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Bloom Syndrome

BSyn

Bloom syndrome is a very rare autosomal recessive genetic disease that stems from mutations in genes responsible for DNA repair. Predisposition to various malignancies (mainly of the hematopoietic system, the gastrointestinal tract, the skin, and the genitourinary tract), photosensitivity, frequent infections of the lungs and ear, growth deficiency, sterility, and learning disabilities are some of the most common findings in this patient population. The diagnosis rests on clinical criteria and molecular genetic studies that confirm mutations responsible for this syndrome.


Presentation

The clinical presentation of patients suffering from Bloom syndrome encompasses a myriad of signs and symptoms [1] [2] [3] [4] [5] [6]:

  • Growth deficits - Virtually all patients with Bloom syndrome have a short stature that is seen as early as birth [1] [5] [6]. A low birth weight with a smaller cranium compared to the rest of the body are typical findings [1] [6]. In fact, body height rarely reaches > 150 cm in adulthood, whereas reduced adipose tissue formation (often resulting in a "wasting" appearance of the patient) is also common [1] [5] [6].
  • Facial changes - In addition to growth abnormalities, patients have very narrow facies with prominent ears and nose [1] [5] [6]. Other notable changes are an underdeveloped mandible and a high-pitched voice [1].
  • Skin lesions - The entire skin is sensitive to ultraviolet light and changes are initially observed in the first few years of life. Erythema and telangiectasia of the face in a "butterfly" pattern, but also of the entire skin, loss of eyelashes, as well as the formation of blistering lesions and fissures of the lower lips are known features [1] [5] [6].
  • Sterility and infertility - Male patients with Bloom syndrome almost always suffer from oligospermia or azoospermia, resulting in sterility [1] [5] [6]. Conversely, infertility is rarely encountered in females, but a premature menopause is readily noted [1] [6] [7].

Other important signs and symptoms of Bloom syndrome are variable intellectual disability, feeding problems (often due to gastroesophageal reflux disease), immunosuppression that predisposes to infection (lungs, skin, and ears are main sites), retinopathies, glucose intolerance, and a very frequent occurrence of one or more malignant diseases - lymphomas and gastrointestinal neoplasias being the most common [1] [2] [4] [5] [6].

