A case of severe TBCE-negative hypoparathyroidism-retardation-dysmorphism syndrome: Case report and literature review

作者：Ryabets Lienhard Anna; Ayuthaya Satja Issaranggoon Na; Graham John M; Pitukcheewanont Pisit^*

来源：American Journal of Medical Genetics, Part A, 2018, 176(8): 1768-1772.

DOI：10.1002/ajmg.a.38851

• congenital hypoparathyroidism
• CASC5 gene
• hypoparathyroidism-retardation-dysmorphism syndrome
• sanjad-sakati syndrome
• severe microcephaly
• TBCE gene

Hypoparathyroidism-retardation-dysmorphism syndrome (HRD) is a rare autosomal recessive disorder attributed to the mutations in the tubulin-specific chaperone E (TBCE) gene, which is vital for microtubule function during mitosis, organelle positioning, and neuronal cytokinesis. HRD is a congenital syndromic hypoparathyroidism associated with growth deficiency, microcephaly, intellectual disability, ocular anomalies, and facial dysmorphism. To our knowledge, there is only one published case of mild HRD-like syndrome with no identifiable genetic etiology. We report a case of severe TBCE-negative phenotypic HRD in a 4-year-old female from India presenting with hypocalcemic seizures due to congenital hypoparathyroidism, extreme microcephaly, growth deficiency, ocular anomalies, and facial dysmorphism. SNP microarray and whole exome sequencing (WES) did not detect any abnormalities in TBCE or other genes of interest. WES revealed two variants of unknown clinical significance in CASC5 gene, which codes for a protein in the kinetochore and, interestingly similar to TBCE, is essential for proper microtubule function during mitosis and cell proliferation and has been implicated in primary microcephaly disorders. However, further targeted sequencing in the parents revealed both variants inherited from the unaffected mother. Significant copy number variant noise in the proband and her parents limited further analysis. At this time the role of variants in the CASC5 gene is unclear and cannot explain our patient's phenotype. In conclusion, we report a severe case of phenotypic HRD syndrome, in which extensive genetic evaluation failed to reveal an etiology. Our case demonstrates that the pathogenesis of HRD may be genetically heterogenous, meriting further genetic investigations.

• 出版日期2018-8