The value of whole exome sequencing for genetic diagnosis in a patient with Bloom syndrome
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BRIEF REPORT
The value of whole exome sequencing for genetic diagnosis in a patient with Bloom syndrome E. Cottrell1 · T. Ladha1 · H. Borysewicz‑Sańczyk2 · B. Sawicka2 · M. O. Savage1 · A. T. Bossowski2 · H. L. Storr1 Received: 24 July 2020 / Accepted: 23 September 2020 © Italian Society of Endocrinology (SIE) 2020
Introduction Bloom syndrome (OMIM #210900) is a rare autosomal recessive disorder caused by loss-of-function mutations in the BLM gene. BLM encodes RecQ helicase, an enzyme involved in DNA stability. Impaired enzyme function leads to increased frequency of sister chromatid exchanges and predisposition to early-onset malignancy [1]. The diagnosis of Bloom syndrome may not be obvious to clinicians and the presentation of a child with notable but uncharacterised dysmorphic features offers a challenging diagnostic scenario. Classic dysmorphic features seen in Bloom syndrome include a long, narrow face, micrognathism and prominent nose and ears in association with pre- and post-natal growth failure, skin rash following sun exposure, hyper-pigmented areas or cafe-au-lait lesions; high-pitched voice and immunodeficiency [2]. The most serious complication is the significant increase in malignancy risk due to genomic instability [3]. We undertook genetic analysis on a patient born small for gestational age with undiagnosed dysmorphic short stature. Next-generation sequencing confirmed the aetiology and significantly impacted the patient’s management.
Patient details A 5-year-old presented to a local endocrinology clinic with significant short stature. She was born at term (39 weeks gestation) with a birth weight and length of 1580 g (SDS * A. T. Bossowski [email protected] 1
Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
Department of Paediatrics, Endocrinology and Diabetes with a Cardiology Division, Medical University of Bialystok, ul. Waszyngtona 17, 15‑274 Białystok, Poland
2
− 4.7) and 44 cm (SDS − 2.9), respectively, consistent with birth size small for gestational age (SGA). She was the only child of non-consanguineous parents, both with normal heights and phenotypes. The patient suffered recurrent upper and lower respiratory tract infections, frequently requiring courses of antibiotics. Total IgA and IgM levels were low (IgA: 0.21 g/l; NR 0.65–2.4 g/l, IgM 0.27 g/l; NR: 0.6–1.75 g/l). IgE and IgG levels were normal. At 1.2 year, she was reviewed by a clinical geneticist and Silver–Russell syndrome was suspected but testing was negative (11p15 LOM). Hypothyroidism was diagnosed at 1.4 years (TSH 123.4 IU/ml; NR 0.33–6.3), free T4 0.53 mg/dl; NR 0.7–1.48). Anti-TPO antibodies were 57 IU/ml (NR T, c.1933C>T, p.Q645*) in the proband. No other potentially causative variants were identified. This BLM variant creates a stop codon leading to early termination of the protein and is a recognised cause of Bloom syndrome [4]. Sanger sequencing confirmed both parents as heterozygous for the variant (Fig. 2). Growth hormone the
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