble the striking phenotype of RSTS1.

Genetic Heterogeneity of Menke-Hennekam Syndrome

Menke-Hennekam syndrome-2 (MKHK2; 618333) is caused by heterozygous mutation in exons 30 or 31 of the EP300 gene (602700). Mutation elsewhere in that gene results in RSTS2 (613684).

Clinical Features

Menke et al. (2016) reported 11 patients carrying mutations in CREBBP (exon 30 or 31) whose phenotype differed substantially from Rubinstein-Taybi syndrome (RSTS1; 180849). None had broad thumbs or characteristic facial features, and 3 had only somewhat broadened halluces. All had developmental delay or intellectual disability, 5 had short stature, and 7 had microcephaly. Facial characteristics were variable and included short palpebral fissures, telecanthus, depressed nasal bridge, short nose, anteverted nares, short columella, and long philtrum. Six of the 11 had autistic behavior and 2 had self-injurious behavior. Other symptoms were recurrent upper airway infection in 5, feeding problems in 7, and impaired hearing in 7. No major malformations occurred.

Menke et al. (2018) reported an additional 11 patients with MKHK1 and compared them to the previously reported patients. Almost all patients had impaired intellectual development, with autistic behavior in more than half. Short stature, microcephaly, feeding problems, and vision and hearing impairment were frequent. Malformations were uncommon and included cleft palate, congenital heart anomaly, renal anomaly, malrotation, and cryptorchidism. Cerebral anomalies (white matter atrophy, hypoplasia or agenesis of corpus callosum) were seen in 3 of 4 previously unreported patients tested. Facial features were variable but patients with mutations in a restricted 3-prime region resembled each other (see GENOTYPE/PHENOTYPE CORRELATIONS). Only 2 had broad halluces. None of the patients had broad or angulated thumbs, or any other characteristic typical of RSTS.

Inheritance

In all MKHK1 patients but 1 included in the reports of Menke et al. (2016), Menke et al. (2018), and Angius et al. (2019), the mutations were shown to have arisen de novo. The only patient in which mode of inheritance could not be established was patient C16 of Menke et al. (2018), whose parents were deceased.

Genotype/Phenotype Correlations

Menke et al. (2018) noted that MKHK1 patients with mutations at the 3-prime end of CREBBP between basepairs 5,595 and 5,614 share facial characteristics consisting of ptosis, telecanthus, short and upslanting palpebral fissures, depressed nasal bridge, short nose, anteverted nares, short columella, and long philtrum. The facial characteristics change with age and are best recognized in infancy.

Molecular Genetics

Menke et al. (2016) reported 10 novel missense variants (e.g., 600140.0009-600140.0012) in CREBBP, all in the last part of exon 30 or the first part of exon 31, in 11 patients with Menke-Hennekam syndrome. All mutations occurred de novo.

Menke et al. (2018) reported 9 different mutations (e.g., 600140.0010-600140.0012), 6 of them novel, in exon 30 or 31 of the CREBBP gene in 11 previously unreported patients with MKHK1. Eight mutations were missense and 1 was a 3-bp deletion; all but 1, in a patient whose parents were deceased, were shown to have occurred de novo. Menke et al. (2018) also reported 2 patients with MKHK2 (618333) with mutations in EP300 (602700) in locations homologous to those found in CREBBP.

Angius et al. (2019) reported a 17-year-old Sardinian boy with MKHK1 who carried a novel de novo missense variant (E1724K; 600140.0013) in exon 30 of CREBBP. He presented with mild intellectual impairment and dysmorphisms as well as obesity, and did not resemble patients with classical Rubinstein-Taybi syndrome. Angius et al. (2019) noted that obesity had also been reported in 3 of the patients of Menke et al. (2018).