Bloom Syndrome (Congenital Telangiectatic Erythema)

Bloom syndrome (congenital telangiectatic erythema) is a rare autosomal recessive disorder. It was first described in 1954 by David Bloom in a series of patients with telangiectatic erythema on the face and dwarfism.[1] Bloom syndrome has three cardinal features: sun sensitivity, telangiectatic erythema of the face, and stunted growth.

Owing to the genomic instability present in this disease, patients with Bloom syndrome show a much higher incidence of malignant neoplasms, which is the major cause of death in such patients. No patients have been reported to reach age 50 years.

Variable degrees of immunodeficiency are present in these patients, predisposing them to various infections; this acts as an additional factor for the high incidence of cancers in Bloom syndrome patients.

Bloom syndrome (congenital telangiectatic erythema) is caused by a mutation in both alleles of the gene designated BLM, traced to band 15q26.1.[2, 3, 4, 5]  (see the image below). BLM encodes 1417 amino acids that code for a protein in the nuclear matrix of growing cells, which is a member of the RecQ family of helicases. This protein plays a pivotal role in DNA recombination and repair. BML mutations thus result in defects in DNA repair and genomic instability in the somatic cells, predisposing the patients to cancer development.[6]

The BLM mutations can be found in compound heterozygous forms, homozygous forms, or as single gene mutation forms.

There is a 10-fold increase in the sister chromatid exchanges,[7] in addition to the presence of chromatid gaps, breaks, and gross structural rearrangements.[7, 8]  Sister chromatid exchanges are considered a sensitive indicator for cell genome instability, as they are thought to be the outcome of DNA double-strand breaks resulting from homologous recombination repair.[9]

Over 60 mutations of the BLM gene have been found in Bloom syndrome. The most common mutation is the deletion of 6 nucleotides at position 2281 and their replacement with 7 others, which occurs most commonly in Ashkenazi Jews.[10]

In 1989, Nicotera et al suggested that the major biochemical defect in persons with Bloom syndrome is chronic overproduction of the superoxide radical anion. They thought that inefficient removal of peroxide might be responsible for the high rates of sister chromatid exchange and chromosomal damage in Bloom syndrome cells.[11]

MM1 and MM2 are proteins identified in Bloom syndrome and Fanconi anemia, creating a link between them. The gene encoding these proteins is FANCM. Both diseases show phenotypical similarity and both demonstrate bone marrow failure, skeletal growth deficiency, short stature, and predisposition to hematological malignancies, although they are genetically unrelated. Both diseases involve the BRAFT and FANCM complexes, which are important in DNA repair.[12, 13]

Bugreev et al suggest that a function of BLM is stimulation of RAD51 DNA pairing; results from their study show the importance of the RAD51 nucleoprotein filament conformation for stimulating DNA pairing by BLM.[14]

Photosensitivity in Bloom syndrome patients is a result of increased susceptibility to 313-nm light, approaching the ultraviolet (UV)–A range. The minimal erythema dose threshold for both UV-A and UV-B are reduced.[15] Cellular sensitivity in Bloom syndrome patients is in the form of phototoxicity and not photocarcinogenicity, as is seen in xeroderma pigmentosa.[16] Bloom syndrome patients exhibit a greater vulnerability of their DNA to UV radiation than DNA of healthy populations.

Bloom syndrome patients also demonstrate impairment in lymphocytic proliferation, deficient immunoglobulin synthesis, and lowered response to mitogen stimulation, resulting in impairment of both cellular and humoral immune responses.[17]

The overall result of the genomic instability in the proliferating cells is a high risk of malignancy, reduced fertility or infertility, B- and T-cell immunodeficiencies, and cutaneous manifestations, including photosensitivity, poikiloderma, and telangiectatic erythema.

Bloom syndrome (congenital telangiectatic erythema) is genetic with an autosomal recessive pattern of inheritance. The gene locus is band 15q26.1.

