A rare homozygous variant in TERT gene causing variable bone marrow failure, fragility fractures, rib anomalies and extremely short telomere lengths with high serum IgE

Mahmoud I Elbadry; Ahmed Tawfeek; Tomonori Hirano; Mohamed A El-Mokhtar; Mohamed Kenawey; Ahmed M Helmy; Seishi Ogawa; M Zulf Mughal; Yasuhito Nannya

doi:10.1111/bjh.19176

A rare homozygous variant in TERT gene causing variable bone marrow failure, fragility fractures, rib anomalies and extremely short telomere lengths with high serum IgE

Br J Haematol. 2024 Mar;204(3):1086-1095. doi: 10.1111/bjh.19176. Epub 2023 Nov 5.

Authors

Mahmoud I Elbadry¹, Ahmed Tawfeek², Tomonori Hirano³, Mohamed A El-Mokhtar^{4

5}, Mohamed Kenawey^{6

7}, Ahmed M Helmy⁸, Seishi Ogawa^{3

9

10}, M Zulf Mughal¹¹, Yasuhito Nannya^{3

12}

Affiliations

¹ Division of Haematology, Department of Internal Medicine, Faculty of Medicine, Sohag University, Sohag, Egypt.
² Department of Clinical and Chemical Pathology, Faculty of Medicine, Sohag University, Sohag, Egypt.
³ Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
⁴ Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Asyut, Egypt.
⁵ Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon.
⁶ Orthopedic Surgery Department, Faculty of Medicine, Sohag University, Sohag, Egypt.
⁷ Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁸ Department of Internal Medicine, Faculty of Medicine, Sohag University, Sohag, Egypt.
⁹ Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
¹⁰ Department of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
¹¹ Pediatric Bone Disorders, Al Jalila Children's Speciality Hospital, Dubai, UAE.
¹² Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

PMID: 37926112
DOI: 10.1111/bjh.19176

Abstract

By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF), raccoon eyes, dystrophic nails, rib anomalies, fragility fractures (FFs), high IgE level, extremely short telomere lengths (TLs), and skewed numbers of cytotoxic T cells with B and NK cytopenia. Haploinsufficiency in the other family members resulted in short TL and osteopenia. These patients also had the lowest bone mineral density Z-score compared to other BMF-patients. Danazol/zoledronic acid improved the outcomes of BMF and FFs. This causative TERT variant has been observed in one family afflicted with dyskeratosis congenita (DC), and thus, we also define a second report and new phenotype related to the variant which should be suspected in severe cases of DC with co-existent BMF, FFs, high IgE level and rib anomalies.

Keywords: TERT mutation; fragility fracture; high serum IgE; unclassifiable inherited bone marrow failure.

MeSH terms

Dyskeratosis Congenita* / genetics
Humans
Immunoglobulin E / genetics
Mutation
Pancytopenia*
Rib Fractures*
Telomerase* / genetics
Telomere

Substances

Immunoglobulin E
Telomerase
TERT protein, human