Clinical characteristics.

Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include cancer of a wide variety of types and anatomic sites, diabetes mellitus as a result of insulin resistance, chronic obstructive pulmonary disease, and hypothyroidism.

Diagnosis/testing.

The diagnosis of BSyn is established in a proband with characteristic clinical features and biallelic pathogenic variants in BLM identified by molecular genetic testing.

Management.

Treatment of manifestations: Increased-calorie-density formulas and foods may promote weight gain; consultation with gastroenterologist or feeding specialist and treatment for gastroesophageal reflux disease as needed; standard dietary treatment for dyslipidemia. Skin protection, including avoiding excessive sun exposure, sun-protective clothing and broad-brimmed hat, UV-blocking sunglasses, and use of broad-spectrum sunscreen with SPF of at least 30; standard treatment of skin cancers. Individuals with recurrent infections and defects in humoral immunity may be treated with immunoglobulins to decrease frequency and severity of infections. Developmental services and educational support as needed. In persons with cancer, modification of chemotherapy dosage and duration per oncologist. Fertility treatments as needed; standard treatment of diabetes mellitus and hypothyroidism. Cough assist devices, vibration vests, and daily nasal lavage for mucociliary clearance for bronchiectasis.

Surveillance: Monitor growth, feeding, and for gastroesophageal reflux at each visit throughout childhood; annual lipid profile beginning at age ten years. Skin exam with a dermatologist upon recognition of suspicious skin lesions and annually thereafter. Assess for recurrent, severe, or opportunistic infections at each visit. Developmental, neurobehavioral, and psychological assessment as needed. Clinical assessment for hematuria and/or abdominal mass and abdominal ultrasound examination every three months until age eight years for Wilms tumor. Screening and family education regarding signs and symptoms of leukemia and lymphoma at every health visit. Whole-body MRI every one to two years beginning at age 12 to 13 years for risk of lymphoma. Annual colonoscopy beginning at age ten to 12 years. Fecal immunochemical testing every six months beginning at age ten to 12 years. Annual breast MRI in women beginning at age 18 years. Annual fasting blood glucose and hemoglobin A1c beginning at age ten years. Annual serum TSH with reflex to thyroxine beginning at age ten years. Assess for recurrent and/or chronic pulmonary disease at each visit.

Agents/circumstances to avoid: Sun exposure to the face and other exposed skin, particularly in infancy and early childhood, should be avoided. Exposure to ionizing radiation should be minimized. Dose reductions and shortened courses of chemotherapy when needed to avoid significant side effects and toxicity (including secondary malignancies). Alkylating agents and radiation therapy are considered high risk and are avoided when possible in those with BSyn.

Evaluation of relatives at risk: It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from avoidance of sun exposure and early surveillance for cancer.

Genetic counseling.

BSyn is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a BLM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being a heterozygote (carrier), and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes (carriers) are not at risk of developing BSyn; the cancer risk of heterozygotes as a group remains unclear. Once the BLM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. BSyn is included on most expanded carrier screening panels.

Suggestive Findings

Bloom syndrome (BSyn) should be suspected in an individual with any of the following clinical or cytogenetic findings.

Clinical findings

• Prenatal-onset growth deficiency that usually affects linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood
• Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution
• Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population

Cytogenetic findings. Increased numbers of sister-chromatid exchanges (SCEs)

Establishing the Diagnosis

The diagnosis of BSyn is established in a proband with biallelic pathogenic (or likely pathogenic) variants in BLM identified by molecular genetic testing (see Table 1).

Note: (1) An increased frequency of SCEs on specialized cytogenetic studies may be helpful in circumstances where BLM variant analysis is inconclusive. SCE analysis alone is not sufficient to confirm a diagnosis of BSyn because increased SCEs are also observed in persons with biallelic pathogenic variants in RMI1, RMI2, and TOP3A [Hudson et al 2016, Martin et al 2018]. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (3) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

The range of clinical features in persons with Bloom syndrome (BSyn) has been tracked through the Bloom Syndrome Registry. The clinical and genetic histories have been obtained from registered persons diagnosed between 1954 and 2023, and their clinical courses have been followed [German & Passarge 1989, German 1993, German & Ellis 2002]. The main clinical features of BSyn are discussed here.

Growth deficiency. The most consistent clinical feature of BSyn seen throughout all stages of life is growth deficiency affecting height, weight, and head circumference. Body proportions are normal.

