Evidence continues to emerge that alterations in telomeres are associated with a wide range of pathologies. Telomeres cap the ends of chromosomes and contribute to genomic stability. They also shorten slightly every time a somatic cell divides, which sets an upper limit on cellular proliferative capacity. The great majority of cancers evade this normal limit on cellular proliferation by acquiring the capacity to counteract normal telomere shortening via increased activity of a telomere lengthening mechanism – either the telomerase reverse transcriptase, or a recombination-dependent telomere copying process. In contrast, there is a growing list of mutated genes causing excessive telomere shortening and therefore premature proliferative failure in various organ systems, with protean clinical manifestations that are collectively known as "short telomere syndromes" (or "telomeropathies"). Prominent clinical manifestations include bone marrow failure, mucocutanous abnormalities and pulmonary fibrosis, but many organs and tissues may be affected. Paradoxically, there is a high risk of cancer, presumably because of genomic instability resulting from failure of the telomeric capping function. Endocrinologists may be consulted about short stature or early-onset osteoporosis which are relatively common or, less commonly, hypogonadism, or for management of the side effects of androgen treatment for bone marrow failure, of corticosteroid treatment of graft-versus-host-disease, or of cancer treatment. Between the two extremes of cancer – where telomere shortening is completely prevented – and the excessive telomere shortening characteristic of the short telomere syndromes, more moderate changes in telomere length appear to be risk factors for a range of common diseases. A number of lifestyle and metabolic risk factors, including obesity, physical inactivity, and insulin resistance, have been associated with shorter telomeres. Cross-sectional studies have shown an association between shorter telomeres and type 2 diabetes, but the causal relationship is not clear. Possible explanations include that (i) short telomeres are a biomarker of known risk factors, (ii) short telomeres contribute directly to aetiology of type 2 diabetes, perhaps through proliferative failure of islet cells, and/or (iii) the metabolic disturbances characteristic of this condition cause telomere shortening. However, there is some evidence that short telomeres are an independent risk factor for type 2 diabetes.
Osteoporosis may be present
Treatment of BMF with androgens – requires periodic endocrine evaluation
Patients receiving androgen therapy should be monitored 2732 regularly by an endocrinologist for androgen-associated side 2733 effects impacting growth, bone age (early fusion of epiphyses), 2734 gonadal function, and lipid profile in case there is a need for 2735 intervention. Persistently low HDL and high LDL levels may be 2736 of concern for future cardiovascular risk in patients on long-term 2737 (2–5 years or more) androgen therapy, but usually return to 2738 baseline values within 3–6 months after discontinuing this 2739 treatment. Thyroid function is not affected by androgen 2740 treatment, but thyroid binding globulin level has been found to 2741 be reduced in patients using oxymetholone.
Despite preventive measures, patients may still develop 3384 GVHD, ranging in severity from limited skin involvement to 3385 life-threatening multi-organ failure. Corticosteroids such as 3386 methylprednisolone are first-line therapy for GVHD, and 3387 adequate control may require long-term immunosuppression
DC patients should undergo regular, comprehensive multi-3487 disciplinary evaluations with appropriate targeted testing in the 3488 years following HCT. Late effects of alkylating agents and 3489 radiation include malignancy, fertility problems, and endocrine 3490 defects, which are known DC-associated complications. Chronic 3491 GVHD and prolonged use of corticosteroids or other 3492 immunosuppressive therapies may exacerbate bone disease and 3493 magnify risk of malignancy in DC.
Overlap between manifestations 3560
of DC and HCT late effects
|
Endocrine |
Skeletal defects, short stature, hypogonadism |
Thyroid defects, growth hormone deficiency, fertility problems, hypogonadism, metabolic syndrome |
It appears that endocrine hormone deficiencies, such as 4976 hypothyroidism, growth hormone deficiency (GHD), 4977 hypogonadism, diabetes, or short stature, are not common in 4978 patients with DC. However, abnormalities related to the skeleton 4979 are seen with higher incidence compared to the general 4980 population.
|
Reported endocrine and skeletal abnormalities in DC 4991 Features |
Patients |
Source |
|
|
Short stature |
20% |
DC registry in United Kingdom1 |
|
|
Hypogonadism/undescended testes |
6% |
||
|
Osteoporosis/avascular necrosis/scoliosis |
5% |
||
|
Osteopenia/avascular necrosis |
10% |
Literature review3 |
|
|
Growth hormone deficiency |
1 patient |
Case report4 |
|
Bony abnormalities, including AVN of the hips and shoulders, 4994 osteopenia and osteoporosis, and scoliosis were reported in 4995 approximately 5% of patients with DC1, but may be more 4996 frequent than reported to date (unpublished data – NCI cohort). 4997 Many patients with DC (~75%) also have dental abnormalities 4998 such as shortened roots or taurodontism.5
Growth and growth hormone 5070
Short stature is reported in 12% of cases in the literature and 5071 in approximately 20% of patients in the UK DC registry of 5072 patients with DC.1,3 In contrast, the NCI cohort notes that short 5073 stature is very rare in individuals with DC, perhaps being more 5074 Chapter 5: Genetic Counseling
240
common in very severely affected patients. While the precise 5075 mechanism is unknown, their short stature does not appear to be 5076 related to growth hormone deficiency,4 and growth hormone 5077 therapy is not recommended unless the patient is proven to have 5078 this deficiency.
Hypogonadism 5080
A small number of severely affected males reported decreased 5081 sperm or testosterone production, or both, a condition known as 5082 hypogonadism.8,17 Animal models have demonstrated that at 5083 least one of the DC mutations may lead to testicular atrophy in 5084 males and decreased fecundity in both males and females, but 5085 this has not been duplicated in human studies.18,19