Constitutional trisomy 8 mosaicism in a healthy bone marrow donor: Confirmation of first reported donor origin trisomy 8
Authors: Naseem Uddin, Marc S. Williams, Sarah T. South
Journal: American Journal of Hematology (2010)

Incidental identification of constitutional chromosomal aberrations in bone marrow donors is occasionally documented in the literature. Frey et al. in 2008 [1] published the report of a stem cell recipient who developed trisomy 8 (T8) post transplant and based on the recipient workup suggested a donor origin of T8. Here, we present the donor workup that corroborated their suspicion and confirmed, for the first time, donor origin of T8 in the stem cell recipient. We have also discussed the management dilemma such incidental diagnosis presented for the donor and other implications of this diagnosis. The donor, a 29-year-old female, was referred to our institute for evaluation of possible constitutional trisomy 8 mosaicism (CT8M) after the recipient (published by Frey et al. [1]) developed T8 with complete engraftment. The donor had normal predonation peripheral blood counts and donated for a same gender, matched unrelated recipient. Her medical history was unremarkable with the exception of unusual skin pigmentation limited to her right upper arm that she attributed to a burn when she was a child. She had three pregnancies resulting in three healthy, developmentally normal children; no history of miscarriage or stillbirth. Family history was unremarkable. A physical examination targeted for signs associated with CT8M was normal. Specifically, she had normal cognitive development, normal weight, height, and head circumference; and the following pertinent negatives: forehead configuration; eye examination (including direct fundoscopy); facial structure; neck; sternum; cardiac examination; abdomen; back; and extremities. The only abnormality noted was a subtle pigmentary abnormality of the right upper arm. This consisted of two hypopigmented stripes that appeared to follow the lines of Blaschko. They showed no evidence of atrophy or scarring, which argued against a burn injury. No other abnormalities of pigmentation were noted, although the patient was not examined with a Wood's lamp. In addition to blood, a punch biopsy from the right upper arm involved in the pigmentary abnormality was obtained and sent for cytogenetic analysis. Blood: 47,XX,+8[4]/46,XX[16] Blood: nuc ish 8cen(D8Z2x3)[72/200] Skin fibroblasts: 47,XX,+8[1]/46,XX[50] A: G-banded karyogram from stimulated blood cultures showing trisomy 8. B: Interphase nucleus from peripheral blood hybridized with chromosome 8 FISH probe (CEP 8, spectrum orange) showing three signals for chromosome 8. C: G-banded karyogram from skin fibroblasts with trisomy 8. [Color figure can be viewed in the online issue, which is available at www.wileyonlinelibrary.com.] Although apparent mosaicism level in fibroblasts was below the generally accepted definition of clonality for trisomies (i.e., at least two cells with the same abnormality), the decision to call the results abnormal was based on consistency with the blood findings. The clinical and diagnostic workup thus confirmed the diagnosis of CT8M in the donor with no other signs and symptoms related to CT8M. Salient features of CT8M include facial dysmorphism characterized by prominent forehead, low-set and/or malformed ears, broad bulbous nose, high arched or cleft palate, prominent nares, everted lips, and micrognathia [2]. In addition, microcephaly, flattened occiput, mild to moderate mental retardation, skeletal abnormalities, and several other less frequent clinical features have been described [2, 3]. However, clinical features can be very variable and mild [2, 3]. No good correlation exists between the extent and severity of clinical manifestations and the measureable level of mosaicism [2]. Increased risk of spontaneous abortions is possible but as CT8M is believed to be mostly a postzygotic nondisjunction event [2, 4], increased risk of T8 mosaicism in the progeny seems unlikely. Our patient did not report repeated miscarriages. Successful pregnancies with normal karyotype have been reported in patients with T8 mosaicism [3, 5]. As the donor had completed her family, reproductive risks were not of a continued concern. Hematological malignancies and occasional solid tumors have been described in both phenotypically normal and abnormal CT8M patients [6-13]. There are several case reports and small studies that address increased susceptibility to neoplasia (especially