Collapse
  • Mounting evidence has implicated a function for BLM during DNA replication; specifically, BLM might be involved in rescuing stalled or collapsed replication forks by a recombination-based mechanism.[ncbi.nlm.nih.gov]
  • One possible role for BLM would be to prevent DNA structures that arise at blocked or collapsed replication forks from being processed into mature recombinants ( 5, 6 ).[doi.org]
High Pitched Voice
  • Bloom syndrome listen (… SIN-drome) A rare, inherited disorder marked by height that is shorter than average, a narrow face with redness and a rash, a high-pitched voice, and fertility problems.[cancer.gov]
  • People with Bloom syndrome are much smaller than average, and often have a high-pitched voice and characteristic facial features including a long, narrow face; small lower jaw; and prominent nose and ears.[hon.ch]
  • People with Bloom syndrome have a high pitched voice and unique facial features, including a long narrow face, a small jaw, and large ears and nose.[diseaseinfosearch.org]
  • Reddened areas can also be seen on other areas which are exposed to the sun, such has hands. a high pitched voice changes in the shape of the face, such as a long face and a small lower jaw, as well as large ears and a prominent nose changes in skin colour[medic8.com]
  • Other characteristics include a high-pitched voice, dilated blood vessels appearing on the skin and in the eyes, hyper- and hypo-pigmentation, infertility in males due to an inability to produce sperm, and early menopause and reduced fertility in females[brighthub.com]
Abdominal Pain
  • Metabolic syndrome presenting as abdominal pain. Saudi J Med Med Sci 2017;5:172-4 How to cite this URL: Al-Dossary MY, Hasan MA, Al-Dhafeeri AH, Al-Nafea NM. Metabolic syndrome presenting as abdominal pain.[sjmms.net]
  • Dyspepsia is upper abdominal pain or discomfort that is episodic or persistent and often associated with belching, bloating, heartburn, nausea or vomiting. 1 The condition is reported to occur in approximately 25 percent (range: 13 to 40 percent) of the[aafp.org]
  • He had episodes of abdominal pain and loose stools throughout childhood.[ped-rheum.biomedcentral.com]
  • (Figs. 1,2) Depending on the level and extent of venous occlusion, and its rate of development, the clinical presentation can vary from ascites, abdominal pain and hepatomegaly to more serious problems such as hepatic failure and encephalopathy.[bhj.org.in]
  • Bowel distention may be responsible for GI symptoms, such as crampy abdominal pain, bloating, and diarrhea.[emedicine.medscape.com]
Failure to Thrive
  • Common clinical features of Bloom syndrome A butterfly-shaped rash over the nose and cheeks Lip lesions with blisters and/or fissures Small or very small size at birth Failure to thrive in infancy Very short stature Very small head Skin telangiectasias[forgottendiseases.org]
  • On the other hand, lack of eating has been associated with failure to thrive or anorexic-like tendencies [ 12, 21, 29 ]. Failure to thrive is associated with a child’s inability to gain weight, grow or feed normally [ 29 ].[ncbi.nlm.nih.gov]
  • At 17 months old, he was hospitalized for worsening failure to thrive (weight A liver biopsy revealed mild to moderate chronic active hepatitis (primarily lymphocytic without plasma cells) and interface hepatitis without significant fibrosis, viral inclusions[ped-rheum.biomedcentral.com]
  • Introduction Dubowitz syndrome was originally described in 1965 in a girl with intrauterine growth retardation (IUGR), eczema, short stature, failure to thrive, a high-pitched cry, presumed autosomal recessive inheritance and a distinctive facies (large[journals.plos.org]
Abdominal Mass
  • Recommended Surveillance for Individuals with Bloom Syndrome (BSyn) Manifestation Evaluation Frequency Wilms tumor Abdominal ultrasound Screen for signs/symptoms incl hematuria & a painless abdominal mass Every 3 mos from time of diagnosis to age 8 yrs[ncbi.nlm.nih.gov]
Skeletal Dysplasia
  • CHST3 -Related Skeletal Dysplasia Andrea Superti-Furga and Sheila Unger. Initial Posting: September 1, 2011; Last Update: January 31, 2019.[ncbi.nlm.nih.gov]
Cafe-Au-Lait Spots
  • Bloom syndrome is a rare autosomal recessive disorder characterized by short stature, brachydactyly, malar hypoplasia and facial telangiectasia, erythema and cafe au lait spots. Affected individuals have an increased risk of developing malignancies.[radiopaedia.org]
  • […] are exposed to the sun, such has hands. a high pitched voice changes in the shape of the face, such as a long face and a small lower jaw, as well as large ears and a prominent nose changes in skin colour – areas may be darker or lighter than normal cafe-au-lait[medic8.com]
  • There are other dermatologic changes, including hypo-pigmented and hyper-pigmented areas, cafe-au-lait spots, and telangiectasias, which can appear on the face and on the ocular surface.[en.wikipedia.org]
Urticaria
  • […] skin) (infected) 701.9 Touraine-Solente-Golé syndrome (acropachyderma) 757.39 Tumor (M8000/1) - see also Neoplasm, by site, unspecified nature White-Darier 757.39 Tylosis 700 palmaris et plantaris 757.39 Uehlinger's syndrome (acropachyderma) 757.39 Urticaria[icd9data.com]
Petechiae
  • Evaluation Frequency Wilms tumor Abdominal ultrasound Screen for signs/symptoms incl hematuria & a painless abdominal mass Every 3 mos from time of diagnosis to age 8 yrs Leukemia Screening & family education on signs/symptoms incl pallor, abnormal bleeding, petechiae[ncbi.nlm.nih.gov]
Narrow Face
  • Bloom syndrome - congenital telangiectatic erythema and dwarfism with normal body proportions except for a narrow face and dolichocephalic skull.[medical-dictionary.thefreedictionary.com]
  • Bloom syndrome listen (… SIN-drome) A rare, inherited disorder marked by height that is shorter than average, a narrow face with redness and a rash, a high-pitched voice, and fertility problems.[cancer.gov]
  • People with Bloom syndrome are much smaller than average, and often have a high-pitched voice and characteristic facial features including a long, narrow face; small lower jaw; and prominent nose and ears.[hon.ch]
  • Dolichocephaly, narrow face, prominent nose and ears, and malar and mandibular hypoplasia can be observed. Subcutaneous adipose tissue is sparse.[orpha.net]
  • Typically those affected have a narrow face and redness of the skin of the face, which is aggravated by sunlight.[cafamily.org.uk]
Malar Rash
  • Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition.[ncbi.nlm.nih.gov]
  • To date, he has not presented with any malignancy or characteristic malar rash.[casereports.bmj.com]
  • No abnormal skin findings in persons w/ RMI1 pathogenic variants No malar rash in persons w/ TOP3A pathogenic variants RMI2 1 RECQ-mediated genome instability 2 (OMIM 612426 ) AR TOP3A 1 Microcephaly, growth restriction, & increased sister-chromatid exchange[ncbi.nlm.nih.gov]
Dyspareunia
  • A 37-year-old woman, para 0-0-2-0, with BS was referred to the gynecologic oncology service for a suspicious mass in the vagina associated with dyspareunia and vaginal bleeding.[ncbi.nlm.nih.gov]
Vaginal Bleeding
  • A 37-year-old woman, para 0-0-2-0, with BS was referred to the gynecologic oncology service for a suspicious mass in the vagina associated with dyspareunia and vaginal bleeding.[ncbi.nlm.nih.gov]