Cytogenetic findings in a Bloom syndrome patient with acute myeloid leukemia of the French-American-British subtype M1 showed preferential occurrence of total or partial loss of chromosome 7.

Mutation of the DNA ligase I gene may account for the primary metabolic defect in Bloom syndrome, not due to a reduction in the number of protein molecules or to inhibitory substances, but rather to the ATP-binding and hydrolytic activity of the enzyme. DNA ligase I and DNA polymerase alpha are enzymes that function during DNA replication; DNA ligase II and DNA polymerase-beta function during DNA repair.[18]

Frequency

United States

More than 170 case reports of Bloom syndrome (congenital telangiectatic erythema) have been made. The frequency of parental consanguinity is much greater than in the general population.

International

Bloom syndrome (congenital telangiectatic erythema) is more common in Ashkenazi Jews, with an estimated carrier frequency of 1:120 and a reported prevalence of approximately 1 in 48,000 persons, accounting for 25% of the patients in the Bloom syndrome patient registry.[19]

The Bloom Syndrome Registry (BSR) was established in 2009. The total number of patients is less than 300. Of the registered patients, 75.2% were non-Jews.[20] However, it has been reported in Japan and other countries, with increased risk in cases with parental consanguinity.

Race

Bloom syndrome (congenital telangiectatic erythema) is more common in eastern European Ashkenazi Jews.

Sex

The male-to-female ratio for Bloom syndrome (congenital telangiectatic erythema) is 1.3:1.

Age

Bloom syndrome (congenital telangiectatic erythema) occurs in the first few months of life.

Increased risk of premature death in the second or third decade occurs secondary to malignancies. Patients with Bloom syndrome (congenital telangiectatic erythema) are estimated to develop malignancy at a rate 150-300 times higher than the general population. Twenty percent of Bloom syndrome patients develop malignancy during their life time.[21]  Various types of leukemia develop at a mean age of 22 years. Patients who survive beyond age 22 years develop solid tumors at an average age of 35 years. Fortunately, these tumors are sensitive to chemotherapy and radiotherapy.

Early diagnosis of leukemia is, at present, not known to improve the chances of curative therapy. Frequent hematologic examinations in children are not advised for fear of untoward psychologic effects. Allogeneic marrow grafting has not been performed in Bloom syndrome patients. Men with Bloom syndrome are sterile; women have reduced fertility and a shortened reproductive span. Bloom syndrome patients who become pregnant are at high risk for premature delivery. Intelligence is usually normal, although mild deficiency has occurred in a few affected persons. Diabetes occurs in approximately 10% of individuals with Bloom syndrome.

Resistance to infections gradually improves with age, as do erythema and photosensitivity.

Bloom Syndrome Registry

Laboratory of Human Genetics

New York Blood Center

310 East 67th Street

New York, NY 10021

(212) 570-3075; Fax (212) 570-3195

Contact person: James L German III, MD

Growth delay is the most impressive clinical feature of Bloom syndrome (congenital telangiectatic erythema) and is usually the first manifestation that causes the parents to seek medical attention. Other associated physical features and immunodeficiency are not present or recognizable at birth. The growth deficiency has a prenatal onset, apparent from term birth measurements, and persists throughout life. More than half the children are significantly underdeveloped in physical stature until age 8 years.

Patients with Bloom syndrome demonstrate recurrent respiratory and gastrointestinal tract infections.

Physical examination findings in Bloom syndrome (congenital telangiectatic erythema) vary and involve stunted growth, cutaneous manifestations, ocular manifestations, musculoskeletal manifestations, fertility concerns, immunologic manifestations, and a predisposition to malignancies, among others.

Stunted growth

Prenatal and postnatal growth deficiency is noted in Bloom syndrome patients. The length and weight are both affected, but with normal body proportion (primordial stunted growth). The average birth weight reported for children with Bloom syndrome was 1.868 g in females and 1.890 g in males.[22] The child typically has reduced subcutaneous fat, yielding a wasted appearance. Small stature results from intrauterine growth restriction and the constant postnatal growth restriction.[23]

The mean final adult stature reported in males was 148.5 cm and 141.5 cm in females, with a mean weight of 41.3 kg in males and 36.6 kg in females.[22] Despite this stunted growth, normal growth hormone production and secretion was noticed in these patients, as well as normal serum concentrations of insulinlike growth factor 1 and insulinlike growth factor binding protein 3.

