Cleft Palate, Cardiac Defects, And Mental Retardation

A number sign (#) is used with this entry because of evidence that cleft palate, cardiac defects, and mental retardation (CPCMR) is caused by heterozygous mutation in the MEIS2 gene (601740) on chromosome 15q14.

Clinical Features

Percin et al. (1995) reported a family in which members in 3 generations showed various combinations of malformations: congenital heart defect (primum type atrial septal defect in 1 and Fallot pentalogy in another), cleft lip/palate, short stature, microcephaly, distally-placed thumbs, short second and fifth fingers, long and broad first toes, wide distance between first and second toes, and medial dorsal curvature of the fourth toes with syndactyly of the second and third toes. Whereas some members of the family had full signs of the syndrome, others had fewer and less severe anomalies of the same structures. One of the affected members of the family had an occult right cleft lip.

Johansson et al. (2014) studied 5 patients from 4 families with deletions at chromosome 15q14 (see 616898), all involving the MEIS2 gene, as well as a family in which a mother and 3 children had an intragenic duplication in MEIS2. Overall, 7 of 9 patients had clefting, ranging from mild (submucous cleft palate) to severe (cleft lip and palate), and 3 of 9 had ventricular septal defects (VSDs). All patients had delayed motor development, and most had learning difficulties, at worst in the mild intellectual disability range. Affected individuals exhibited overlapping facial features, including broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip, but individually they were not considered to be dysmorphic.

Louw et al. (2015) described a 5-year-old girl with severely delayed motor development, moderate intellectual disability with poor speech, and multiple congenital malformations. She had cleft palate, congenital heart defects, including atrial septal defect (ASD), VSD, and aortic coarctation, and feeding problems due to gastroesophageal reflux, with oral aversion, aerophagia, and achalasia requiring gastrostomy and Botulinum neurotoxin A infiltrations. She also had mild distal skeletal anomalies, including broad first ray of hands and feet, a gap between the first and second toes, and syndactyly of the second and third toes. In addition, she had dysmorphic facial features, including arched and laterally extended eyebrows, mildly upslanting palpebral fissures, deeply set eyes, bitemporal narrowing, tented upper lip, thin upper vermilion, and full lower vermilion. Brain imaging was normal.

Fujita et al. (2016) reported a 2.75-year-old French girl who had severe intellectual disability, cleft palate, ASD and VSD, and mild facial dysmorphism, including large forehead, mild trigonocephaly, sparse eyebrows, deeply set eyes, large and low-set ears, full cheeks, and thin upper vermilion. She had serious feeding difficulties with gastroesophageal reflux, requiring gastrostomy at 3 months. She also had moderate delay in motor development and severe hypermetropia.

Inheritance

Percin et al. (1995) suggested autosomal dominant inheritance for this disorder because of the involvement of 3 generations, variable expressivity, pleiotropism, and lack of consanguinity in the family.

Molecular Genetics

In a mother and 3 children with cleft palate and mildly delayed motor development and/or mild intellectual disability, Johansson et al. (2014) performed array-based genomic copy number analysis and identified heterozygosity for a 58-kb intragenic duplication in the MEIS2 gene (601740.0002).

In a 5-year-old girl with cleft palate, congenital heart defects, severely delayed motor development, and moderate intellectual disability, Louw et al. (2015) identified a de novo heterozygous 3-bp in-frame deletion in the MEIS2 gene (601740.0001).

In a 2.75-year-old French girl with cleft palate, atrial and ventricular septal defects, delayed motor development, and severe intellectual disability, Fujita et al. (2016) performed whole-exome sequencing and identified heterozygosity for a de novo nonsense mutation in the MEIS2 gene (S204X; 601740.0003).