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A refractory bicytopenia in a pregnant woman

  • Mathieu Gerfaud-Valentin
    Correspondence
    Corresponding author at: Service de Médecine Interne, Hôpital Universitaire de la Croix Rousse, Groupement Hospitalier Nord, 103 grande rue de la Croix Rousse, 69004 Lyon, France.
    Affiliations
    Service de Médecine Interne, Hôpital Universitaire de la Croix Rousse, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France

    Univ. Lyon, University Claude Bernard Lyon 1, HESPER EA 7425, F-69008 Lyon, France
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  • Florence Chaudot
    Affiliations
    Service de Médecine Interne, Hôpital Universitaire de la Croix Rousse, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France

    Univ. Lyon, University Claude Bernard Lyon 1, HESPER EA 7425, F-69008 Lyon, France
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  • Pascal Seve
    Affiliations
    Service de Médecine Interne, Hôpital Universitaire de la Croix Rousse, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France

    Hospices Civils de Lyon, Pôle IMER, Lyon F-69003, France

    Univ. Lyon, University Claude Bernard Lyon 1, HESPER EA 7425, F-69008 Lyon, France
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      Keywords

      1. Indication

      A 24-year-old woman was referred to our hospital for an anaemia with thrombocytopenia worsening since 3 months at 36 amenorrhoea weeks of her first pregnancy. She had no significant past medical history. However, a macrocytosis (mean corpuscular volume (MCV), 113 fL) investigated one year earlier remained unexplained. Her body mass index was 18.2 kg/m2 (1.48 m; 40 kg). The physical examination revealed skin hyperpigmentation (“café-au-lait” spots) of the trunk, left thumb deformity (Fig. 1a) and triangular facial dysmorphia with micrognathia (Fig. 1b).
      Fig. 1
      Fig. 1Dysmorphic features and medullar hypocellularity in a 24-year-old pregnant woman with bicytopenia. a. Left thumb deformity. b. Micrognathia and triangular facial dysmorphia. c. Bone marrow biopsy showing severe bone marrow hypocellularity (< 5%), no megakaryocyte.
      Despite vitamin B12, folates and iron supplementation, and a therapeutic test with corticosteroids, haemoglobin felt to 65 g/L (MCV 120 fL) and platelets to 17G/L. Laboratory analysis revealed: reticulocytes 50 G/L, haptoglobin 0.64 mg/L (0.54–1.44); haemoglobin electrophoresis: HbA1 92.1% (96–99), HbA2 2.30% (<3.30), HbF 5.6% (<2). Bone marrow aspirate and karyotype were unremarkable. A bone marrow biopsy showed a severe hypocellularity (cellularity <5%) (Fig. 1c). The peripheral blood flow cytometry was negative for paroxysmal nocturnal haemoglobinuria.
      Transfusions were needed. Six months after the delivery, the cytopenias resolved, without a bone marrow transplant.
      What is the diagnosis?

      2. Discussion

      The patient's short stature, dysmorphic features, and persistently elevated foetal haemoglobin were consistent with an inherited bone marrow failure syndrome (IBMFs), especially Fanconi Anaemia (FA). The chromosomal breakage test with Mitomycin C attested a defect in DNA repair (43 mitosis on 50 with at least one chromosome break, 17 with ≥3 breaks, 4 radial figures). The FANCD2 mono-ubiquitination test in fibroblasts showed a FA core. Fibroblast DNA screening for FANC gene mutations confirmed heterozygous c.3188G > A/p. (Trp1063*) mutation and heterozygous deletion of the exons 21 and 22 of FANC A genes.
      IBMFs are genetic disorders characterized by hematopoietic aplasia, physical abnormalities, and cancer predisposition (acute myeloid leukemia and solid tumors) [
      • Shimamura A.
      • Alter B.P.
      Pathophysiology and management of inherited bone marrow failure syndromes.
      ]. FA is the most frequent IBMFs, in which the most commonly reported physical caracteristics are short stature, “café-au-lait” spots, pigmentation disorders, thumb abnormalities, microcephaly, microphthalmia, structural renal anomalies, and hypogonadism [
      • Shimamura A.
      • Alter B.P.
      Pathophysiology and management of inherited bone marrow failure syndromes.
      ,
      • Soulier J.
      Fanconi Anemia.
      ]. In the adulthood, these syndromes may be mistaken for acquired aplastic anaemia, hypoplastic myelodysplastic syndromes, or paroxysmal nocturnal haemoglobinuria which remain the main differential diagnoses. However, an early diagnosis is beneficial since it leads to FA-related malignancies screening. Furthermore, it helps to anticipate the management of high-risk pregnancies by a multidisciplinary collaboration to lead to healthy live births despite pregnancy complications related to the underlying disease [
      • Gansner J.M.
      • Achebe M.M.
      • Gray K.J.
      • Yefidoff-Freedman R.
      • Labovitis E.
      • Parnes A.
      • et al.
      Pregnancy outcomes in inherited bone marrow failure syndromes.
      ].

      Conflict of interest statement

      CHAUDOT Florence: None.
      Dr. GERFAUD-VALENTIN Mathieu received honoraria:
      - Advisory boards for SOBI.
      - Lectures for Novartis and Board.
      Pr SEVE Pascal received honoraria:
      - advisory boards for Abbvie and Novartis.
      - lectures for LFB, Roche, SOBI, Abbvie, Pfizer.

      References

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        Blood Rev. 2010; 24: 101-122
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        Hematology Am Soc Hematol Educ Program. 2011; 2011: 492-497
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        Pregnancy outcomes in inherited bone marrow failure syndromes.
        Blood. 2017; 130: 1671-1674