The affected fetus is smaller than normal for gestational age. The mean birth weight of affected males is 1,760 g (range: 900-3,189 g) and of affected females, 1,754 g (range: 700-2,892 g). The average adult height of men is 149 cm (range: 128-164 cm) and of women, 138 cm (range: 115-160 cm).

Plasma growth hormone concentration is normal. Growth hormone therapy has not consistently increased growth rate in most persons, but some have experienced improved linear growth.

Subcutaneous adipose tissue is sparse throughout childhood and adolescence, but adults may develop central obesity. Providing increased calories in childhood and adolescence does not usually result in substantial changes in growth parameters, particularly linear growth. Studies of small cohorts have shown that supplemental feeding may result in increased fat deposition in individuals with BSyn. In addition, lipid profile abnormalities were identified in five of ten individuals tested [Diaz et al 2006].

Serial measurements of 136 individuals with BSyn (81 male, 55 female) showed that mean head circumference was below normal at all ages [Keller et al 1999]. The head shape is often described as long and narrow [Cunniff et al 2017].

Feeding problems. Most parents report that feeding is an issue for their newborns, infants, and young children. Many infants have had gastrostomy tubes placed. In a minority of infants with BSyn, nursing and eating are normal. The child with BSyn characteristically eats slowly, has a decreased appetite, and eats a limited variety of foods. Due to poor weight gain, formula and nutritional supplements with increased caloric density are prescribed in infancy and childhood. Despite these maneuvers, weight gain continues to be modest, and children rarely have a normal weight for age. Gastroesophageal reflux is common and may contribute to the feeding issues.

Facial features. The facial appearance of people with BSyn is variable and may be indistinguishable from unaffected persons of similar age and size. More commonly, the face appears narrow, with underdeveloped malar and mandibular prominences and retrognathia or micrognathia (see Figure 1). A paucity of subcutaneous fat may cause the nose and/or ears to appear prominent.

Figure 1.

Individual with Bloom syndrome showing characteristic long, narrow face and erythematous rash. Reproduced with permission from Cunniff et al [2017]

Skin lesions. The skin at birth and during early infancy appears normal; however, typically following sun exposure during the first or second year of life, a red, sun-sensitive rash appears on the nose and cheeks and sometimes also on the dorsa of the hands and forearms (see Figure 1). This rash varies in severity and extent among affected individuals; in some, it is minimal. It is usually characterized by telangiectasia but in others is described as poikiloderma. In severely affected individuals, the lesion can be bright red and can extend onto adjacent areas.

Additional dermatologic manifestations include cheilitis, blistering and fissuring of the lips, eyebrow and eyelash hair loss, alopecia areata, and vesicular and bullous lesions with excessive or intense sun exposure. Café au lait macules and areas of hypopigmented skin are more numerous and larger than in those without BSyn.

Immunodeficiency. In children and adults who have had laboratory evaluation of their immune system, the concentration of one or more of the plasma immunoglobulins is usually abnormally low. IgM and IgA levels are most commonly affected. Although the numbers of T and B cells are usually normal, variable abnormalities of the adaptive immune system suggest a possible role in the frequent infections reported in affected individuals.

Infections. Parents of children with BSyn report that their affected children have more childhood infections than their sibs and peers; none, however, has had an opportunistic infection, and few persons with BSyn have had bacterial sepsis, meningitis, or pneumonia.

Fertility. Most men with BSyn assessed for infertility have had azoospermia or severe oligospermia. There is, however, one confirmed case of paternity [Ben Salah et al 2014]. Women with BSyn, although often fertile, may enter menopause prematurely. Eleven women with BSyn followed in the Bloom Syndrome Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size.

Intelligence. There are no systematic studies of academic achievement or cognitive performance in persons with BSyn. The great majority appear to perform within the normal range of intellectual development. Some have required academic support for attention-related issues and task orientation, but it is not clear that the prevalence of these problems is different from that seen in the general population. Many others have excelled in school, with some earning graduate degrees.

Other clinical features. Major anatomic defects are not increased in frequency. In the 294 persons in the Bloom Syndrome Registry as of 2023, only single examples of the following have occurred: tracheoesophageal fistula, cardiac malformation, absent thumbs, and absence of a toe and malformation of a thumb.

Medical complications of BSyn include cancer, diabetes mellitus, pulmonary disease, and hypothyroidism.