Feeding problems

Feeding problems are typically significant in infants and children. There is lack of interest in eating. Some patients have gastroesophageal reflux, vomiting, and diarrhea. The low body mass index in these children was noted to improve after age 8 years, and some adults developed central obesity.[24]

Cutaneous manifestations

Skin findings in Bloom syndrome include telangiectatic erythema, which is usually not congenital, appearing on average at age 8 years. It appears as macules or plaques in a butterfly distribution on the face and other photodistributed areas (eg, ears, eyelids, forearms, dorsa of the hands). Blistering, hemorrhage and crusts may occur.

Patients with a dark skin phenotype demonstrate fewer cutaneous manifestations. Absence of photosensitivity, facial erythema, and telangiectasia was reported in Japanese and Latin American patients.[25]

The characteristic rash develops later in life, mainly on the face following a butterfly distribution on the cheeks and nose, mostly in the form of telangiectasia and erythema. It is exacerbated by sun exposure and may develop on other sun-exposed skin such as the dorsum of hands, forearms, and ears.[26]

Other cutaneous manifestations reported include cheilitis, fissuring, blistering, poikiloderma, eyebrow or eyelash hair loss, and alopecia areata.[27]

Extensive vesicular and bullous eruptions have been reported with sun exposure, and an absence of the characteristic photosensitivity has also been reported.[28, 29]

Café au lait macules with adjacent hypopigmented areas appear as twin spotting. They are fewer and smaller than in non–Bloom syndrome patients.[30]

There is increased risk for skin cancers. Basal cell carcinoma is the most common, followed by squamous cell carcinoma. Melanomas have not been reported in Bloom syndrome patients.[31] Most cancers had occurred in sun-exposed skin, but skin of hip and base of the penis have been reported.[32] Multiplicity of skin cancer in individual patients is uncommon. However, multiple basal cell carcinomas on the face and neck in a Bloom syndrome patient have been reported.[33]

Facial features

Bloom syndrome patients show variable facial features, commonly a long and narrow face, retrognathia or micrognathia, and an underdeveloped malar area. The head circumference of most patients with Bloom syndrome is below the third percentile. The nose and/or ears of Bloom syndrome patients are often prominent, owing to the decreased amount of subcutaneous fat.[22]

Ocular manifestations

Scleral telangiectasias, bulbar conjunctival telangiectasia, conjunctivitis, sectoral iris pigment alteration, lens opacities, leukemic retinopathy, retinoblastoma, lateral strabismus, ectropion, and bilateral optic nerve hypoplasia are reported.[34, 35]

Musculoskeletal abnormalities

Affected individuals have long limbs, disproportionally large hands and feet, and progressive contracture of hands and feet. Upper extremities are long in proportion to body length.

Quick, birdlike movements are characteristic.

Clinodactyly and syndactyly may be seen.[36]

Fertility

Male patients are infertile (primary hypogonadism), and female patients are subfertile (premature menopause).

Immunologic abnormalities

Patients with Bloom syndrome are predisposed to respiratory and gastrointestinal infections as a result of a deficiency of immunoglobulin A.[17] Bacterial infections are more frequent than viral infections. Chronic lung disease is the second leading cause of death in Bloom syndrome patients.[37]

It should be noted that most Bloom syndrome patients do not have meningitis, bacterial sepsis, pneumonia, recurrent abscesses, or opportunistic infections, as are seen in primary immunodeficiency patients.[38]

Predisposition to malignancy

There is marked predisposition to early development of cancer. About 25% of patients develop malignancy, at a mean age of 20.7 years. Neoplasms of all types and sites may develop. The most common cancers reported in Bloom syndrome include lymphomas, leukemia, oral/esophageal squamous cell carcinoma, and adenocarcinoma of the sigmoid colon.[39]

