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Positive JAK2-V617F leading to diagnosis of Gaucher's disease
  1. Stella Appiah-Cubi1,
  2. Bridget S Wilkins2,
  3. Claire Harrison1
  1. 1Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, UK
  2. 2Department of Histopathology, Guys and St Thomas Hospital NHS Trust, London, UK
  1. Correspondence to Dr Stella Appiah-Cubi, Haematology, Guys and St Thomas' NHS Foundation Trust, Guys Hospital, Great Maze Pond, London SE1 9RT, UK; sacubi{at}

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A 41-year-old lady of Afro-Caribbean origin was referred to our unit for further investigation of pancytopenia and splenomegaly; a diagnosis of primary myelofibrosis was suspected.

Two years previously, she had been investigated in her local hospital for pancytopenia (haemoglobin 10.9 g/dl, mean cell volume (MCV) 79 fl, platelet count 111×109/l and white blood cell (WBC) 2.9×109/l). Systemic enquiry revealed that she had bony aches and pains and menorrhagia. She was known to have uterine fibroids but there was no other medical or family history of note.

Clinical examination indicated moderate splenomegaly and her spleen measured 22 cm on a CT scan. A blood film was unremarkable but testing for JAK-2V617F by standard allele-specific PCR was positive. Bone marrow aspiration yielded a hypercellular sample but films did not show characteristic features of a myeloproliferative neoplasm (MPN). Histology of a bone marrow trephine specimen examined in parallel was initially interpreted likewise.

At this stage, she was referred to our unit for further investigations and management advice. Repeat testing for JAK2-V617F was negative. Review of her bone marrow histology confirmed absence of myeloproliferative features and noted the presence of scattered Gaucher-type storage macrophages (figure 1). The possibility of Gaucher's disease was raised. Rare Gaucher-type cells were also found on retrospective review of aspirated bone marrow films (figure 1). Peripheral blood was sent for testing at the Supraregional Lysosomal Storage Disorders Unit. This confirmed compound heterozygous Gaucher's disease with R496H–R359X mutations as demonstrated in the surveyor sequencing images (figure 2); plasma chitotriosidase was 5358 nmol/h/ml (normal range (NR) 0–150).

Figure 1

Main picture: cluster of Gaucher-type storage macrophages with characteristic ‘crumpled tissue paper’ appearance of cytoplasm. Bone marrow trephine (BMT) histology, H&E stain original magnification ×40. Insert A: Gaucher cell in aspirated bone marrow film, MGG, original magnification ×100. Insert B: Gaucher cells highlighted by CD68R immunostaining in BMT section, original magnification ×100.

Figure 2

Sequencing of the glucocerebrosidase gene shows the patient to have two different mutations. The two images show the site of these mutations in exons 8 and 11, respectively. Both the images show the reference sequence above the patient sequence and demonstrate the base changes associated with these two mutations. These base changes correspond to the R359X and R496H mutations respectively and, in conjunction with the low enzyme and grossly elevated plasma chitotriosidase activity, confirm the patient to be compound heterozygous for Gaucher disease, which is an autosomal recessive condition.

Gaucher's disease can be difficult to diagnose: clinical features such as bone pain, fatigue, cytopenias and splenomegaly have many potential causes.1 This case also illustrates a potential pitfall of relying excessively upon molecular testing for JAK2- V617F to indicate a diagnosis of MPN without critical evaluation of both bone marrow cytology and histology in parallel. The findings in our patient support the case for evaluating bone marrow cytology and histology in all patients with suspected MPN to confirm the diagnosis or indicate an alternative cause for suggestive clinical features. Issues also arise regarding the comparability of JAK2-V617F testing undertaken on different occasions or in different laboratories. The outcome for this patient suggests value in retesting if results appear anomalous and highlights the need for external quality assurance.


Robert Baker, Senior BMS, Lysosomal Storage Disorders / Molecular Lab, Haematology Dept, Royal Free Hospital, Pond Street, London, NW3 2QG.



  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.