Workup

Because of numerous complications and associated conditions that occur, up to one-third of patients die in their third decade of life [6]. For this reason, an early diagnosis is critical. The physician must obtain a detailed patient history that will focus on the onset of symptoms and their progression. A heterogeneous anamnesis (particularly from the parents) might be useful in the case of younger children and adolescents. In addition to a complete family history (which must be covered due to the autosomal recessive pattern of inheritance), Ashkenazi Jew ancestry carries a very high risk for the development of Bloom syndrome (carrier state is estimated in approximately 1 in 100 individuals), meaning that demographic factors should also be thought of when establishing the cause [1] [3]. An early onset of chronic obstructive pulmonary disease (COPD) and diabetes mellitus is an additional clue that points toward this diagnosis [1]. If solid evidence toward Bloom syndrome is obtained during history taking and physical examination (which is essential for establishing the main clinical findings), a definitive diagnosis can be pursued through genetic testing. Identification of mutations in the BLM gene that codes for the RecQL3 helicase enzyme (a very important enzyme involved in DNA repair) confirm the diagnosis [1] [3].

Treatment

Treatment is targeted at the various manifestations of the disease. Supplementation with growth hormone has proven ineffective in resolving growth abnormalities. Feeding through intubation can help in increasing fat deposition but has no effects on growth. Because many chemotherapeutic agents are directed at mechanisms involved in cell replication and differentiation, it is often necessary to reduce both the dose and duration of cancer treatment. The absence of specific information about dosage and duration of the treatment in those patients is particularly challenging for the physician. Diabetes mellitus in patients with Bloom is not treated in a different manner than that occurring in the normal population. Finally, psychosocial intervention is very important. Family and teachers are advised to behave with the patients according to their true age rather than what is suggested by their stature.

Prognosis

Patients with Bloom syndrome have 150 to 300 times the risk of developing malignancies in comparison to normal individuals. Malignancies will occur in around 20% of patients, particularly leukemias that usually manifest around a mean age of 22 years. Patients who survive beyond 22 years will develop solid tumors at an average of 35 years. Around 10% of patients are affected by diabetes mellitus across their life time, although the risk of infection and the sensitivity to sunlight decreases with age.

Etiology

Bloom syndrome is transmitted in an autosomal recessive fashion, so that each parent of the individual affected carries one copy of the gene with the mutation without showing any symptoms. The gene involved is the BLM gene, resulting in a defective BLM protein. This protein plays a critical role in several domains. A mutation increases chromosomal exchange, in particular between sister chromatids and paternal and maternal chromosomes. In addition, BLM abnormalities impair the repair of DNA damage caused as a result of exposure to ultraviolet light, manifesting in increased sensitivity to sunlight. Mutations accumulate in the genome and ultimately increase the risk of cancer in patients suffering from this disorder. 

