IARS2-related disease manifesting as sideroblastic anemia and hypoparathyroidism: A case report.

Background: IARS2 (EC6.1.5) is a mitochondrial isoleucine-tRNA synthetase. Despite the fact that only fewer than 30 patients have been reported in the literature, mitochondrial disorders caused by pathogenic variants in the IARS2 gene (OMIM: 616007) have a very broad and variable clinical phenotype spectrum. We present a child who has sideroblastic anemia and hypoparathyroidism as a result of a previously unreported mutation in the IARS2 gene. Case presentation: A 14-year-old girl who had been anemic for 12 years was diagnosed with pure red cell aplasia (hemoglobin 42 g/L, reference range 110-160) at the age of 2. Her anemia was resistant to high-dose intravenous gamma globulin and cyclosporine therapy and required monthly blood transfusions to maintain normal hemoglobin levels. She developed cataracts at the age of 6 and was cured by phacoemulsification. At the age of 8, she visited the endocrine department, because of mental and physical retardation accompanied by repeated convulsions, and the antiepileptic treatment was ineffective. She was diagnosed with hypoparathyroidism. To control the convulsions, she was given calcitriol orally as well as large doses of calcium supplements. Due to severe growth and development delays, delayed sexual development, and hypokinesia at the age of 13.5Y, the parents agreed to a whole-exon gene sequencing test. IARS2 gene compound heterozygous variants c.2450G > A (p.Arg817His) and c.2511del (p.Leu838Phefs*69) were discovered. The girl was then diagnosed with IARS2-related disease and given a cocktail therapy of coenzyme Q10, vitamin B2, L-Carnitine and vitamin E. Although the child's clinical symptoms improved, she still experienced intermittent claudication and hip joint pain. The vitamin B6 was discontinued after three months due to its ineffectiveness in treating anemia. Because the child's ferritin levels remained elevated, she was also prescribed long-term oral deferiprone therapy. Conclusion: Our findings broaden the clinical and genetic spectrum of IARS2-associated disease, and case summaries help raise clinical awareness of IARS2-associated disease and reduce under- and misdiagnosis.

A three-year clinical investigation of a Chinese child with craniometaphyseal dysplasia caused by a mutated ANKH gene.

BACKGROUND: Craniometaphyseal dysplasia (CMD) is a rare genetic disorder. Autosomal dominant CMD (AD-CMD) is caused by mutations in the ANKH gene. Affected individuals typically have distinctive facial features including progressive thickening of the craniofacial bones. Treatment for AD-CMD primarily consists of surgical intervention to release compression of the cranial nerves and the brain stem/spinal cord. To alleviate progression of the clinical course and improve the quality of life in children waiting to undergo the necessary surgery, we investigated clinical changes in a diagnosed patient with AD-CMD over three years. CASE SUMMARY: A 17-mo-old boy presented with progressive nasal obstruction, snoring and hearing loss symptoms. Physical examination showed enlargement of the head circumference and clinical features such as wide nasal bridge, paranasal bossing, widely spaced eyes with an increased bizygomatic width, and a prominent mandible. The patient underwent otolaryngological examination, endoscopy, hearing test, laboratory examination of phosphorus and bone metabolism, cranial and femoral computed tomography, X-ray and next-generation sequencing. The patient was diagnosed with AD-CMD due to p.Phe377 deletion (c.1129_1131del) on exon 9 of the ANKH gene. After adherence to a prescribed low-calcium diet, the boy's alkaline phosphatase (ALP) levels continuously decreased to within the normal range. However, after 14 mo of dietary intervention, his parents altered his diet to an intermittent low-calcium diet to include milk and eggs. The patient's ALP was slightly higher than normal after the dietary change but remained close to the normal range. His serum osteocalcin changed to within normal levels after dietary regulation for 33 mo. His serum combined beta C-terminal telopeptide of type I collagen also continuously decreased after the nutritional intervention, although still slightly higher than normal levels. Despite fluctuating blood test results, the boy's nasal symptoms were markedly relieved and steadily improved after dietary intervention. No significant changes were found in the craniofacial bones by cranial radiography. Close monitoring of clinical features is still ongoing. Calcitriol treatment is currently under consideration and a surgical procedure is planned as necessary in the future. CONCLUSION: We herein report the first Chinese case of AD-CMD with heterozygous mutation of p.Phe377 deletion (c.1129_1131del) on the ANKH gene. Biochemical alterations were significantly improved after dietary intervention indicating that a low-calcium diet may be applied in pediatric AD-CMD patients with ANKH mutations to help alleviate phenotypic manifestations and improve the quality of life before surgical intervention. Further large scale studies are needed to replicate these findings and to establish the appropriate timing for nutritional and surgical interventions.