Bloom's syndrome: what is it, causes, symptoms, treatment, prognosis

What is Bloom Syndrome?

Bloom's syndrome, also called Bloom-Torre-Macheikik syndrome or congenital telangiectatic erythema, is a rare genodermatosis characterized by genome instability and a predisposition to the development of various types of cancer. Bloom's syndrome is caused by mutations in a gene BLM, which induces the formation of an abnormal DNA helicase protein. The most notable signs include prenatal growth failure, mild immunodeficiency, excessive photosensitivity with lupus-like skin lesions on the face, type 2 diabetes mellitus and hypogonadism. The increased risk of malignant neoplasms in Bloom's syndrome leads to a reduction in life expectancy and an increase in pathological lesions in patients.

Signs and symptoms

The most consistent clinical sign of Bloom syndrome, seen at all stages of life, is poor growth, which affects height, weight and head circumference. This growth deficit begins before birth and the affected fetus is usually less than normal for gestational age. The average birth weight of sick boys is 1760 g (range 900–3189 g) and for girls 1754 g (range 700–2892 g). However, the proportions of the body are normal. The average height of adult male and female patients is 149 cm (range 128–164 cm) and 138 cm (range 115–160 cm), respectively.

Although the appearance of people with the disorder varies and may be indistinguishable from healthy people of the same age and size, infants and adults with Bloom syndrome usually have a distinctly narrow head and face, but are of normal proportions body. The thinned subcutaneous fat may cause the nose and / or ears to protrude. Despite the very small head circumference, most patients have normal intellectual abilities.

More details about the symptoms are written below in the "History and Physics" section..

Causes

Bloom's syndrome is a rare autosomal recessive disorder of chromosomal instability. The disorder is due to mutations in a gene BLMlocated at 15q26.1. Gene BLM encodes BLM helicase, which forms a complex with two other proteins, DNA topoisomerase IIIα and RMI. Gene mutations BLM cause errors during DNA replication and lead to more numerous chromosomal rearrangements and breakdowns. As a result of the high degree of genome instability, people with Bloom syndrome are at increased risk of developing malignant neoplasms.

Epidemiology

Bloom syndrome is extremely rare in most populations, with only 281 patients on the Bloom syndrome registry as of 2018. It was most often described among the Ashkenazi Jewish population. They account for 25% of affected people worldwide (approximately 1% of Ashkenazi Jews carry the BLMAsh mutation). There are about 170 cases reported in the United States of America. The disorder is more common in children whose parents are blood relatives than in the general population. There is a slight predominance of men.

Pathophysiology

Gene BLM encodes the RecQ helicase, RECQL3, otherwise known as the Bloom syndrome protein. Helicases unwind double-stranded and multi-stranded DNA or RNA during replication and transcription. In particular, the RECQ helicase family acts as a guardian of the genome, maintaining DNA stability in response to replicative, transcriptional, and telomeric stress. This family of helicases is highly conserved in all species; there are five RECQ-like (RECQL) helicases in mammals. Of the five helicases RECQL, three were associated with progeroid and / or carcinogenic diseases in humans. These include Bloom's syndrome, Werner's syndrome and Rothmund-Thomson syndrome with mutations in BLM, WRN and RECQL4 respectively. Mutated RECQL helicases have harmful genomic effects due to dysregulation of DNA unwinding. In particular, in patients with Bloom's syndrome, the rate of sister chromatid exchanges increases tenfold. In addition, the predominance of chromosomal breaks and rearrangements in Bloom's syndrome further emphasizes the important function of RECQL helicases in genome regulation.

Histopathology

Bloom syndrome histopathology often mimics lupus erythematosus. There is a pronounced vacuolar border with degeneration of basal liquefaction, erasure of reticular ridges and blockage of follicles. A thickening of the basement membrane may or may not be noticed. In the dermis there is a moderate superficial infiltration of lymphocytes, mainly T-lymphocytes. Capillary dilation is also present in the papillary dermis. Direct immunofluorescence shows nonspecific IgM deposits along the basement membrane area of ​​the affected skin.

Diagnostics

- History and physics.

Individuals with Bloom syndrome have severe prenatal and postnatal growth retardation, microcephaly, and characteristic facial features (keeled shape, hypoplasia of the zygomatic bone, protruding noses and protruding ears). A high-pitched voice and the absence of the upper lateral incisors are also often present. Parents of children with Bloom's syndrome often seek medical help because of the small stature of the child with a proportional body size. Thus, these children are often mistakenly diagnosed with dwarfism.

