Draft:Al-Kaissi Syndrome

Al Kaissi Syndrome (ALKAS) is a rare autosomal recessive developmental disorder characterized by a range of physical and neurological abnormalities. It has been identified in families of Tunisian, Algerian, Saudi Arabian, and Turkish descent.

Genetics

The syndrome results from homozygous mutations in the CDK10 gene located on chromosome 16q24.3. It encodes cyclin-dependent kinase 10, a protein kinase involved in cell cycle control, transcription, and development. CDK10 partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2, which are crucial for modulating cellular growth and ciliogenesis. The loss-of-function mutations in CDK10 lead to impaired degradation of ETS2, affecting transcriptional regulation necessary for development. Additionally, these mutations alter ciliogenesis by affecting the PKN2-RhoA pathway, leading to abnormal cilia formation and function, which is essential for signal transduction during embryonic and postnatal development. This genetic mutation is inherited in an autosomal recessive manner, meaning both parents must carry one copy of the mutated gene to confer a 25% risk to their offspring.

Clinical Presentation

Individuals with Al Kaissi Syndrome typically present with severe prenatal and postnatal growth retardation. Neurologically, they exhibit generalized hypotonia and significant delays in developmental milestone, including speech, sitting, and walking. Intellectual disability can range from moderate to severe. Dysmorphic features include a triangular face, small chin, narrow forehead, low-set ears, hypertelorism, ptosis, and a broad nasal tip. Musculoskeletal abnormalities often involve cervical spine malformations and small hands with deep palmar creases.

Pathophysiology

Al Kaissi Syndrome stems from homozygous mutations in the CDK10 gene, which disrupts the function of cyclin-dependent kinase 10, a crucial enzyme for cell cycle regulation and cellular proliferation. CDK10 normally partners with cyclin M to phosphorylate substrates like ETS2, facilitating their degradation and regulating transcription. The mutations lead to a loss of kinase activity, impairing cell cycle progression during the G2-M phase. This disruption affects normal cellular growth and division, contributing to the severe growth retardation and developmental delays seen in affected individuals. Additionally, the impaired regulation of actin cytoskeleton dynamics and ciliogenesis due to altered phosphorylation of PKN2 further exacerbates developmental anomalies.

Diagnosis

Diagnosis involves clinical evaluation and genetic testing to identify mutations in the CDK10 gene. A brain MRI may reveal underdevelopment of the corpus callosum in some patients. Due to overlapping symptoms with other disorders, a multidisciplinary approach involving ophthalmologists, neurologists, and pediatricians is often necessary for accurate diagnosis. The exact number of people diagnosed with Al Kaissi Syndrome is not precisely known. As of 2022, only 10 patients from 6 unrelated families had been reported in the literature with bi-allelic variants in CDK10. Additionally, 4 new patients from France and the Netherlands were identified at that time. This suggests that fewer than 20 cases have been officially diagnosed and reported in medical literature as of 2022. Due to the rarity of the condition and potential underdiagnosis, the actual number of affected individuals worldwide may be higher than what has been reported in scientific publications.

Treatment

Currently, there is no known treatment for Al Kaissi Syndrome. Management focuses on supportive care to address specific symptoms and improve quality of life.