More than one cancer occurring in a patient has been reported.[40] BLM mutation was found to increase the susceptibility to breast cancer, and a higher probability of colorectal carcinoma was found in heterozygous carriers of the BLM mutation.[41, 42] Bloom syndrome registry data suggest that 46% of registered patients develop cancers, with epithelial tumors being most frequent (52.5%), followed by lymphoid neoplasms (24%).[20] It was reported that 12% of Bloom syndrome patients develop colorectal cancer, mainly in their second decade of life.[40]

Other general associations

Patients have a high-pitched voice. Congenital heart disease and annular pancreas have been reported. Type 2 diabetes mellitus develops in about 15% of patients, and the risk increases with age.[37] Severe pulmonary involvement with parenchymal destruction, respiratory failure, emphysema, and bronchiectasia has been reported in Bloom syndrome. It has been suggested that recurrent lower respiratory tract infections since childhood could play a role in these changes.[43, 44] Other uncommon features include eyebrow hair loss, alopecia areata, reticular pigmentation on the forehead and trunk, flat nose, wide fingernails, and short sharpened distal phalanges.[45]

Men with Bloom syndrome (congenital telangiectatic erythema) are sterile; women have reduced fertility and a shortened reproductive span.

Recurrent respiratory and gastrointestinal tract infections and the development of chronic lung disease are additional complications, as is the early development of different types of cancers at any site. Type 2 diabetes is found in 15.8% of patients.[20]

Bloom syndrome should be suspected if any of the clinical or cytogenetic criteria described below are found.[47]

Clinical findings are as follows:

• Prenatal-onset retarded growth that usually includes weight gain, linear growth, and head circumference and that persists into infancy, childhood, and adulthood
• Moderate-to-severe growth retardation together with photosensitive erythematous rash that commonly involves the face in a butterfly distribution
• Moderate-to-severe growth retardation and an early diagnosis of cancer

Cytogenetic findings are as follows:

• Increased numbers of sister-chromatid exchanges
• Increased quadriradial configurations (Qrs) in cultured blood lymphocytes
• Chromatid gaps, breaks, and rearrangements

The diagnosis of Bloom syndrome (congenital telangiectatic erythema) can be confirmed or excluded by a laboratory test known as a chromosome study; blood and skin cells show a characteristic pattern of chromosome breakage and rearrangement. Testing for chromosome instability, including the presence of quadriradicals and increased sister chromatid exchanges, is performed at the US National Institutes of Health and US Armed Forces Institute of Pathology laboratories.

Prenatal diagnosis

Prenatal diagnosis of Bloom syndrome is possible with amniocentesis for amniotic fluid cell culture to assess for a high number of sister chromatid exchanges; DNA analysis will be available in the near future.

Genetic screening and counseling

Genetic screening is recommended for populations at high risk for being a carrier of the disease, such as Ashkenazi Jews. Targeted mutation analysis and polymerase chain reaction (PCR) to examine the DNA for the BLM 6-deletion/7-insertion mutation should be performed.

Genetic counseling could be offered to parents of patients with Bloom syndrome. Being an autosomal recessive disease in its mode of transmission, the risk of having the disease in siblings of heterozygous carriers is estimated to be 25%.[48]

Screening for complications

Immunoglobulin levels should be checked; decreased immunoglobulin A and immunoglobulin M, with or without immunoglobulin G changes, are expected.

There is no consensus regarding cancer surveillance in Bloom syndrome patients. The most important recommendation is to observe Bloom syndrome patients for any signs and symptoms that warrant further investigations (eg, complete blood cell count with any constitutional symptoms). Unintentional weight loss should be investigated thoroughly. Screening colonoscopy could be considered from age 16 years and carried out regularly, but there is no consensus for the appropriate interval.[38]

Periodic evaluation for leukemia and early screening for breast, cervical, and colorectal cancers are recommended. MRI and ultrasonography are recommended rather than other radiologic diagnostic modalities, in order to minimize the exposure to radiation in such vulnerable patients.