Cancer is the most frequent medical complication and the most common cause of death in individuals with BSyn. Although the wide distribution of cell types and anatomic sites of cancer resemble that in the general population, it occurs more frequently and at much earlier ages in individuals with BSyn. Development of multiple cancers in a single individual is also much more common. Table 2 summarizes the 251 malignant neoplasms diagnosed in 155 persons followed in the Bloom Syndrome Registry from 1954 to 2022.

Myelodysplasia has been diagnosed in 24 persons in the Bloom Syndrome Registry at a median age of 23 years (range: 3-47), and it has progressed to acute myelogenous leukemia in at least seven. In all but three individuals, myelodysplasia was preceded by some form of cancer for which chemotherapy and/or radiotherapy had been administered.

Diabetes mellitus. Abnormalities in insulin release and glucose tolerance have been detected in the eight healthy children (ages nine months to 13 years) and the three healthy young adults with BSyn (ages 22, 28, and 28 years) appropriately studied [Diaz et al 2006]. Because of insulin resistance, BSyn-related diabetes mellitus resembles type 2 diabetes but has a much earlier age of onset. Paradoxically, diabetes in persons with BSyn commonly occurs in the setting of low body mass index (BMI), rather than high BMI. Diabetes has been diagnosed in 51 of 294 persons in the Bloom Syndrome Registry (17.3%) at a mean age of 26.2 years (range: 4-48 years). Although most individuals do not have severe complications, a small number of individuals have required insulin or have developed retinopathy.

Chronic obstructive pulmonary disease. Chronic bronchitis and bronchiectasis are common, and pulmonary failure has been the cause of death in six persons.

Hypothyroidism has been recorded in 14 persons in the Bloom Syndrome Registry. Thyroid hormone replacement therapy (levothyroxine) is the commonly reported treatment for underactive thyroid in individuals with BSyn.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

Few individuals with BSyn have been reported in the medical literature since its description half a century ago [Bloom 1954], and currently 294 individuals are known to the Bloom Syndrome Registry.

Although rare in all populations, BSyn is relatively less rare among individuals of Ashkenazi Jewish descent. The predominant BLM pathogenic variant identified in individuals of Ashkenazi Jewish descent is c.2207_2212delinsTAGATTC, designated blm^Ash. The approximate carrier frequency of the blm^Ash allele is 1/157 Ashkenazi Jews dwelling in the United States [Fares et al 2008] and 1/111 Ashkenazi Jews dwelling in Israel [Peleg et al 2002].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BSyn, in addition to the routine medical history, family history, and physical examination, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment recommendations for persons with BSyn have been published [Cunniff et al 2018]. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

Health supervision recommendations for surveillance in persons with BSyn have been published [Cunniff et al 2018]. It should be recognized, however, that these recommendations are based on limited data from the Bloom Syndrome Registry and on expert opinion. There are currently no clinical trials or case-control studies that address outcomes in people with BSyn. Because of the unusually high risk for early development of cancer, much of the health supervision effort is directed to early detection and treatment.

Agents/Circumstances to Avoid

Sun exposure to the face and other exposed skin, particularly in infancy and early childhood, should be avoided.

Exposure to ionizing radiation should be minimized. People with BSyn should avoid unnecessary x-rays and CT scans; MRI and ultrasound are preferred imaging modalities when able to be used.

Chemotherapy can have significant side effects and toxicity (including secondary malignancies). Dose reductions and shortened courses of treatment are generally utilized for individuals with BSyn. Alkylating agents and radiation therapy are considered high risk and are avoided when possible in those with BSyn.

Evaluation of Relatives at Risk

It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from avoidance of sun exposure and early surveillance for cancer (see Surveillance).

• Molecular genetic testing for the BLM pathogenic variants identified in the proband can be used to evaluate sibs.
• An unusually low birth weight followed by short stature throughout childhood is typically present in affected sibs; sibs of normal stature are likely unaffected and may not need further testing.

See Genetic Counseling for issues related to the testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Eleven women with BSyn followed in the Bloom Syndrome Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size.

See MotherToBaby for more information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Bloom syndrome (BSyn) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a BLM pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a BLM pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [Woodage et al 1994].
• Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of BLM heterozygotes among individuals with mesothelioma [Bononi et al 2020], endometrial cancer, and colorectal cancer [Schayek et al 2017].

Sibs of a proband

• If both parents are known to be heterozygous for a BLM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being a heterozygote (carrier), and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of BLM heterozygotes among individuals with mesothelioma [Bononi et al 2020], endometrial cancer, and colorectal cancer [Schayek et al 2017].

