Successful pregnancies after bone marrow transplantation for Fanconi anemia

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Fanconi anemia (FA) is a rare autosomal recessive chromosome instability syndrome characterized by progressive bone marrow (BM) failure, skeletal defects, reduced fertility and increased susceptibility to malignancy. Endocrinopathies are a common feature of FA and pregnancy is uncommon.1 FA cells of all organ tissues are hypersensitive to DNA crosslinking agents and to oxygen and have cell cycle abnormalities. Hematopoietic stem cell transplantation (HSCT), using an adapted attenuated conditioning regimen, represents the only curative therapy capable of restoring normal hematopoiesis in patients with FA. Nevertheless, HSCT only cures hematopoietic disorder of FA and does not change the instability syndrome outside the BM.

A 17-year-old girl was diagnosed with FA following identification of pancytopenia. Initial CBC was: hemoglobin 6.8 g/dl (reticulocytes 34 × 109/l), platelets 31 × 109/l and WBC 4.3 × 109/l (neutrophils: 1.7; lymphocytes: 2.3). The BM biopsy showed severe medullary hypoplasia. The chromosome breakage test using mitomycin was positive for FA with a greater than 12-fold patient/control ratio. Past medical history was unremarkable. Menarche occurred at age 11 followed by regular menstrual cycles. Physical examination disclosed no stigmata of FA. At 3 months following diagnosis, she was transplanted with an HLA-matched sibling BM. The conditioning regimen contained cyclophosphamide (20 mg/kg total dose, over 4 days), thoraco-abdominal irradiation (500 cGy) and antithymoglobulin (Atgam, Pharmacia & Upjohn; 60 mg/kg total dose, over 4 days). GVHD prophylaxis consisted of cyclosporin A and short-course methotrexate. Engraftment was observed on day +19. She has had stable 90% donor chimerism, with normal CBC. The patient had received various combinations of estrogens and progestagens since the age of 17 for birth control, but experienced mood swings and weight gain. Secondary amenorrhea, associated with hot flushes, dyspareunia and a decrease in breast volume, was diagnosed 18 months after transplantation, following cessation of her contraception. Hormonal dosages were: estradiol <50 pmol/l (N>110–183), FSH: 97.4UI/l (N<15 in luteal phase) and LH: 53UI/l (N<20 in luteal phase). Thyroid function tests were normal (TSH: 1.9 mU/l). She had no evidence of other endocrine disorders. In total, 30 months after transplantation, the gynecological status remained unchanged and was considered permanent. The patient was referred for oocyte donation but presented with an unstimulated pregnancy. In total, 52 months after transplantation, she delivered a 4030 g normal male at 39.5 weeks gestation. The patient has since had a second pregnancy ending with the birth of a normal female baby at +66 months following transplant (weight=4050 g).

The occurrence of pregnancy in nontransplanted Fanconi patients is rare. Infertility is due to secondary amenorrhea, anovulatory menstrual cycles and/or premature menopause.2 A case report of a male patient with FA described a histological picture of ‘Sertoli-cell-only’ defect in the testes.3 Recent experimental studies showed that in animal models of FA, such as Fancg/Xrcc9 null mice or mice mutant for FA complementation group C, the number of germ cells was dramatically reduced, suggesting that FA complementation groups are required for mitotic proliferation of primordial germ cells.4, 5, 6 However, the pathophysiology of ovarian failure has not been clearly elucidated in human females and no histo-pathologic study has been published. Causes may be multifactorial, as suggested by some FA patients presenting with hypergonadotropic hypogonadism caused by germ cell insufficiency, with or without associated pituitary stalk interruption.7

The increased sensitivity to DNA-damaging agents in FA requires the use of an attenuated conditioning regimen before HSCT to avoid lethal toxicity. Nevertheless, patients with FA who undergo HSCT still present toxicity comparable to that of patients transplanted for other diseases given conventional conditioning regimens. In the largest available retrospective study, Guardiola et al8 showed a significant correlation between severity of toxicity after HSCT and severity of FA, that is, limited vs extensive associated malformation syndrome. Among the different toxicities observed after HSCT, sterility is frequent.9, 10 Therefore, the risk of permanent secondary amenorrhea and sterility appears elevated in female patients grafted for FA and the risk must be presented to patients before HSCT. In this report, ovarian failure was probably due to primary gonadal failure, a variant of that described in transgenic mice and in the human male. Three distinct factors can be incriminated: hypergonadotropic hypogonadism related to FA status, thoraco-abdominal radiotherapy and greater toxicity from chemotherapy in cells presenting increased sensitivity to DNA damage. Nevertheless, the case reported here suggests that pregnancy still remains a possibility, at least in patients presenting with a mild FA phenotype.


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Dalle, J., Huot, C., Duval, M. et al. Successful pregnancies after bone marrow transplantation for Fanconi anemia. Bone Marrow Transplant 34, 1099–1100 (2004) doi:10.1038/sj.bmt.1704680

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