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Bloom syndrome (often abbreviated as BS in literature) is a rare
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...
recessive
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
characterized by short stature, predisposition to the development of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
, and genomic instability. BS is caused by mutations in the '' BLM'' gene which is a member of the RecQ DNA
helicase Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
family. Mutations in genes encoding other members of this family, namely '' WRN'' and '' RECQL4'', are associated with the clinical entities Werner syndrome and Rothmund–Thomson syndrome, respectively. More broadly, Bloom syndrome is a member of a class of clinical entities that are characterized by chromosomal instability, genomic instability, or both, and cancer predisposition. Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive crossovers between homologous chromosomes and sister chromatid exchanges (SCEs). New York dermatologist Dr. David Bloom discovered and first described the condition in 1954. Bloom syndrome has also appeared in the older literature as Bloom–Torre–Machacek syndrome.


Presentation

The most prominent feature of Bloom syndrome is proportional small size. The small size is apparent in utero. At birth, neonates exhibit rostral to caudal lengths, head circumferences, and birth weights that are typically below the third percentile. The second most commonly noted feature is a rash on the face that develops early in life due to sun exposure. The facial rash appears most prominently on the cheeks, nose, and around the lips. It is described as
erythema Erythema (, ) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology inc ...
tous, which is red and inflamed, and telangiectatic, which is characterized by dilated blood vessels at the skin's surface. The rash commonly also affects the backs of the hands and neck, and it can develop on any other sun-exposed areas of the skin. The rash is variably expressed, being present in a majority but not all persons with Bloom syndrome, and it is on average less severe in females than in males. Moreover, the sun sensitivity can resolve in adulthood. There are other dermatologic changes, including hypo-pigmented and hyper-pigmented areas, cafe-au-lait spots, and
telangiectasia Telangiectasias (), also known as spider veins, are small dilated blood vessels that can occur near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. These dilated blood vessels can develop anywhere ...
s, which can appear on the face and on the ocular surface. There is a characteristic facial appearance that includes a long, narrow face; prominent nose, cheeks, and ears; and
micrognathism Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnor ...
or undersized jaw. The voice is high-pitched and squeaky. There are a variety of other features that are commonly associated with Bloom syndrome. There is a moderate
immune deficiency Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affec ...
, characterized by deficiency in certain immunoglobulin classes and a generalized proliferative defect of B and
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s. The immune deficiency is thought to be the cause of recurrent
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
and middle ear infections in persons with the syndrome. Infants can exhibit frequent gastrointestinal upsets, with reflux, vomiting, and diarrhea, and there is a remarkable lack in interest in food. There are endocrine disturbances, particularly abnormalities of
carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...
,
insulin resistance Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...
and susceptibility to
type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
,
dyslipidemia Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of ...
, and compensated
hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
. Persons with Bloom syndrome exhibit a paucity of subcutaneous fat. There is reduced fertility, characterized by a failure in males to produce
sperm Sperm (: sperm or sperms) is the male reproductive Cell (biology), cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm ...
(azoospermia) and premature cessation of menses (premature
menopause Menopause, also known as the climacteric, is the time when Menstruation, menstrual periods permanently stop, marking the end of the Human reproduction, reproductive stage for the female human. It typically occurs between the ages of 45 and 5 ...
) in females. Despite these reductions, several women with Bloom syndrome have had children, and there is a single report of a male with Bloom syndrome bearing children. Although some persons with Bloom syndrome can struggle in school with subjects that require abstract thought, there is no evidence that
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
is more common in Bloom syndrome than in other people. The most serious and frequent complication of Bloom syndrome is
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. In the 281 persons followed by the Bloom Syndrome Registry, 145 persons (51.6%) have been diagnosed with a malignant neoplasm, and there have been 227 malignancies. The types of cancer and the anatomic sites at which they develop resemble the cancers that affect persons in the general population. The age of diagnosis for these cancers is earlier than for the same cancer in normal persons, and many persons with Bloom syndrome have been diagnosed with multiple cancers. The average life span is approximately 27 years. The most common cause of death in Bloom syndrome is cancer. Other complications of the disorder include chronic obstructive lung disease and type 2 diabetes. There are a variety of excellent sources for more detailed clinical information about Bloom syndrome. There is a closely related entity that is now referred to as Bloom-syndrome-like disorder (BSLD) which is caused by mutations in components of the same protein complex to which the ''BLM'' gene product belongs, including '' TOP3A'', which encodes the
type I topoisomerase In molecular biology Type I topoisomerases are enzymes that cut one of the two strands of double-stranded DNA, relax the strand, and reanneal the strand. They are further subdivided into two structurally and mechanistically distinct topoisomeras ...
, topoisomerase 3 alpha, '' RMI1'', and ''RMI2''. The features of BSLD include small size and dermatologic findings, such as cafe-au-lait spots, and the presence of the once pathognomonic elevated SCEs is reported for persons with mutations in ''TOP3A'' and ''RMI1''. Bloom syndrome shares some features with Fanconi anemia possibly because there is overlap in the function of the proteins mutated in this related disorder.


