Bloom Syndrome

Etiology

Bloom syndrome is a rare autosomal recessive disorder of chromosomal instability. It is due to mutations in the BLM gene located at 15q26.1. The BLM gene encodes a BLM helicase, which forms a complex with two other proteins, DNA topoisomerase IIIα and RMI. Mutations in the BLM gene generate errors during DNA replication and lead to more numerous chromosomal rearrangements and breakages. As a result of the high rate of genomic instability, individuals with Bloom syndrome are at increased risk of developing malignancies.[4][5][6][7]

Epidemiology

Bloom syndrome is an extremely uncommon disorder in most populations, with only 281 patients listed in the Bloom syndrome registry as of 2018.[3] It has been most commonly described in the Ashkenazi Jewish population. They account for 25% of affected individuals worldwide (approximately 1% of Ashkenazi Jews are carriers of the BLMAsh mutation). About 170 cases have been reported in the United States of America.[8][9] Parental consanguinity is more common than in the general population. There is a slight male predominance.[10]

Pathophysiology

The BLM gene encodes a RecQ helicase, RECQL3, otherwise known as the Bloom syndrome protein (Blm).[11] Helicases unwind double and multi-stranded DNA or RNA during replication and transcription. The RECQ helicase family, in particular, act as genome guardians by maintaining DNA stability in response to replicative, transcriptional, and telomeric stress. This family of helicases is highly conserved throughout species, with five RECQ-like (RECQL) helicases existing in mammals. Of the five RECQL helicases, three have been associated with progeroid and/or carcinogenic diseases in humans. These include Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome with mutations in BLM, WRN, and RECQL4, respectively.[12][13][14] Mutated RECQL helicases have deleterious genomic effects due to the deregulated unwinding of DNA. Patients with Bloom syndrome, in particular, have a 10-fold increase in the rate of sister-chromatid exchanges. In addition, the prevalence of chromosomal breakage and rearrangement in Bloom syndrome further highlights the important function of RECQL helicases in genome regulation.[11]

Histopathology

Histopathology in Bloom syndrome often mimics lupus erythematosus. There is a marked vacuolar interface with basal liquefaction degeneration, effacement of the rete ridges, and follicular plugging. Basement membrane thickening may or may not be seen. In the dermis, there is a moderate, superficial infiltrate of lymphocytes, predominately T cells. Capillary dilation is also present in the papillary dermis. Direct immunofluorescence shows non-specific IgM deposits along the basement membrane zone of lesional skin.[15]

History and Physical

Patients suffering from Bloom syndrome are distinguished by severe prenatal and postnatal growth retardation, microcephaly, and characteristic facies (keel-shaped, malar hypoplasia, nasal prominence, and protuberant ears). A high-pitched voice and absent upper lateral incisors are also frequently present. Parents of children with Bloom syndrome often seek medical attention because of the child's small stature with proportional body size. As such, these children are often misdiagnosed with dwarfism.[3][16]

Cutaneous features include photosensitivity and a distinctive lupus-like malar rash. UV-induced erythematous lesions may similarly occur on other sun-exposed areas such as the forearms and dorsal hands. Telangiectasias and poikiloderma occur early in the first or second year of life in response to sun exposure. Small clusters of telangiectases often appear within the rash and the sclera of the eyes. Other skin findings include mouth fissures, café-au-lait spots, and well-demarcated patchy areas of dyschromia (hypo- and hyper-pigmentation).[11][17][18][14]

Other abnormalities include hypogonadism, male infertility, premature menopause in women, intellectual disability, and late-onset, non-insulin-dependent diabetes mellitus. Patients have mild immunodeficiency leading to recurrent otitis media and sinopulmonary infections during infancy. This is due to reduced levels of plasma immunoglobulins, including IgA, IgM, and occasionally, IgG. Severe dehydration can occur in infancy from vomiting, diarrhea, and gastroesophageal reflux. Aspiration from reflux disease may contribute to the increased incidence of pneumonia and the development of chronic lung disease in these patients. Pulmonary failure is the second leading cause of death in this population.[11][16][19][14]

