Case 2 A 12 year old Ashkenazi Jewish girl was reffered to the department of peadiatrics because of short stature. She was the second child of the first cousin marriage. She had a slender body frame, short stature, and microcephaly. Her face was long and narrow with prominent nose, and malar and mandibular hypoplasia. The sopts of hyper and hypo pigmentation were obsereved in the trunk and limbs. What is the molecular basis of the disease? Describe the process of Mismatch repair of DNA.

Bloom syndrome

Table of content What is bloom syndrome Genetics Symptoms Differential diagnosis Diagnosis Process of mismatch repair

What is bloom syndrome Bloom syndrome also known as Bloom–Torre–Machacek syndrome, is a rare autosomal recessive disorder characterized by short stature and predisposition to the development of cancer. Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive homologous recombination. Bloom syndrome is an extremely rare disorder in most populations and the frequency of the disease still remains unknown. However, the disorder is most common amongst people of Central and Eastern European (Ashkenazi) Jewish background. Approximately 1 in 48,000 Ashkenazi Jews are infected with Bloom syndrome and about one-third of individuals are affected worldwide.

Genetics Bloom syndrome is inherited through an autosomal recessive pattern. Mutations in the BLM gene are what causes Bloom syndrome. The BLM gene is responsible for making a member of the protein family known as RecQ helicases. Helicases are enzymes that attach to DNA and temporarily unravel the double helix of the DNA molecule. This unravelling is essential for DNA replication in preparation for cell division and for the repair of the damaged DNA molecule. RecQ helicases maintain the structure of the DNA so therefore they are commonly known as caretakers of the genome.

Symptoms Bloom syndrome is a type of progeroid syndrome, and shows much of the common characteristics, such as short stature and a rash that develops early on in life when areas of the skin are exposed to the sun. The skin rash is erythematous, telangiectatic, infiltrated, and scaly, and it appears in the butterfly-shaped patch of skin across the nose and on the cheeks. This rash can develop on other sun-exposed areas such as the backs of the hands. Other clinical features include a high-pitched voice; distinct facial features, such as a long, narrow face, micrognathism, and prominent nose and ears; pigmentation changes of the skin including hypo- and hyper-pigmented areas and cafe-au-lait spots, telangiectasias (dilated blood vessels) which can appear on the skin but also in the eyes, moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes, that apparently leads to recurrent pneumonia and ear infections. Bloom syndrome shares many phenotypes with Fanconi anemia and this may be because of overlap in the function of the proteins mutated in this related disorder.

Differential diagnosis Russell-silver syndrome: it is a growth disorder characterized by slow growth before and after birth. Babies with this condition have a low birth weight and often fail to grow and gain weight at the expected rate. Many children with Russell-Silver syndrome have a small, triangular face with distinctive facial feature Rothmund-Thomson syndrome: it is a rare condition that affects many parts of the body, especially the skin. It is also characterized by sparse hair, eyebrows, and eyelashes; slow growth and small stature

Differential diagnosis Cockayne syndrome: it is a rare disorder characterized by short stature and an appearance of premature aging. Features of this disorder include a failure to gain weight and grow at the expected rate, microcephaly, and impaired development of the nervous system. Affected individuals have photosensitivity, and even a small amount of sun exposure can cause a sunburn.

Diagnosis Bloom syndrome is diagnosed using any of three tests ; the presence of quadriradial (Qr, a four- armed chromatid interchange) in cultured blood lymphocytes. the elevated levels of Sister chromatid exchange in cells of any type. the mutation in the BLM gene.

Process of mis- match It focuses on the replication errors that has occurred in S phase. To distinguish between the template(parent) and the new strand, we use DNA dimethylase, it puts a methyl group on the parent stand, the new strands cannot be methylated because it does not have a methyl group. This enables it to be able to distinguish between the two strands. In prokaryotic replication (E. Coli) detection of mis- match is by using mutS, mutH and mutL, we have human counterparts too which are HMSH2 and HMLH1, these 3 proteins are put at the sight of mismatch (instead of C binding to G, it might bind to T). The mis-match is removed by exonuclease activity. After removal, DNA polymerase comes back and fixes the nucleotide, then DNA ligase seals it up. This repairs happens in G2 phase.