Introduction
Telomere biology disorder (TBD) is a group of diseases that is heterogeneous (a medical condition with several causes) in nature. It develops from mutation (alteration in the structure of the genes) in germlines (a series of germ cells), which affects the gene involved in telomere maintenance. Telomere is a structure at the end of chromosomes, providing genomic stability (it is a feature of every organism to preserve and transmit genetic material from generation to generation).
Telomere protects the stability of chromosomes from breakdown during cell division (mitosis) or aberrant fusion from neighbor chromosomes. Mutation in genes affects the normal structure of the telomere, which results in the development of this disorder with various actions like pulmonary fibrosis, liver cirrhosis, etc. The exact mechanisms of telomere biology syndrome have not been fully understood yet. There is no specific cure, and organ transplant is only the treatment of the choice. If the transplant is unsuitable for patients, some therapeutics are applied for telomere biology syndromes, namely androgen hormonal therapy, nontransplant treatment for bone marrow failure, and non-transplant treatment in liver cirrhosis. This article aims to explain the symptoms and treatment of telomere biology syndrome.
What Are Telomere Biology Disorders?
Telomere biology disorder (TBD) is also known as short-term telomere syndrome or telomeropathies. Telomere is the end part of the chromosome which provides stability to the gene. Telomeres protect the chromosome from deterioration during cell division. During the cell division, telomeres shorten. The genetic mutation affects the telomere balance, which results in a disorder of premature aging with various manifestations like bone marrow failure, pulmonary fibrosis, liver cirrhosis, premature graying, and increased cancer risk. Dyskeratosis congenita (DC) is the typical type of TBD that was first described by Zinsser as a skin disease. Dyskeratosis congenita is characterized by the trial of skin pigmentation, nail dystrophy, and oral leukoplakia, with other systemic features diagnosed later. The incidence of dyskeratosis congenita among all TBD accounts for less than five percent, and the estimated incidence is one in 10 lakhs.
What Causes Telomere Biology Disorders?
TBD is caused by a gene mutation. The first identified gene mutation is dyskeratosis congenita (DC) related mutation which is caused by DKC1 mutations. TBD generally occurs due to the germline (sex chromosome) mutation, which affects the telomere. TBD can be a sex-linked genetic disorder or occurs as a result of a disturbance in family inheritance (a process in which traits are carried to children from parents). The exact mechanism of TBD has yet to be identified.
What Are the Clinical Presentations Of Telomere Biology Disorder?
Some clinical presentations of this disorder have been described here:
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Childhood Onset Syndrome - Dyskeratosis congenita (a very rare condition that affects skin and nails) can be described as a childhood telomere biology disorder which is an inherited bone marrow failure condition with aplastic anemia (a condition in which the bone marrow does not produce an adequate number of new blood cells). It occurs due to X-linked inheritance. It may present within the first decade of life.
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Pulmonary Manifestation- The most common telomere biology disorder is idiopathic pulmonary fibrosis. It is a condition in which there is increasing lung fibrosis (thickening and scarring of lung tissue) with faster lung function deterioration. The prevalence of pulmonary manifestations is 1.25 to 23.4 per 100,000 in Europe. Pulmonary manifestation commonly affects male smokers over 60 and typically has usual interstitial pneumonia (a lung disease that causes difficulty in breathing). At least 30 % of patients with sporadic or familial pulmonary fibrosis have genetic predisposing factors that are known to increase the risk of pulmonary fibrosis.
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Hematological Manifestations- Aplastic anemia and myelodysplastic syndrome (MDS). The condition in which bone marrow is injured and does not produce enough healthy blood cells. Macrocytosis (small-sized blood cell), isolated cytopenias, paroxysmal nocturnal hemoglobinuria, and essential thrombosis (difficulty in blood clotting) are the other hematological manifestations of TBD.
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Hoyeraal-Hreidarsson Syndrome (HHS)- It is a severe X-linked multisystem disorder with mantle disability, delays in intrauterine growth, ataxia (impaired coordination), and immunodeficiency.
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Revesz Syndrome- A rare condition characterized by skin hyperpigmentation, nail dystrophy, oral leukoplakia, high risk of bone marrow failure.
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Hepatobiliary Manifestation- The person having telomere biology disorder involved with liver manifestation, including transaminitis and nonalcoholic steatohepatitis. Over 40 % of the patients have liver involvement in the TBD. Biopsy findings include inflammatory and fibrotic components of liver degeneration (liver fibrosis).
What are the Symptoms Of Telomere Biology Disorder?
There are no common references or standard methods available for measuring the length of telomeres. As there are no established diagnostic criteria, it is often unrecognized or under-recognized. Some criteria are available for the diagnosis of telomere biology disorder.
The following are the symptoms of telomere biology disorder:
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Abnormal skin pigmentation.
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Nail dystrophy (nail degeneration).
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Leukoplakia (a condition in which thick white patches appear in the mouth).
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Growth retardation.
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Development delay.
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Immunodeficiency.
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Skin pigmentation.
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Premature graying of hair.
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Epiphora (watery eyes).
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Osteoporosis (a condition in which bone degeneration occurs, making bone prone to fracture).
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Short stature (short height).
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Avascular necrosis of the hips or shoulders.
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Risk of cancer.
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Aplastic anemia (a condition in which red blood cells are not formed in bone marrow).
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Bone marrow failure.
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Small-sized brain (microcephaly).
How To Diagnose Telomere Biology Disorder?
The telomere biology disorder is diagnosed by clinical representation. The characteristics such as abnormal skin pigmentation, nail dystrophy, and leukoplakia represent dyskeratosis congenita. TBD's distinct features are growth retardation, developmental delay, microcephaly, bone marrow failure, and immunodeficiency.
TBD can be diagnosed by measuring telomere length. Currently, no common reference or gold standard method to measure telomere length exists. The earliest method used to measure TL is terminal restriction fragment (TRF) analysis by Southern blot, which measures the average TRF. Now, quantitative polymerase chain reaction (qPCR) is used to measure the length of the telomere. However, it is difficult to diagnose TBD due to the challenging presentation of clinical symptoms. A thorough family history and evaluation of other involved organ systems should be considered to diagnose TBD. Pulmonary, hematological, and liver should be defined to help facilitate recognition of TBD.
What Are the Treatments For Telomere Biology Disorder?
Through the management of symptoms such as fatigue, dyspnea (shortness of breath), pain, and psychological support, the quality of life of a person can be improved because there is no specific cure available. Immunotherapies and chemical inhibitors of telomerase and a nucleoside analog are approaches to targeting telomere biology disorders. Peptide vaccines and DNA vaccines which supply immunogenic TERT (type of protein) can be given.
Conclusion:
Telomere biological disorder is a syndrome of premature aging as telomeres shorten with age. It is a very rare and complicated disorder with very short treatment options. Awareness of telomere biology disorder is needed to improve the overall care of persons affected by this disorder. It should be decreased or controlled through genetics counseling, patient education, and surveying the patients. Through diet, stress management, and exercise, the telomere biology disorder can be hacked out in some ways.