Genetics

Bloom syndrome is an autosomal recessive disorder, caused by mutations in the maternally- and paternally-derived copies of the gene ''BLM''. As in other autosomal recessive conditions, the parents of an individual with Bloom syndrome do not necessarily exhibit any features of the syndrome. The mutations in BLM associated with Bloom syndrome are nulls and catalytically inactive missense mutations. The cells from persons with Bloom syndrome exhibit a striking genomic instability that is characterized by hyper-recombination and hyper-mutation. Human BLM cells are sensitive to DNA damaging agents such as UV and methyl methanesulfonate, indicating deficient repair capability. At the level of the chromosomes, the rate of sister chromatid exchange in Bloom's syndrome is approximately 10-fold higher than normal, and quadriradial figures, which are the cytologic manifestations of crossing-over between homologous chromosomes, are highly elevated. Other chromosome manifestations include chromatid breaks and gaps, telomere associations, and fragmented chromosomes. The hyper-recombination can also be detected by molecular assays The ''BLM'' gene encodes a member of the protein family referred to as RecQ helicases. The diffusion of BLM has been measured to 1.34 \tfrac in nucleoplasm and 0.13 \textstyle \tfrac at nucleoli DNA helicases are enzymes that attach to DNA and temporarily unravel the double helix of the DNA molecule. DNA helicases function in DNA replication and DNA repair. BLM very likely functions in DNA replication, as cells from persons with Bloom syndrome exhibit multiple defects in DNA replication, and they are sensitive to agents that obstruct DNA replication. The BLM helicase is a member of a protein complex with topoisomerase III alpha, RMI1, and RMI2, also known as BTRR, Bloom Syndrome complex, or the dissolvasome. Disruption of the proper assembly of the Bloom Syndrome complex leads to genome stability, genetic dependence on cellular nucleases GEN1 and MUS81, and loss of normal cell growth. Bloom-like phenotypes have been associated with mutations in topoisomerase III alpha, RMI1 and RMI2 genes.


Relationship to cancer and aging

As noted above, there is a greatly elevated rate of mutation in Bloom syndrome and the genomic instability is associated with a high risk of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
in affected individuals. The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity, that is, synchronous or metachronous cancers. There was at least one person with Bloom syndrome who had five independent primary cancers. Persons with Bloom syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 26 years old.


Pathophysiology

When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. Lack of BLM protein or protein activity leads to an increase in mutations; however, the molecular mechanism(s) by which BLM maintains the stability of the chromosomes is still a very active area of research. Persons with Bloom syndrome have an enormous increase in exchange events between
homologous chromosome Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same locus (genetics), loci, where they provide points along e ...
s or
sister chromatids A sister chromatid refers to the identical copies ( chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the du ...
(the two DNA molecules that are produced by the DNA replication process), and there are increases in chromosome breakage and rearrangements compared to persons who do not have Bloom's syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research.


Diagnosis

Bloom syndrome is diagnosed using any of three tests - the presence of quadriradial (Qr, a four-armed chromatid interchange) in cultured blood lymphocytes, and/or the elevated levels of sister chromatid exchange in cells of any type, and/or the mutation in the BLM gene. The US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) announced on February 19, 2015, that they have authorized the marketing of a direct-to-consumer genetic test from
23andMe 23andMe Holding Co. is an American personal genomics and biotechnology company based in South San Francisco, California. It is best known for providing a direct-to-consumer genetic testing service in which customers provide a saliva testing, sali ...
. The test is designed to identify healthy individuals who carry a gene that could cause Bloom Syndrome in their offspring.


Treatment

Bloom syndrome has no specific treatment; however, avoiding sun exposure and using
sunscreen Sunscreen, also known as sunblock, sun lotion or sun cream, is a photoprotection, photoprotective topical product for the Human skin, skin that helps protect against sunburn and prevent skin cancer. Sunscreens come as lotions, sprays, gels, fo ...
s can help prevent some of the cutaneous changes associated with photo-sensitivity. Efforts to minimize exposure to other known environmental mutagens are also advisable in multiple forms.


Epidemiology

Bloom syndrome is extremely rare in most populations and the frequency of the disease has not been measured in most populations. However, the disorder is relatively more common amongst people of Central and Eastern European
Ashkenazi Ashkenazi Jews ( ; also known as Ashkenazic Jews or Ashkenazim) form a distinct subgroup of the Jewish diaspora, that Ethnogenesis, emerged in the Holy Roman Empire around the end of the first millennium Common era, CE. They traditionally spe ...
Jewish background. Approximately 1 in 48,000
Ashkenazi Jews Ashkenazi Jews ( ; also known as Ashkenazic Jews or Ashkenazim) form a distinct subgroup of the Jewish diaspora, that emerged in the Holy Roman Empire around the end of the first millennium CE. They traditionally speak Yiddish, a language ...
are affected by Bloom syndrome, who account for about one-third of affected individuals worldwide.


Bloom's Syndrome Registry

The Bloom's Syndrome Registry lists 283 individuals reported to have this rare disorder (as of 2020), collected from the time it was first recognized in 1954. The registry was developed as a surveillance mechanism to observe the effects of cancer in the patients, which has shown 122 individuals have been diagnosed with cancer. It also acts as a report to show current findings and data on all aspects of the disorder.


See also

*
Accelerated aging disease Progeroid syndromes (PS) are a group of rare genetic disorders that mimic Physiology, physiological senescence, aging, making affected individuals appear to be older than they are. The term ''progeroid syndrome'' does not necessarily imply progeri ...
* Bloom syndrome (gene) *
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
* Progeria * Tumor M2-PK


References

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Further reading

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External links

* {{Progeroid syndromes Chromosome instability syndromes Genodermatoses Autosomal recessive disorders Rare syndromes Ashkenazi Jews topics IUIS-PID table 3 immunodeficiencies DNA replication and repair-deficiency disorders Progeroid syndromes Syndromes with tumors Syndromes affecting stature Diseases named after discoverers