Cleft Palate, Psychomotor Retardation, And Distinctive Facial Features

A number sign (#) is used with this entry because of evidence that a syndrome of cleft palate, psychomotor retardation, and distinctive facial features is caused by heterozygous mutation in the KDM1A gene (609132) on chromosome 1p36.

Clinical Features

Tunovic et al. (2014) reported a 32-month-old male born to healthy parents with no consanguinity. Ethnicity was Asian and Caucasian. Birthweight was greater than 97th percentile, length greater than 90 percentile, and head circumference was 90th to 97th percentile. A U-shaped cleft of the secondary palate was identified and repaired at 11 months. Mild chordee, hypospadias, and patent foramen ovale were present. Laminectomy was performed at 26 months of age to correct spinal stenosis. The patient had displayed global developmental delay from infancy and at age 3 was unable to walk or speak, although receptive language skills were present. Physical exam at 32 months of age showed weight at the 19th percentile, height at the 31st percentile, and head circumference at the 85th percentile. He had a slightly elevated anterior hairline, sparse temporal and eyebrow hair and frontal bossing, bilateral ptosis, minor downslanting of palpebral fissures, slightly blue sclerae, and widely spaced eyes. The nose was anteverted with a wide nasal bridge and narrow nasal tip. Fingers were tapered, with brachydactyly of the fingers, fifth finger clinodactyly, short thumbs, and hypoplastic toenails. The patient had central hypotonia with hypertonia of the legs that included scissoring and clonus. Brain MRI in the neonatal period showed dysmorphic corpus callosum with a thin callosal body and a disproportionately small cerebellum.

Chong et al. (2016) described 2 patients (families B and C), both male, who shared clinical features and who carried heterozygous missense mutations in the KDM1A gene (see MOLECULAR GENETICS). Chong et al. (2016) compared these patients to the one reported by Tunovic et al. (2014) (family A). All 3 patients had developmental and speech delay. Sitting age was delayed in all, with patient A sitting at 20 months, B at 11 months, and patient C at 18 months. While patient A had not achieved walking by age 4 years, patient B walked at 3 years of age, and patient C at 7.5 years. All 3 had palatal anomalies, hypotonia, downslanting palpebral fissures, prominent forehead, wide nasal bridge, thin upper lip, and widely spaced teeth. Patients B and C had conical canines, brachycephaly, calcaneal valgus, exotropia, and strabismus. While patient B had macrocephaly, delayed myelination, prominent horns of lateral ventricles, white matter hypoplasia, and thin corpus callosum, patient C had no brain malformations except macrocerebellum. Patient C, who had had a single febrile seizure, also had oculomotor apraxia, cryptorchidism, supernumerary nipple, hypertrichosis, and synophrys. Patient C had been enrolled in the study of Rauch et al. (2012) from the German Mental Retardation Network.

Cytogenetics

Using chromosome microarray, Tunovic et al. (2014) found that their patient carried a maternally inherited copy number gain at Xq12, arr Xq12(65,083,017-65,823,985)x2 mat, containing the MIR223 (300694), VSIG4 (300353), HEPH (300167), and EDA2R (300276) genes. This small duplication was reported to be of unknown significance and was not present in the patient's typically developing older brother.

Molecular Genetics

In a patient with global developmental delay and clinical features overlapping those of KBG (148050) and Kabuki (see 147920) syndromes, Tunovic et al. (2014) detected heterozygosity for 2 sequence variants. One was an in-frame 3-nucleotide deletion in the ANKRD11 gene (611192). Out-of-frame deletions in this gene cause the KBG syndrome. The second was a missense substitution in the KDM1A gene, tyr785 to his (Y785H; 609132.0001). This variant was considered likely pathogenic due to the substitution of a neutral tyrosine residue with a positively charged histidine at an evolutionarily conserved residue, but deleterious sequence variants in KDM1A had not previously been associated with a phenotype in human patients. Both variants occurred de novo and were detected by whole-exome sequencing.

Chong et al. (2016) reported 2 patients with missense mutations in KDM1A gene (E403K, 609132.0002; D580G, classified as a variant of unknown significance, 609132.0003). Both mutations occurred de novo and were not present in public databases.

Other Features

Chong et al. (2016) detailed how patients B and C in their report were identified through the efforts of the parents of patient A to find more individuals with a phenotype and/or genotype similar to that of their son, and to recruit researchers to study their child's condition, using social media.