DNP 810 Topic 2 Discussion Question One
DNP 810 Topic 2 Discussion Question One
Identify a complex inheritance health issue you encountered in your clinical practice or personal life. How would you approach working with a patient of a complex inheritance health issue? Explain. Support your rationale with a minimum of two scholarly sources.
Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell disease and cystic fibrosis, are caused by variants (also known as mutations) in single genes. The causes of many other disorders, however, are much more complex. Common health problems such as heart disease, type 2 diabetes, and obesity do not have a single
genetic cause—they are influenced by multiple genes (polygenic) in combination with lifestyle and environmental factors, such as exercise, diet, or pollutant exposures. Conditions caused by many contributing factors are called complex or multifactorial disorders.
Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. It may be difficult to identify the role of genetics in these disorders, particularly because families often also share environments and may have similar lifestyles. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Researchers continue to look for major contributing genes for many common, complex disorders.
Thrombocytopenia–absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow’s milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).
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Thrombocytopenia–absent radius (TAR) syndrome (MIM 274000) is a clinically well-characterized malformation syndrome. According to the diagnostic criteria defined by J. Hall in 1969, typical clinical features are hypomegakaryocytic thrombocytopenia and bilateral absence of the radius in the presence of both thumbs.1 These characteristic patterns differentiate TAR syndrome from other conditions with involvement of the radius—that is, Holt-Oram syndrome (MIM 142900), Roberts syndrome (MIM 268300), and Fanconi anemia (MIM 227650)—in which the thumb is usually absent or severely hypoplastic. Additional skeletal features associated with TAR syndrome include shortening and, less commonly, aplasia of the ulna and/or humerus. In the latter situation, the five-fingered hand arises from the shoulder. The hands may show limited extension of the fingers, radial deviation, and hypoplasia of the carpal and phalangeal bones. The lower limbs are frequently involved, but usually to a lesser extent than are the upper limbs. Dislocation of the hips and subluxation of the knees resulting in coxa vara are common.
Extraskeletal manifestations comprise cardiac abnormalities, such as tetralogy of Fallot and atrial septal defects, and abnormalities of the genitourinary tract. Cow’s milk allergy or intolerance appears to be relatively common among patients with TAR syndrome and may provoke eosinophilia.2 Patients with TAR syndrome typically present with petechiae and severe bleeding during the first years of life. Platelet counts are often <50 platelets/nl (normal range 150–400 platelets/nl) due to impaired presence or maturation of megakaryocytic progenitors in the bone marrow.3,4 Although platelet counts ameliorate over time, patients remain thrombocytopenic with continued risk of bleeding. In addition, young patients with TAR syndrome have been reported to have leukemoid reactions with white blood counts exceeding 35,000 cells/mm3. Similar to the thrombocytopenia, they are transient in nature and not associated with true leukemia.5
The genetic basis of TAR syndrome remains unclear. Different modes of inheritance—that is, autosomal recessive, autosomal dominant, or autosomal dominant with reduced penetrance—have been discussed in the literature.1,2,6 Generally, the pattern of inheritance is most consistent with autosomal recessive inheritance.7 However, there does not appear to be an increased incidence of consanguinity in families with TAR syndrome, as would be expected for a rare autosomal recessive disorder. Several families have been reported with affected individuals spread across 2 or even 3 generations,6 an unexpected finding in nonconsanguineous pedigrees. In addition, parent-to-child transmission has been reported.8 Several explanations have been put forward to explain these unusual observations. Hall et al.7 suggested that patients with TAR syndrome may be genetic compounds. In this case, TAR syndrome would follow a digenic inheritance similar to the situation described for Bardet-Biedl syndrome.9 Also, the possibility that Roberts syndrome and TAR syndrome are allelic conditions has been discussed.
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