Bloom syndrome: research and data priorities for the development of precision medicine as identified by some affected families

Abstract

Bloom syndrome (BS) is a rare, autosomal recessive genetic disorder characterized by short stature, a skin rash associated with sun exposure, and an elevated likelihood of developing cancers of essentially all types, beginning at an early age. Cancer is the leading cause of death for persons with BS, and its early onset results in a reported median lifespan of <30 years. With fewer than 300 documented cases since BS was first described in 1954, its rarity has challenged progress in advancing both the care of and the cure for persons with BS. Presently, there are no known clinically actionable targets specific to persons with this cancer predisposition syndrome, despite the fact that standard cancer treatments are often contraindicated or must be substantially modified for persons with BS. Herein, Zachary Rogers recounts his experience as a cancer patient with BS contemplating a substantially customized chemotherapy regimen that highlights the need for development of individualized treatments in the BS community. We also outline a patient-centered research and community action road map with the goal of improving and prolonging the lives of persons with Bloom syndrome, including the facilitation of precision medicine development specific to this condition.

Premature aging disorders: A clinical and genetic compendium

“…74,75 2.2.2 | Bloom Syndrome (MIM #210900)Bloom syndrome is a rare "chromosomal breakage syndrome" with approximately 300 affected individuals documented in the Bloom Syndrome Registry 76,77. Patients typically present with an erythematous rash in a butterfly distribution across the nose and cheeks in the first years of life that is exacerbated by sun exposure and spreads on the dorsum of hands and forearms 78.…”

Pancreatic cancer in bloom syndrome

“…It is odd, as PC is common in other syndromes with DNA replication errors like lynch syndrome, BRCA mutations, retinitis pigmentosa, and so on. 1–4 Ashkenazi Jews have an increased incidence of BS and thus have an increased risk of developing PC.…”

“…Bloom’s syndrome (BS) was first described in 1954, 1 but fewer than 300 cases were documented. 2 It is a rare autosomal recessive genetic disorder characterized by defects in the BLM gene, which codes for the DNA repair enzyme RecQL3 helicase, resulting in genetic instability characterized by elevated levels of spontaneous sister chromatid exchanges (SCEs) and chromosomal radial formation. 3 The Ashkenazi Jewish population is particularly susceptible, as ~1% of this population is heterozygous carriers of the BLM gene.…”

“…The clinical picture frequently includes short stature, a facial rash, and recurrent infections due to severe immunodeficiency. The genomic instability is also manifested by an increased susceptibility to a wide range of cancers, in particular, hemato-oncology and gastrointestinal tumors; thus, frequent screenings and awareness by physicians are imperative 1–4 . DNA sequencing can be used to diagnose carriers, and high-risk populations should undergo genetic testing.…”

Helicase Mechanisms During Homologous Recombination in Saccharomyces cerevisiae

“…For instance, mutations in BLM (Bloom syndrome helicase), a human homolog of Sgs1, cause Bloom syndrome, which is characterized by extreme UV sensitivity, extensive chromosomal rearrangements, and a predisposition to cancers (6,15,44,(49)(50)(51). Bloom syndrome patients are so susceptible to DNA damage that they cannot be subjected to normal chemotherapeutic or radiation treatments without risk of secondary cancers (28). Given that yeast Sgs1 and human BLM are closely related, Sgs1 has provided an important model system for understanding how RecQ helicases function in humans.…”