Patients suffering from Bloom syndrome have a high predisposition for various malignancies. Up to 50% of these patients will be diagnosed with cancer at some point in their life. Tumor development occurs on average at an earlier age than the general population. Patients may have multiple independent primary cancers with a broad range of types and localization. The mean age of cancer diagnosis is 23 years and death typically occurs before 30 years of age. Leukemias (myeloid or lymphoid) and non-Hodkin lymphomas are the most common type of cancer in the first two decades of life (mean age is 20 years). Lymphomas occur 150 to 300 times more frequently than in the healthy population. Unfortunately, 10% of patients will develop a second malignancy. These may include carcinomas of the respiratory tract, gastrointestinal tract (especially colorectal), breast, liver, skin (basal cell carcinoma and squamous cell carcinoma), osteosarcoma, retinoblastoma, and brain tumors. The most common of these is colorectal carcinoma. Complications from malignancy are the main cause of death.[11][19][14]

Evaluation

If suspected clinically, the diagnosis of Bloom syndrome is confirmed by cytogenetic analysis showing increased numbers of sister chromatid exchanges or quadriradial configurations in lymphocytes or fibroblasts. The targeted mutational analysis may also be performed. Genetic and prenatal testing is recommended for high-risk carrier populations. 

Laboratory studies include a complete blood count with differential showing low normal lymphocytes. These patients often have higher effector memory T cells but reduced memory B cells. Plasma serum IgM, IgA, and occasionally, IgG levels are decreased.[20]

Treatment / Management

A multidisciplinary approach is especially important in the management of these patients. Due to the rarity of this condition and its complexities, there is no consensus for management or treatment. During the neonatal period, strict fluid management is needed to prevent life-threatening dehydration. Supplemental feeding via gastrostomy tubes may be useful in preventing dehydration and malnutrition but does not appear to improve linear growth. Growth hormone administration seems ineffective in increasing growth rate or adult height. Furthermore, it may increase the risk of tumor development. Appropriate antibiotics are used to treat infections. IV immune globulin replacement may be used in patients with significant immunodeficiency. Close follow-up with endocrinology is needed to treat diabetes mellitus. Dermatologic recommendations include frequent skin screenings and avoidance of sun exposure.[21][22](B3)

According to one study, hematologic malignancy screening should be avoided in children due to the lack of prognostic benefit with early diagnosis. However, adults benefit from surgical resection of carcinomas at an early stage and thus, annual breast, cervix, and colon cancer screenings are recommended. Due to the high risk of chromosomal breakage, the radiation exposure must be minimized. Magnetic resonance imaging and ultrasound should be used in place of computed tomography and radiographs for cancer screening and diagnosis. Because of the risk of increased toxicity, chemotherapeutic agents may need dose-adjusted. 5-fluorouracil, in particular, has been shown to induce higher levels of DNA fragmentation. Radiotherapy must be avoided. Proton beam therapy has been shown to be a safer alternative than radiotherapy.[23][24](B3)

Differential Diagnosis

Differential diagnoses include the following:

Disorders of Short Stature with Normal Body Proportions

• Skeletal dysplasia
• Growth hormone deficiency
• Constitutional delay

Genetic Photosensitivity Disorders

• Xeroderma pigmentosa
• Cockayne syndrome
• Rothmund-Thomson syndrome
• Smith-Lemli-Opitz syndrome

Chromosomal Breakage Disorders

• Nijmegen breakage syndrome
• DNA ligase IV deficiency
• Cernunnos deficiency

Prognosis

Many patients with Bloom syndrome survive to adulthood. The mean age of death is 26 years of age, most commonly from complications of malignancy. The second most common cause of death is chronic lung disease.[3][11]

Complications

Patients often develop severe bone marrow suppression and toxicity even with reduced doses of chemotherapy and radiation. Malignancies are, therefore, very difficult to treat; although, there has been some success with proton beam therapy. However, even patients in cancer remission often succumb to complications from pneumonia, chronic lung disease, hepatic disease, or sepsis.[24]