Case StudyCase 1
A 37-year-old Caucasian woman with spherocytosis reported since childhood presented with swollen ankles, gradually increasing abdominal girth, sudden weight gain (3 kg in 6 days), fatigue and exertional dyspnoea.
Patient history showed delayed growth during childhood, hepatosplenomegaly from 3 years of age (resulting in an incorrect diagnosis of spherocytosis) and a severe sport-related fracture of the humerus with humeral head necrosis. No alcohol abuse, liver disease/hepatitis, blood coagulation abnormalities or prothrombotic diseases were reported. The first of the patient’s two pregnancies resulted in post-partum bleeding requiring a blood transfusion.
Physical examination revealed pallor, hepatosplenomegaly and oedema in both legs, which resolved with diuretics (a sign of portal hypertension). Blood examination showed leucopenia (1,730/mm3), thrombocytopenia (92,000/mm3) and normochromic, normocytic anaemia (haemoglobin [Hb] 7.8 g/dl, mean corpuscular volume [MCV] 90.1 fl) with mildly increased ferritin (352 ng/ml). Transferrin saturation (TSAT), serum iron levels, haemolytic indices, folate/vitamin B12 and renal and liver function were normal. Autoimmune, virological and neoplastic diseases were excluded. Blood smear and osmotic globular resistance tests excluded spherocytosis. Splenomegaly (diameter 18 cm) and hepatic stiffness (7.4 KPa; normal value <5 KPa) consistent with stage 1 fibrosis were confirmed.
Liver disease (but not Gaucher disease [GD]) was suspected and therefore a liver biopsy was performed. Significant portal and lobular infiltration with aggregatedCD68-positive polygonal cells and granulated cytoplasm was observed, with no iron overload.
GD was suspected at this point.
Further tests showed significantly elevated chitotriosidase activity (14,290 nmol/h/ml; normal value <100), low β-glucosidase activity (28 nmol/h/mg; normal range 200–500) and the identification of β-glucosidase (GBA) gene mutations, all of which led to a diagnosis of GD type 1.
Treatment with enzyme replacement therapy (ERT) led to improved laboratory parameters after 1 year. The patient is currently well and continues to receive ERT with no side effects.
The (mis)diagnosis of spherocytosis disguised the patients’ clinical manifestations of GD from childhood to adult life, thereby exposing her to an inappropriate liver biopsy and delaying appropriate management.
Case StudyCase 2
A 15-month-old child presented with persistent fever, cough and mild respiratory distress. Initial tests showed hepatosplenomegaly, leukocytosis with lymphocytosis (white blood cell count [WBC] 30,130/μl; L 73%), microcytic anaemia (Hb 8 g/dl; MCV 63 fl), thrombocytopenia (114,000/μl) and increased C-reactive protein (CRP; 10.8 mg/dl; normal volunteers <0.5 mg/dl).
The child was admitted to the paediatric ward with a suspected infection and was treated with cefotaxime three times daily.
The patient’s medical history revealed growth delays from 6 months of age, previous hospital admissions for fever and a urinary tract infection, normal neurological development (other than a minor speech delay) and no pathological eye movements. Serological and microbiological tests were positive for cytomegalovirus (CMV), but negative for
lymphoproliferative disease and Epstein Barr virus. Reduced TSAT (4%) with mildly increased ferritin levels suggested that microcytic anaemia was partially related to iron deficiency. Haemolytic indices were normal.
Fever and respiratory distress gradually improved, CRP levels normalised and CMV infection resolved. However, hepatosplenomegaly persisted (spleen length, 10.9 cm) and anaemia associated with fluctuating, mild thrombocytopenia (113,000–190,000/μl) did not improve after oral iron therapy.
A bone marrow aspirate showed no signs of haematological disease; however, a diagnosis of GD could not be excluded based on this finding.
The combination of growth retardation, anaemia, thrombocytopenia and hepatosplenomegaly suggested a lysosomal storage disease (LSD). A dried blood spot (DBS) test showed reduced β-glycosidase activity and molecular analysis detected a homozygous mutation in the GBA gene (c.1226A>G/c.1226A>G; N370S/N370S). GD type 1 was diagnosed and ERT was prescribed.
Anaemia and thrombocytopenia resolved after 3 months; hepatosplenomegaly and growth parameters improved up to 1-year post-treatment, with no side effects.