Offspring of a proband

• Children born to a female with BSyn are usually heterozygous for a BLM pathogenic variant. However, because approximately 1% of individuals of Ashkenazi Jewish descent carry a BLM pathogenic variant, the risk for BSyn in the children of a union between a female with BSyn and a reproductive partner of Ashkenazi Jewish ancestry whose BSyn carrier status has not been determined is 1/200.
• Children born to a female with BSyn and a reproductive partner who is a carrier of a pathogenic variant have a 50% chance of having BSyn and a 50% chance of being carriers.
• Males with BSyn tend to be infertile.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a BLM pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the BLM pathogenic variants in the family.

Population Screening

Individuals of Ashkenazi Jewish ancestry. Because of the relatively increased carrier rate of the blm^Ash allele in the Ashkenazi Jewish population (see Prevalence), individuals of Ashkenazi Jewish ancestry should be aware of their carrier risk, and practitioners should consider screening in this population [ACOG Committee on Genetics 2017].

Expanded carrier screening. BSyn is included on most expanded carrier screening panels. The American Academy of Medical Genetics and Genomics includes BSyn among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be offered for the reproductive partners of individuals known to be carriers of BSyn.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the BLM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Note: Ultrasound measurements are not reliable for estimating gestation age if prenatal diagnosis confirms the diagnosis of BSyn in the fetus.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Bloom syndrome (BSyn) is the prototype of the class of human diseases sometimes referred to as the chromosome breakage syndromes [German 1969]. These include BSyn, Fanconi anemia, ataxia-telangiectasia, ataxia-telangiectasia-like disorder (OMIM 604391), Nijmegen breakage syndrome, and Werner syndrome. These clinically disparate disorders are caused by pathogenic variants in genes encoding enzymes comprising pathways of DNA replication and repair that are responsible for the maintenance of genomic stability. In all of these disorders, the diagnostic cytogenetic abnormalities are accompanied by an increased rate of spontaneous reversion (mutation) to the normal state in somatic cells. This hypermutability explains the cancer predisposition shared by these disorders.

Molecular and genetic evidence implicates RecQ-like DNA helicase BLM (BLM) in the cellular mechanisms that maintain genomic stability [Hickson et al 2001, Monnat 2010, Larsen & Hickson 2013, Suhasini & Brosh 2013, Cunniff et al 2017]. The major consequence of loss of BLM function for a somatic cell is an abnormally high rate of recombination and mutation. The pathogenic variants that arise in the cells of a person with BSyn are of several types and affect many regions of the genome. Thus, although the cancer predisposition in BSyn is attributable to the cellular hyper-recombinability and hypermutability, the proportional small size – the constant feature of BSyn – remains unexplained, as do the medical complications of BSyn other than cancer.

Mechanism of disease causation. Loss of function

Author Notes

The Bloom Syndrome Registry is a long-term surveillance program in which the clinical courses of persons diagnosed with Bloom syndrome (BSyn) and close members of their families are followed. The Bloom Syndrome Registry includes individuals with confirmed BSyn living in various parts of the world. The registry is the source of much of the data included in this GeneReview.

Bloom Syndrome Registry Contact Information

Nicole Kucine, MD, MS

Weill Cornell Medicine

525 E 68th St.

Payson-695

New York, NY 10021

Tel: 212-746-3400

Email: ude.llenroc.dem@5109kin

Acknowledgments

The authors would like to acknowledge Dr James L German III (b. January 2, 1926, d. April 21, 2018), who founded the Bloom Syndrome Registry and who dedicated much of his career to the understanding of BSyn and the support of affected persons and their families. They would also like to thank the New York Community Trust and Weill Cornell Medicine's Clinical and Translational Science Center for providing funding.

Author History

Christopher Cunniff, MD, FACMG (2016-present)

Maeve Flanagan, BA; Weill Cornell Medical College (2019-2023)

James German, MD, FACMG (hon); Weill Cornell Medical College (2006-2019)

Nicole Kucine, MD, MS (2023-present)

Katherine Langer, BA (2023-present)

Maureen M Sanz, PhD, FACMG; Molloy College (2006-2019)

Revision History

• 12 October 2023 (sw) Comprehensive update posted live
• 14 February 2019 (sw) Comprehensive update posted live
• 7 April 2016 (sw) Comprehensive update posted live
• 28 March 2013 (me) Comprehensive update posted live
• 24 August 2010 (me) Comprehensive update posted live
• 22 March 2006 (me) Review posted live
• 10 December 2004 (ms) Original submission

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