INTRODUCTION — A number of human genetic disorders cause chromosomal breakage, which is characterized by genome instability that occurs in the basal state (spontaneously) or in response to DNA-damaging agents (table 1). These disorders cause defects in the recognition and/or repair of damage to DNA inflicted by different agents. In most cases, the genome instability is associated with immune deficiency, a predisposition to develop cancer, and premature aging .
This topic review will discuss Bloom syndrome (BS; MIM #210900), one of the chromosomal breakage syndromes that is associated with immunodeficiency. Discussions relating to the other disorders are presented separately. (See "Ataxia-telangiectasia" and "Nijmegen breakage syndrome".)
EPIDEMIOLOGY — BS is a rare disorder, with 281 cases reported in the Bloom's Syndrome Registry through 2018 , as well as other case reports. The exact incidence is unknown. It has been reported in a variety of ethnic groups. However, it is more common in the Eastern European Jewish (Ashkenazi) population (approximately 25 percent of the affected families in the BS registry), with a carrier rate for the Ashkenazi mutation of approximately 1 percent and a disease prevalence of approximately 1:48,000 [3-6]. Intracommunity marriage is common in this population.
PATHOGENESIS — BS (MIM #210900) is an autosomal-recessive chromosomal instability disorder that is caused by pathogenic variants in the BLM gene (MIM#604610) at 15q26.1 [7-9]. This gene encodes a RecQ helicase, RECQL3, called the Bloom syndrome protein (Blm), which helps maintain the stability of DNA when the DNA duplexes are unwound during recombination repair and replication . A significant increase in gene cluster instability and sister chromatid exchange (SCE; homologous recombination associated with crossover) is seen during mitotic recombination in patients with BS [11-14]. Thus, Blm is believed to function primarily as an antirecombinase, mainly by acting as a Holliday junction dissolvase [15,16]. It also interacts with other molecules involved in the sensing and repair of DNA damage [17-19].
CLINICAL MANIFESTATIONS — BS is characterized by [2,7,8,20]:
●Proportionate small stature with mild microcephaly
●Sparse, subcutaneous adipose tissue
●An erythematous rash on the nose and cheeks that occurs during the first two years of life and typically appears after sun exposure
●Café-au-lait spots or hypopigmented skin lesions
●Predisposition to the early development of a wide variety of cancers, most commonly leukemias and non-Hodgkin lymphomas
●Facial anomalies and sun-sensitive facial erythema
●Infertility in males; severely impaired fertility in females
●Variable intellectual ability/intelligence, which can range from normal to impaired
The affected fetus is typically small for gestational age, and intrauterine growth retardation can be severe . There is a characteristic sparseness of subcutaneous adipose tissue, giving infants and young children a wasted appearance.
The major physical feature of BS that usually brings these patients to medical attention is small stature with relatively normal body proportions. Thus, BS can be mistaken for certain forms of dwarfism . The etiology for short stature in BS is not known, although it is not caused by growth hormone deficiency. (See "Diagnostic approach to children and adolescents with short stature".)
Other clinical features may or may not be present and vary in severity. There is a characteristic keel-shaped face with a slightly small dolichocephalic cranium, malar hypoplasia, nasal prominence, small mandible, protuberant ears, and absence of upper lateral incisors.
Individuals are sun sensitive and develop erythematous lesions on exposed regions of the face, often in a lupus-like butterfly distribution [22,23]. The erythema may appear as a faint blush on the cheeks, but, in extreme cases, it may manifest as a bright, red, disfiguring lesion . The rash can also occur on other frequently sun-exposed areas of skin, such as the dorsum of the hands. In addition, patients may develop well-demarcated patchy areas of hypopigmentation and hyperpigmentation (café-au-lait spots and occasionally poikiloderma ), especially on the trunk, and skin and scleral telangiectasia.
Other abnormalities include a high-pitched voice, male infertility (hypogonadism with failure of sperm production) and female subfertility (premature menopause), restricted intellectual ability, and a predisposition to develop late-onset noninsulin-dependent diabetes mellitus. There is a high frequency of impaired glucose tolerance and insulin resistance, and these problems increase with age . Approximately 15 percent of BS patients develop diabetes mellitus type 2 .
Problems with vomiting and diarrhea leading to life-threatening dehydration are common in infancy. Gastroesophageal reflux may play a role in feeding issues and recurrent sinopulmonary infections. BS patients have an increased incidence of otitis media and pneumonia. Chronic lung disease is the second-leading cause of death [21,25].
Patients with BS have a remarkable predisposition to the early development of cancer . Approximately 50 percent of patients will develop cancer by the age of 25 years, and many will have two or more primary malignancies. Cancers of virtually all types and at all locations have been reported. In the first two decades of life, the predominant types are leukemia and non-Hodgkin lymphoma. Myelodysplasia is common and may precede leukemia. Later in life, there are many carcinomas, especially of colon, skin, and breast. Genomic instability probably accounts for the majority of malignancies, although immunodeficiency may account for some of the cancers seen in this syndrome.
Intellectual ability varies from normal to limited. A poorly defined learning disability, manifested by a lack of interest in learning and difficulty with coursework that requires abstract thought, is common .
Heterozygous carriers of the defective BLM gene do not exhibit any of the BS clinical phenotype. In addition, they do not appear to have an increased risk of cancer .
