A Recurrent Biallelic Pathogenic Variant in TBXAS1 Gene Causing Ghosal Hematodiaphyseal Dysplasia
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SCIENTIFIC LETTER
A Recurrent Biallelic Pathogenic Variant in TBXAS1 Gene Causing Ghosal Hematodiaphyseal Dysplasia Agnes Selina 1,2 & Madhavi Kandagaddala 3 & Vrisha Madhuri 1,2 Received: 23 August 2020 / Accepted: 20 November 2020 # Dr. K C Chaudhuri Foundation 2020
To the Editor: Ghosal hematodiaphyseal dysplasia (GHHD) is a rare autosomal recessive disorder with increased bone density, meta-diaphyseal dysplasia, and defective hematopoiesis [1]. We report a known pathogenic variant in TBXAS1 gene from South India, the 5th in Asia, with previously undescribed developmental delay, ptosis, and camptodactyly. A 6-y-old boy, with second-degree consanguinity, presented with difficulty in sitting, standing, and walking. He weighed 2.8 kg (25th centile) at birth and was delivered at term. He stood at 2.5 and walked at three years. He has difficulty in following standard commands. On clinical examination, he had a flat nasal bridge, bilateral ptosis, high arched palate, and bilateral fifth finger camptodactyly. His weight was 19 kg (50th centile), height was 117 cm (75th to 97th centile) and his head circumference was 50 cm (25th to 50th centile). Blood investigations showed a hemoglobin of 9.1 g/dL, hematocrit of 29.5%, and platelet count of 357,000/mm3. The white blood cell count was 8400/mm3 with 50% neutrophils, 44% lymphocytes, 5% monocytes and eosinophils 1%. MCV was 68.4 fL; MCH 21 pG; MCHC 30.7% and RDW 21.9% indicating hypochromic microcytic anemia. Radiographs showed a diffuse expansion of the meta-diaphysis of the long bones with sclerosis, cortical thickening, and hyperostosis. Anterior ends of ribs were expanded and sclerosed. A homozygous pathogenic variant ENST00000416849.6: c.1376G > A p. (Arg459Gln) in
* Vrisha Madhuri [email protected]; [email protected] 1
Department of Pediatric Orthopedics, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu, India
2
Centre for Stem Cell Research, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu 632004, India
3
Department of Radiology, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu, India
exon 12 of the TBXAS1 gene by clinical exome sequencing was identified and segregation analysis showed heterozygous variants in the parents. No other pathogenic variants accounting for the neurological manifestations were present. This variant is recurrent in the Asian population with five probands from Pakistan and India [2, 3]. There are more than 24 cases of GHHD reported till date [3] and in addition 5 variants in the database. The patient is treated with iron and folic acid supplements and hemoglobin is maintained around 9 g/dL at four monthly reviews. The differential diagnosis for skeletal dysplasia with anaemia includes Caffey disease, Camurati–Engelmann disease and osteopetrosis [4]. Radiological and molecular genetic analysis differentiates GHHD in children with unusual anemia. Although steroids are recommended for GHHD [5], our child with moderate anaemia is being followed for intervention when ne
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