Skin features include photosensitivity and a characteristic lupus-like rash on the cheekbones. Erythematous lesions caused by UV radiation can similarly occur in other areas exposed to sunlight, such as the forearms and dorsum of the 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 sclera of the eyes. Other skin signs include cracks in the mouth, milky spots, and well-defined foci of dyschromia (hypo- and hyperpigmentation).

Other anomalies include hypogonadism, male infertility, premature menopause in women, mental retardation and non-insulin dependent diabetes with a late start. Patients are mildly immunocompromised, resulting in a recurrent mean otitis media and synopulmonary infections in infancy. This is due to lowered levels of plasma immunoglobulins, including IgA, IgM, and sometimes IgG. In infancy due to vomiting, diarrhea and gastroesophageal reflux can be severe dehydration. Reflux aspiration may increase morbidity pneumonia and the development of chronic lung disease in these patients. Pulmonary insufficiency Is the second leading cause of death in this population.

Patients with Bloom's syndrome have a high predisposition to various malignant neoplasms. Nearly 50% of patients with Bloom syndrome will be diagnosed with cancer at some point in their lives. Tumor development occurs on average at an earlier age than in the general population. Patients may have multiple, independent primary cancers of various types and locations. The median age at diagnosis of cancer is 23 years, and death usually occurs before 30 years. Leukemias (myeloid or lymphoid) and non-Khodkin lymphomas are the most common type of cancer in the first two decades of life (average age 20 years). Lymphomas occur 150–300 times more often than in a healthy population. Unfortunately, 10% of patients will develop a second malignant neoplasm. These may include lungs' cancer, gastrointestinal tract (especially colorectal cancer), breast, liver, skin (basal cell carcinoma and squamous cell carcinoma), osteosarcoma, retinoblastoma and brain tumors. Complications of malignant neoplasms are the main cause of death.

- Analyzes.

If there is clinical suspicion, the diagnosis of Bloom's syndrome is confirmed by cytogenetic analysis showing an increased number of sister chromatid exchanges or quadriradial configurations in lymphocytes, or fibroblasts. Targeted mutational analysis can also be performed. Genetic and prenatal testing is recommended for populations of high-risk carriers.

Laboratory tests include a complete blood count with a differential count of low normal lymphocytes. These patients often have higher memory effector T cells but lower memory B cells. Plasma levels of IgM, IgA and sometimes IgG are reduced.

Treatment

A multidisciplinary approach is especially important in the management of these patients. Because of the rarity of this condition and its complexity, there is no consensus about management or treatment. During the neonatal period, fluid intake must be strictly controlled to prevent life-threatening dehydration. Gastrostomy tube supplementation may be helpful in preventing dehydration and malnutrition, but does not appear to improve linear growth. Growth hormone administration appears to be ineffective in increasing the rate of growth or growth of an adult. In addition, it can increase the risk of developing a tumor. Appropriate antibiotics are used to treat infections. Immunoglobulin replacement therapy can be used in patients with significant immunodeficiency. For the treatment of diabetes mellitus, close supervision of an endocrinologist is necessary.

According to one study, haematological screening for malignant neoplasms in children should be avoided due to the lack of prognostic benefits in early diagnosis. However, early surgical removal of carcinomas is beneficial for adults, so it is recommended that you get screened annually for breast, cervical, and colon cancers. Due to the high risk of chromosomal rupture, radiation exposure should be minimized. For screening and diagnosis of cancer, magnetic resonance imaging and ultrasound should be used instead of computed tomography and radiography. Due to the risk of increased toxicity, chemotherapeutic agents may need dose adjustment. In particular, 5-fluorouracil has been shown to induce higher levels of DNA fragmentation. Radiation therapy should be avoided. Proton radiation therapy has been shown to be a safer alternative to radiation therapy.

Forecast

Many patients with Bloom syndrome survive to adulthood. The average age of death is 26 years, most often from complications of a malignant neoplasm. The second most common cause of death is chronic lung diseases.

Complications

Patients often develop severe bone marrow depression and toxicity even with reduced doses of chemotherapy and radiation. Consequently, malignant neoplasms are very difficult to treat; although proton radiation therapy has had some success. However, even patients in remission of cancer often die from complications caused by pneumonia, chronic lung disease, liver disease or sepsis.