LABORATORY FINDINGS — Evidence of immunodeficiency has been reported in many BS patients, but it is highly variable and usually not severe [27,28]. Most experience sinopulmonary bacterial infections. Opportunistic infections are not a feature. The molecular basis of the immunodeficiency is unclear. The majority of patients have decreased levels of one or more serum immunoglobulin classes (immunoglobulin M [IgM], immunoglobulin A [IgA], and less commonly immunoglobulin G [IgG]), although the majority have normal antibody responses to vaccines. Patients have low normal lymphocyte numbers with skewing to effector memory T cells. Memory B cell numbers are reduced, and there is impaired class switching to downstream constant region elements, although there is no defect in V(D)J recombination or somatic hypermutation .
The presence of laboratory evidence of immunodeficiency is not highly predictive of risk for infection. Other factors leading to the development of chronic lung disease have not been identified.
DIAGNOSIS — The diagnosis of BS is based upon the characteristic features of small stature but well-proportioned body size and a sun-sensitive, erythematous skin lesion affecting the butterfly area of the face. BS may go unrecognized, or the affected child may be misdiagnosed when the facial lesion is absent.
Once suspected on clinical grounds, the diagnosis is confirmed by finding excessive numbers (10-fold higher) of sister chromatid exchanges (SCEs) on a standard karyotype or performing targeted mutation analysis , investigations that distinguish BS from other chromosomal breakage disorders with similar clinical phenotypes.
A list of laboratories offering clinical testing for BS is available (Genetic Testing Registry [GTR]).
DIFFERENTIAL DIAGNOSIS — Other disorders that can present as short stature but normal weight for height in a child or adult include skeletal dysplasia, growth hormone deficiency, or constitutional delay, among other possible explanations. The combination of clinical and laboratory features should distinguish BS from these other disorders. Specifically, the combination of prenatal proportionate short stature, sun sensitivity, and recurrent sinopulmonary infection in association with an excess of sister chromatic exchanges (SCEs) should raise the suspicion of BS rather than another disorder with short stature. (See "Diagnostic approach to children and adolescents with short stature".)
Clinical features alone do not distinguish BS from other chromosomal breakage disorders, including Nijmegen breakage syndrome, DNA ligase IV deficiency, or Cernunnos deficiency. Additional laboratory testing is needed to distinguish these disorders. (See "Nijmegen breakage syndrome" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and 'Diagnosis' above.)
PRENATAL SCREENING — Prenatal screening in Ashkenazi Jews is discussed separately. (See "Preconception and prenatal carrier screening for genetic disease more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Bloom syndrome'.)
MANAGEMENT — The following measures should be employed :
●Exposure to radiation should be minimized. Magnetic resonance imaging (MRI) and ultrasound should be used instead for diagnostic purposes.
●Efforts should be made to protect the face from the sun. (See "Patient education: Sunburn prevention (Beyond the Basics)".)
●Immune globulin replacement is indicated if there is significant hypogammaglobulinemia and deficiency of antibody production. (See "Immune globulin therapy in primary immunodeficiency" and "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)
●Particular attention should be paid to the prevention of life-threatening dehydration, particularly in infants.
●Gastrostomy tube feedings may be useful for providing nutrition and hydration, although the long benefits of this approach are not proven.
●Infections should be promptly diagnosed and treated. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)
●Patients and their families should be informed about the high risk for development of cancer so that appropriate surveillance can be performed. (See "Screening for breast cancer: Strategies and recommendations" and "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing" and "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for colorectal cancer in patients with a family history of colorectal cancer or advanced polyp".)
Recommendations for screening, diagnosis, and treatment of malignancies are available . Earlier screening for breast and colon cancer is advised.
Once diagnosed, the doses of cancer chemotherapeutic agents may need to be adjusted because of the underlying tendency for chromosomal breakage and recombination. Proton beam therapy has been used successfully in place of radiotherapy .
The immune deficiency in BS is not severe enough in most patients to warrant hematopoietic cell transplantation (HCT), and HCT is likely to induce secondary cancers. Thus, HCT is rarely used for patients with BS.
PROGNOSIS — The majority of patients with BS survive to adulthood. The Bloom's Syndrome Registry reported a mean age at death of 26 years (range <1 to 49 years) in 2009 . The cause of death is usually cancer, commonly leukemia or a malignancy of gastrointestinal origin. Their small size often presents a serious impediment to employment, as do learning disabilities in some patients .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology and pathogenesis – Bloom syndrome (BS) is a rare, autosomal-recessive chromosomal instability disorder that is caused by pathogenic variants in the BLM gene at 15q26.1 (MIM 604610). It occurs most commonly in patients of Eastern European Jewish (Ashkenazi) descent. (See 'Epidemiology' above and 'Pathogenesis' above.)
●Clinical features – BS is characterized by small stature with relatively normal proportions, predisposition to the early development of a wide variety of cancers, facial anomalies and sun-sensitive facial erythema, infertility, and immunodeficiency. (See 'Clinical manifestations' above.)
●Diagnosis – The diagnosis of BS is based upon the characteristic clinical features and is confirmed by finding excessive numbers of sister chromatid exchanges (SCEs) on a standard karyotype or performing targeted mutation analysis. The differential diagnosis includes other causes of proportional short stature. Prenatal screening can be performed for this syndrome in Ashkenazi Jews. (See 'Diagnosis' above and "Diagnostic approach to children and adolescents with short stature".)
●Management – Management includes avoidance of radiographs, adequate sun protection, treatment of infections, provision of adequate nutrition, prevention of dehydration, and performance of cancer surveillance when appropriate. (See 'Management' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
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