hematological) due to a proposed pre-existing first hit in the form of T8 in patients with CT8M [6-13]. However, in our opinion, the evidence of increased risk, at best, is inconclusive, as all the evidence for this association is from case reports or retrospective studies which can be affected by ascertainment bias. Moreover, the exact prevalence of malignancies (e.g., myelodysplastic syndrome (MDS)) in CT8M is unknown. As CT8M can be minimally symptomatic or asymptomatic (as in our case), it is conceivable that prevalence estimates underestimate the number of patients with CT8M as they are based on symptomatic patients. Therefore, a true risk for development of neoplasia can only be ascertained by large-scale prospective studies that include both symptomatic and asymptomatic patients with CT8M. Moreover, T8 as an acquired abnormality has been described in several malignancies, both as sole chromosomal abnormality or part of a complex karyotype, including solid tumors and hematological neoplasms [14]. This lack of association of T8 with a specific neoplasm may suggest that it is a secondary event, even in cases with isolated T8, and the primary events may be cryptic in such cases. Despite this, it is important to keep this association in perspective when managing patients with CT8M. The donor was counseled by one of the authors (Marc S. W) and was referred to a hematologist for additional evaluation and counseling. Ultimately, after a synthesis of the available knowledge with the donor's preferences, we chose in conjunction with the donor to follow with repeat blood counts. Probable association of CT8M with malignancies, particularly myeloid, may present a different challenge while investigating a patient with “acquired” isolated T8, apparently associated with a hematological neoplasm (e.g., MDS). Should additional investigations to rule out CT8M be considered in this situation as suggested by some [12]? We think that the diagnosis of CT8M may not affect the overall management as such and due to high incidence of conditions associated with acquired T8, this may not be a cost-effective approach. However, in circumstances where an apparent acquired T8 persists even after complete treatment of the primary neoplasm or occurs in the absence of a clear association with a neoplasm, it would be prudent to rule out CT8M by cytogenetic analysis of alternative tissue, ideally, unaffected by the primary neoplasm. Association of CT8M with Behcet disease has also been reported [15, 16]; our patient did not report any problem(s) (e.g., recurrent orogenital ulcers, uveitis, skin lesions or arthritis, etc.) concerning this disease at present. Counseling about this association was also provided. It is also important to consider about the risk to the marrow recipient of transplant from a CT8M donor (Frey et al. [1]), which would have been avoided if known but probably cannot be avoided completely given the fact that C8TM can be completely asymptomatic. Again, it would be important to consider this possibility while investigating development of T8 for the first time post stem cell transplant with complete engraftment and in the absence of a development of a new/secondary neoplasm. Additional concern that we would like to raise with respect to the donor is if there is any particular additional risk to potential donors with such condition (like CT8M) when they are exposed to stem cell stimulants (like granulocyte colony-stimulating factor) as preparation of stem cell harvest for transplantation. In summary, the current report confirms the first documented case of donor origin T8 in bone marrow transplant. The diagnosis of CT8M in the donor was completely serendipitous as it was only identified after the recipient developed donor-derived T8, post transplant [1]. This posed a unique management dilemma for a healthy female donor of reproductive age. Because of paucity of data, no conclusions can be drawn for the neoplastic risk in patients with CT8M; therefore, only close follow-up was suggested. Moreover, this case poses additional questions regarding disadvantages or risks for the recipient or donor in such situation and about how prevalent CT8M is in malignancies (particularly myeloid) or vice versa. Naseem Uddin* , Marc S. Williams* §, Sarah T. South* , * Department of Pediatrics, University of Utah, Salt Lake City, Utah, Department of Pathology, University of Utah, Salt Lake City, Utah, ARUP Laboratories, University of Utah, Salt Lake City, Utah, § Intermountain Healthcare, University of Utah, Salt Lake City, Utah.