The major end protein affected in Bloom syndrome is DNA ligase I, an enzyme involved in DNA replication. Scientists were able to show that patients with Bloom syndrome have a DNA ligase I with different physical properties, particularly in regards to heat sensitivity and the ability to aggregate [2] [3]. Other studies further corroborated the connection between Bloom syndrome, DNA Ligase I and metabolic abnormalities associated with the disease, in addition to uncovering the specific pathophysiological mechanisms involved. They report changes in the hydrolytic capacity of DNA Ligase I and its ability to bind ATP, without any reduction of the level of expression of the protein or other inhibitory molecules [4]. DNA Ligase I is part of a broader complex of enzymes involved in DNA repair and replication, that also includes DNA polymerase alpha, DNA polymerase beta and DNA ligase II.

Epidemiology

Bloom syndrome is a rare disease and affects men slightly more than women. Reports in the literature are scarce because only few hundred cases have been recorded, but the available reports indicate a higher incidence of disease in families with consanguinity among parents, as compared to the general population. As revealed through records of Bloom patients' registry, the syndrome has a high carrier frequency in the ratio of 1:120 and accounts for 25 % patients  among Ashkenazi Jews [5]. The syndrome has also been reported from Japan and other countries in families where there is consanguinity among parents. In comparison to the general population, patients also have 150 to 300 times higher risk of developing malignancy in their life time [6]. It is associated with premature delivery in affected pregnant women and diabetes in approximately 10% of patients. It manifests in the first months of life but does not seem to decrease overall intelligence levels, except in select cases.

Sex distribution
Age distribution

Pathophysiology

Bloom syndrome, also known as telangiectacic erythema, results from a mutation to the BLM gene present on chromosome 15. The exact location can be traced to 15q26.1 [7] [8] [9]. The BLM protein is a member of the RecQ family of helicases and is composed of 1417 amino acids. It is usually present in the nuclear matrix and is essential for DNA repair and replication. Mutations in the BML gene lead to defective protein that result in loss of genomic stability in somatic cells, and thus significantly increasing the risk of malignancy [10].

Around 60 mutations of the BLM gene have been associated with Bloom syndrome. Among the most common of mutations, which is present mostly among Ashkenazi Jews, involves a substitution of 6 nucleotides with 7 new ones at position 2281 in the gene sequence. Reports indicate an increased rate of chromatic exchange, chromosomal gaps, breaks and structural rearrangement and is 10 times more elevated in comparison to the normal population [11] [12] [13].

Bloom syndrome has been associated with Fanconi anemia, given the involvement of proteins MM1 and MM2 in both diseases. They tend to show similar phenotypes and share distinctive features such as abnormalities in skeletal growth and short stature, failure of the bone marrow and hematologic cancers. Although the two diseases are not related genetically, pathophysiological mechanisms include disturbances along common pathways in DNA repair, involving the complexes , BRAFT and FANCM [14] [15].

Patients with Bloom syndrome are known to be sensitive to sunlight with a reduction of the threshold for minimal erythema for both, UV-A and UV-B light [16]. This is caused by an increased vulnerability of the DNA to ultraviolet radiation, particularly for wavelengths corresponding to 313 nm. They are especially susceptible to radiation in UV-A range although it is important to note that, unlike in xeroerma pigmentosa, there is increased phototoxicity and not photocarcinogenicity [17].

Other prominent features of the disease are related to the immune system and affect both the humoral and cellular immune responses [18]. They include deficits in lymphocytic proliferation, abnormal immunoglobulin synthesis and impaired reaction to mitogen stimulation.

Prevention

There is no cure for Bloom syndrome but important preventive measures can be performed to reduce the risk of complications. Sunscreens and the avoidance of sunlight may prevent the skin damage associated with sun exposure. In addition, patients are recommended to avoid known mutagens [20]. Immunoglobulin replacement can help in preventing infections due to deficiencies in immunoglobulin production. In addition, patients should be periodically screened for any malignancy [21].

