Ms Binata Marik
Supervisors: Prof. Arundhati Sharma
Country of Origin: India
Project Title: Genetic study in patients with refractory rickets and hypophosphatemia
News Byte: Refractory rickets is a form of rickets which cannot be cured by calcium and vitamin D supplementation. It is caused due to mutations in genes encoding proteins which are involved in renal phosphate reabsorption process, and vitamin D uptake and metabolism. It includes entities such as hypophosphatemic rickets, vitamin D dependent rickets, Dent disease, renal Fanconi syndrome, renal tubular acidosis and oncogenic osteomalacia. Due to lack of awareness about refractory rickets in developing countries, the diagnosis of this entity is often missed and patients receive multiple doses of vitamin D resulting in toxicity. Genetic testing can only provide an accurate diagnosis. Our project focusses on identifying genetic mutations which are responsible for causing refractory rickets in children which helps in better treatment and management of the condition.
Abstract: Refractory rickets is a genetic disorder and hypophosphatemic rickets (HR) is the major form in Indian children. HR is mainly inherited in an X-linked dominant manner due to inactivating PHEX mutations. PHEX, a phosphate regulating protein, downregulates the synthesis of fibroblast growth factor-23 (FGF-23). FGF-23 normally promotes phosphate excretion to maintain phosphate homeostasis. Therefore, PHEX mutations produce defective PHEX protein which fails to regulate FGF-23 expression thereby leading to overproduction of FGF23 promoting phosphaturia resulting in hypophosphatemic rickets. Autosomal dominant, recessive and X-linked recessive forms of hypophosphatemic rickets due to FGF23, DMP1, ENPP1, SLC34A3, CLCN5 and OCRL mutations respectively are also documented. Current methods of diagnosis rely on clinical, biochemical and radiographic parameters, yet diagnosis is not accurate. Genetic testing can only provide an accurate diagnosis. Genetic testing for loss-of-function mutations in PHEX, DMP1, ENPP1, SLC34A3, CLCN5 and OCRL or gain-of-function mutations in FGF-23 can allow diagnosis of X-linked HR (XLHR), autosomal dominant HR (ADHR), autosomal recessive HR (ARHR) and Dent disease based on a single blood draw at any age. Thus, genetic testing can simplify diagnosis of HR in infants and help to discriminate XLHR, ADHR, ARHR and Dent disease from tumor induced osteomalacia (TIO) in older children and adults allowing more informed genetic counseling. Early diagnosis of HR is important, since initiation of treatment (phosphate and calcitriol supplementation) in infancy may allow minimization of skeletal deformities. Genetic testing can also identify carriers in the family who may not be aware of harboring a mutation associated with HR because they are mildly affected by the disease. There was paucity of data on the etiology of refractory rickets in Indian children. The project was proposed to check the genetic profile of the patients with refractory rickets and hypophosphatemia.
Keywords: Hypophosphatemic rickets, PHEX, FGF23, genetic testing, carrier detection, accurate diagnosis
- Marik B, Bagga A, Sinha A, Hari P, Sharma A. Genetics of Refractory Rickets: Identification of Novel PHEX Mutations in Indian Patients and a Literature Update. J Pediatr Genet; 2018;7(2):47-59.
- Marik B, Bagga A, Sinha A, Hari P, Sharma A. Mutational screening in patients with familial hypophosphatemic rickets. J Mol Genet Med; 2018;12:46.
- Marik B. CRISPR-Cas9-A powerful gene editing tool. Future Medicine; 2018 Nov:5(7):92-93.
- Marik B, Bagga A, Sinha A, Hari P, Sharma A. Whole Exome Sequencing Reveals Novel PHEX Mutations in Patients of Sporadic Hypophosphatemic Rickets. Acta Scientific Paediatrics; 2019;2(3):12-14.
- Marik B, Bagga A, Sinha A, Khandelwal P, Hari P, Sharma A. Whole exome sequencing (WES) in patients with hypophosphatemic rickets. Pediatr Nephrol; 2019; 34:1953.
- Marik B, Bagga A, Sinha A, Hari P, Sharma A. Importance of genetic testing in the diagnosis and management of hypophosphatemic rickets. Biochem Mol biol J. 2019; 5: 87.