See the Workup section in the Medscape article Short Stature for detailed information on the workup for short stature.

Evaluation of children with photosensitivity

Phototesting and photopatch testing could be performed. Screening for antinuclear antibodies (ANA) and performing a porphyrin profile to exclude the possibility of lupus erythematosus or erythropoietic porphyria may be warranted.

Skin biopsy

Histopathologic findings from skin biopsies taken from the erythematous lesions show a lupuslike picture: follicular plugging, interface dermatitis, monocellular infiltrate, and perivascular infiltrate. However, the presence of changes in the basement membrane, periadnexal lymphocytic infiltration, and dermal mucin are very rare.[46] Bandlike dense lymphoid infiltrates with epidermotropism, resembling mycosis fungoides, have been reported.

Bloom syndrome (congenital telangiectatic erythema) has no specific treatment, but general management recommendations have been published by Cunniff et al.[49]

Skin

Avoid excessive sun exposure. Cover exposed skin with clothing and use a broad-brimmed hat and UV-blocking sunglasses. Frequent use of sun screens is recommended. Efforts to minimize exposure to other known environmental mutagens are also advisable.[50] Identification of café-au-lait macules by dermatologists would help to identify the risk of neoplasms in these patients.[51]

Psychosocial

Family and teachers are encouraged to relate to Bloom syndrome patients appropriately for their chronologic age rather than the younger age suggested by their unusually small size.

Growth

Growth hormone administration has been reported in the literature to improve linear growth. However, if there is lack of response regarding the velocity of growth, growth hormone should be discontinued owing to increased risk of tumor development. Serum IgE-1 and IgFBp-3levels should be monitored closely during treatment administration.

Nutrition

Gastroenterologist or feeding specialist consultation, institution of high-calorie diets with caution for high-fat or high-cholesterol diet, institution of reflux precautions, and use of antireflux medications are recommended.

Other

Infants, toddlers, and preschool-age children should be closely monitored for cognitive development and school performance.

Diabetes mellitus, thyroid abnormalities, and dyslipidemia should be managed according to standard protocols.

Immunoglobulin replacement can be instituted in cases of severe hypogammaglobulinemia.

Infections and cancerInfections should be managed thoroughly.

Medical treatment of cancers in patients with Bloom syndrome has many challenges; chemotherapy-induced toxicity and the immunodeficiency inherent to the disease may require reductions in the dose and number of treatment cycles of chemotherapy,[52] as it was found that standard chemotherapy has resulted in significant toxicity and some were life threatening. Alkylating agents may increase the risk of secondary malignancy; therefore, they should be avoided. Bloom syndrome and mature B-cell lymphoma has been successfully treated with rituximab.[53]

Surgical oncology care can be instituted as needed for the diagnosis and treatment of malignancies.

The following consultations may be warranted in Bloom syndrome (congenital telangiectatic erythema):

• Dermatologist for establishing the diagnosis, patient and family education, and sun protection guidance

• Pediatric infectious disease specialist for appropriate treatment of gastrointestinal and respiratory tract infections

• Pediatrician for evaluation of stunted growth

• Oncologist for cancer surveillance

• Endocrinologist for short stature and hypogonadism management

Men with Bloom syndrome (congenital telangiectatic erythema) are sterile; women have reduced fertility and a shortened reproductive span. A 19-year-old woman with Bloom syndrome was reported with a successful pregnancy.[54] Preterm labor occurred at 32 weeks' gestation, and the infant was ultimately delivered at 35 weeks' gestation. The infant was at less than the tenth percentile for length and weight for gestational age, but was otherwise healthy. Because preterm labor had occurred in this and a previously reported pregnancy in women with Bloom syndrome, increased surveillance for preterm labor in pregnancies of women with Bloom syndrome is suggested.

Strict photoprotection should be practiced by these patients.