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 chronic obstructive pulmonary disease, diabetes mellitus as a result of insulin resistance, and cancer of a wide variety of types and anatomic sites.

Diagnosis/testing.

The diagnosis of BSyn is established in a proband with characteristic clinical features and/or biallelic pathogenic variants in BLM identified on molecular genetic testing. Identification of increased frequency of sister-chromatid exchanges on specialized cytogenetic studies and exclusion of RMI1, RMI2, and TOP3A-related disorders may be helpful in establishing the diagnosis in those with characteristic clinical features who do not have biallelic pathogenic variants in BLM.

Management.

Treatment of manifestations: Skin protection, including coverage of exposed skin and use of broad-spectrum sunscreen with SPF of at least 30 to reduce the sun-sensitive rash. Increased-calorie-density formulas and foods may promote weight gain. Although growth hormone treatment may improve linear growth, many clinicians caution against its use because of reports of early onset of cancer in some treated children. Developmental services and therapies as needed. Hyperglycemia from insulin resistance is treated as in type 2 diabetes. In persons with BSyn who have cancer, reduced chemotherapy dosage and duration to reduce risks of severe complications; caution should be exercised with use of ionizing radiation or alkylating agents, particularly busulfan, cyclophosphamide, or melphalan. Individuals with recurrent infections and defects in humoral immunity may be treated with gamma globulin infusions to decrease frequency and severity of infections.

Surveillance: Abdominal ultrasound examination every three months until age eight years for Wilms tumor. Screening and family education regarding signs/symptoms of leukemia and lymphoma at every health visit. Whole-body MRI every one to two years beginning at age 12-13 years for risk of lymphoma. Annual colonoscopy beginning at age 10-12 years. Fecal immunochemical testing every six months beginning at age 10-12 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 T4 beginning at age ten years. Annual lipid profile beginning at age ten years.

Agents/circumstances to avoid: Sun exposure may provoke an erythematous rash, especially on the face. Exposure to ionizing radiation should be minimized.

Genetic counseling.

BSyn is inherited in an autosomal recessive manner. Identification of both pathogenic BLM variants in the proband is required for carrier (heterozygote) testing in at-risk families. BLM is included in expanded carrier screening panels, and most pathogenic variants can be identified through sequencing. Preimplantation and prenatal diagnosis are possible if the BLM pathogenic variants have been identified in the at-risk couple.

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 includes 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
• Increased quadriradial configurations (Qrs) in cultured blood lymphocytes (a mean of 1%-2% Qrs are observed in cultured blood lymphocytes from a person with BSyn vs none in controls)
• Chromatid gaps, breaks, and rearrangements

Establishing the Diagnosis

The diagnosis of BSyn is established in a proband by identification of biallelic pathogenic variants in BLM on molecular genetic testing (see Table 1).

Note: An increased frequency of sister-chromatid exchanges (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].

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) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of BSyn is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with growth deficiency are more likely to be diagnosed using genomic testing (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 2018 and their clinical courses have been followed [German & Passarge 1989, German 1993, German & Ellis 2002].

The main clinical features of BSyn are the following:

• Size and appearance. 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. 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. Plasma growth hormone concentration is 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).
  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. A paucity of subcutaneous fat may cause the nose and/or ears to appear prominent.
• Feeding problems. Most parents report that feeding is an issue for their newborns, infants, and young children. The child with BSyn characteristically feeds slowly, has a decreased appetite, and eats a limited variety of foods. In a minority of infants with BSyn, nursing and eating are normal. Because of their slow growth and weight gain, many children are prescribed formula with increased caloric density and later are prescribed nutritional supplements that provide extra calories. Many infants have had gastrostomy tubes placed. Despite these maneuvers, weight gain continues to be modest, and children are rarely in the normal range for growth. Gastroesophageal reflux is common and may contribute to the feeding issues.
• 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. 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 appropriately examined 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 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 281 persons in the Registry as of 2018, 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, all serious, in order of increasing frequency are the following:

• Chronic obstructive pulmonary disease. Chronic bronchitis and bronchiectasis are common, and pulmonary failure has been the cause of death in six persons.
• Myelodysplasia has been diagnosed in 23 persons in the Registry at a median age of 22.1 years (range 3-47), and it has progressed to acute myelogenous leukemia in at least seven. In all but three, the 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 9 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, the diabetes mellitus of BSyn resembles type 2 diabetes but has a much earlier age of onset than in the general population. 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 47 of 281 persons in the Registry (16.7%) at a mean age of 26.6 years (range 4-45 years). Although most individuals do not have severe complications, 16 have required insulin, and retinopathy has developed in two. Lipid profile abnormalities were also identified by Diaz et al [2006] in five of the ten subjects tested.
• Cancer is the most frequent medical complication in BSyn and the most common cause of death. 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 BSyn. Development of multiple cancers in a single individual is also much more common. Table 2 summarizes the cancers diagnosed in individuals followed in the Registry.

Genotype-Phenotype Correlations

Homozygotes and compound heterozygotes. A similar phenotype is produced by either homozygosity or compound heterozygosity for any of the more than 60 pathogenic variants in BLM identified to date.

Prevalence

Few individuals with BSyn have been reported in the medical literature since its description half a century ago [Bloom 1954], and fewer than 300 are known to the Bloom Syndrome Registry.

Although rare in all populations, BSyn is relatively less rare among Ashkenazi Jews. Sixty-seven of the 281 persons in the Registry are of Ashkenazi Jewish ancestry. The predominant BLM pathogenic variant identified in Ashkenazi Jews is c.2207_2212delinsTAGATTC, a 6-bp deletion/7-bp insertion in exon 10 of BLM, often (for brevity) designated blm^Ash; the second most common pathogenic variant is c.2407dupT.

The approximate carrier frequency of the blm^Ash allele:

• One in 100 Ashkenazi Jews dwelling both in New York City [Li et al 1998] and in Israel [Peleg et al 2002]
• One in 37 Ashkenazi Jews dwelling in Israel, all four of whose grandparents were from Poland [Shahrabani-Gargir et al 1998]