Al Kaissi Syndrome

A number sign (#) is used with this entry because of evidence that Al Kaissi syndrome (ALKAS) is caused by homozygous mutation in the CDK10 gene (603464) on chromosome 16q24.

Description

Al Kaissi syndrome is an autosomal recessive developmental disorder characterized by growth retardation, spine malformation, particularly of the cervical spine, dysmorphic facial features, and delayed psychomotor development with moderate to severe intellectual disability (summary by Windpassinger et al., 2017).

Clinical Features

Windpassinger et al. (2017) reported 9 individuals from 5 unrelated consanguineous families with a congenital developmental disorder. The patients were ascertained by 5 different research teams. The families were of Tunisian, Algerian, Saudi Arabian, or Turkish descent. The patients presented at birth with intrauterine growth retardation, severe hypotonia, and dysmorphic facial features. All had poor overall growth and delayed development with moderate to severe intellectual disability and severely delayed language acquisition. All but 1 had striking cervical spine anomalies, including clefting, segmentation anomalies, and improper fusion. Five had a sacral dimple. Dysmorphic facial features were slightly variable, but included synophrys, hypertelorism, epicanthal folds, downslanting palpebral fissures, ptosis, narrow forehead, depressed nasal bridge, broad nasal tip, long smooth philtrum, small chin, triangular face, low-set and posteriorly rotated ears, and high-arched palate. Most patients had small hands with deep palmar creases, and some had joint hyperlaxity or pes planus. Brain imaging in 3 patients showed thin corpus callosum, although 3 other patients had normal brain MRI. Two patients had atrial septal defects.

Inheritance

The transmission pattern of ALKAS in the families reported by Windpassinger et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 9 patients from 5 consanguineous families with ALKAS, Windpassinger et al. (2017) identified homozygous mutations in the CDK10 gene (603464.0001-603464.0004). The mutations, which were found by a combination of array CGH, whole-genome homozygosity mapping, and whole-exome sequencing, segregated with the disorder in all families. There were 2 splice site mutations, 1 frameshift, and an intragenic deletion, all predicted to result in a loss of function. Fibroblasts derived from 1 patient showed decreased levels and activity of CDK10.

Animal Model

Windpassinger et al. (2017) found that Cdk10-null mice showed partial prenatal lethality, with fewer than 6% born, and very few surviving the first day of life. Cdk10-null embryos showed severe growth retardation, and newborn mutant pups had significant skeletal abnormalities, including reduced volume of mineralized matrix in the skull, bifidity or clefting of C1 (atlas) or C2 (axis), absence of the dens, and volume reduction of mineralized matrix in the femur, tibia, and fibula. Abnormalities were observed in other organs as well, including the kidney, lung, heart, spleen, liver, and muscle. Gene expression studies showed dysregulation of multiple gene pathways, including those involved in metabolic processes and ciliogenesis. Mutant cells did not show a defect in cell proliferation or cell cycle progression, but did show longer cilia compared to wildtype.