Summary

David Bloom was the first to describe Bloom syndrome in 1954 in a group of patients suffering from facial erythema and short stature [1]. The disease is most commonly encountered among Ashkenazi Jews (Jews of Central and Eastern European origin) and is chiefly characterized by growth abnormalities and sun sensitivity usually manifested by erythema of the face upon sun exposure. The facial rash has a butterfly shape over the cheeks and the nose and can also involve other areas of the body subjected to sunlight, including the forearms and the back of hands. 

Individuals with Bloom syndrome also suffer from a range of other abnormalities. They commonly develop frequent infections of the lung and the middle ear, most likely due to a higher incidence of gastroesophageal reflux associated with aspiration. As the age advances, the patient is more likely to have chronic obstructive pulmonary disease with severe bronchiectasis, as well as diabetes mellitus resembling the disease in the normal population. They are at a significantly increased risk of acquiring various malignancies that can affect different tissues at different sites of the body, necessitating frequent screening and monitoring. In addition, the disease affects the reproductive system with women undergoing early menopause although retaining their ability to conceive and men unable to produce sperm, leading to infertility.

Bloom syndrome is a genetic disease inherited in an autosomal recessive fashion. Individuals usually have a defective BLM gene, resulting in abnormalities in DNA replication and repair. 

Patient Information

Bloom syndrome was first described in 1954 by dermatologist David Bloom. It is a rare genetic disease, chiefly characterized by growth abnormalities and short stature. Patients usually retain normal body proportions although the head is disproportionately smaller. Increased sensitivity to sunlight, resulting especially in cracking and blistering of the lower lip, is another prominent feature and can be prevented with adequate avoidance of sun exposure. Growth abnormalities are commonly noticed at birth and infants typically show problems with feeding and decreased interest in nursing and eating. Patients develop frequent infections, especially of the lung (pneumonia) and the middle ear (otitis media), possibly resulting from the increased risk of aspiration and gastroesophageal reflux.

Bloom syndrome additionally affects the development of reproductive system. While women undergo premature menopause, they retain their ability to conceive. But, men are faced with an inability to develop normal sperm (azoospermia), leading to infertility. Patients with Bloom syndrome have a higher risk of developing several specific disorders as they age. These include chronic obstructive disease, mild diabetes mellitus that closely resembles the disease observed in the normal population as well as a variety of cancers that can affect different tissue types in various locations. The risk of developing malignancy makes it particularly important for patients to undergo regular screening and monitoring for the early detection of any cancer and the prevention of resulting complications. Patients with Bloom syndrome appear to have a normal mental capacity but demonstrate a decreased interest in learning, with a select few being affected by mental retardation.

References

Article

  1. Sanz MM, German J, Cunniff C. Bloom’s Syndrome. 2006 Mar 22 [Updated 2016 Apr 7]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  2. Diaz A, Vogiatzi MG, Sanz MM, German J. Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom's syndrome. Horm Res. 2006;66:111–7.
  3. Peleg L, Pesso R, Goldman B, Dotan K, Omer M, Friedman E, Berkenstadt M, Reznik-Wolf H, Barkai G. Bloom syndrome and Fanconi's anemia: rate and ethnic origin of mutation carriers in Israel. Isr Med Assoc J. 2002;4:95–7.
  4. Arora H, Chacon AH, Choudhary S, et al. Bloom syndrome. Int J Dermatol. 2014;53(7):798-802.
  5. Bhisitkul RB, Rizen M. Bloom syndrome: multiple retinopathies in a chromosome breakage disorder. Br J Ophthalmol. 2004;88(3):354-357.
  6. Cunniff C, Bassetti JA, Ellis NA. Bloom’s Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition. Molecular Syndromology. 2017;8(1):4-23.
  7. Masmoudi A, Marrakchi S, Kamoun H, Chaaben H, Ben Salah G, et al. Clinical and laboratory findings in 8 patients with Bloom's syndrome. J Dermatol Case Rep. 2012;6:29–33.

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Last updated: 2019-07-11 21:58