Case Report: Pancytopenia as an indicator for lysosomal storage disease (Gaucher's Disease)

Introduction

Lysosomal deposit disorders constitute a rare group of recessive hereditary monogenic diseases, resulting from the abnormal accumulation of non-degraded material in the lysosomes of different cells of the organism, as a result of the total or partial functional loss of specific lysosomal enzymes or cofactors involved in the degradation of these materials; the resulting lysosomal dysfunction leads to cell dysfunction and clinical anomalies¹. The most common lysosomal storage disease is Gaucher disease (GD), with an estimated frequency of 1:40.000 to 1:86.000 inhabitants in the general population, except for the Jewish Ashkenazi ethnic group were it is estimated to be 1:850 births², characterized by the defective function of the catabolic β-glucocerebrosidase enzyme, which leads to an accumulation of glucocerebroside in the lysosomes of different cells³, causing pancytopenia, hepatosplenomegaly, bone involvement and, sometimes neurological alteration⁴. The phenotype is variable and there are three clinical subtypes, which are classified by the absence or presence and progression of neurological involvement: type 1 or non-neuropathic form; type 2, the acute neuropathic form of infantile onset; and type 3, the neuronopathic form of juvenile onset⁵.

In Ecuador, there are very few reported cases of this pathology, and information on this disease is very limited⁶. In symptomatic patients, GD is usually a progressive disease that, if left untreated, can cause irreversible organ damage, severe morbidity, reduced quality of life and even premature death⁷.

Despite the availability of accurate and minimally invasive diagnostic tests, patients are often misdiagnosed as a result of the lack of experience with GD and the prolonged delay in accurate diagnosis, and this is likely to be translated into relative rarity of this disease⁸. Therefore, greater knowledge of the clinical and demographic characteristics of this clinical entity can improve early recognition, reduce the rate of inaccurate or delayed diagnoses for patients with GD, allowing timely treatment aimed at reducing morbidity and preventing irreversible sequels⁶.

Description of the case

A 29-year-old housewife from Loja-Ecuador, of mixed ethnicity, with no relevant family or personal history, presented to the outpatient service of the Isidro Ayora General Hospital, Loja, Ecuador. She presented with a pulsating holocraneal headache of slight intensity. Concomitantly, she presented with heartburn which responded positively to self-medication with omeprazole; additionally, she mentioned she was experiencing progressive loss of weight, fatigue and pain in the lower limbs and hands. Physical examination showed ecchymosis and petechiae scattered throughout the body. In the abdomen, hepatosplenomegaly was palpable. Routine laboratory results are summed up in the table below (Table 1).

Viral serology tests for hepatitis B, C and human immunodeficiency virus were negative. An ultrasound of the upper abdomen was performed, where there was evidence of a distended liver without occupant injuries and splenomegaly [Figure 1]. Hepatosplenomegaly was observed in the CT-Scan in addition to incipient degenerative osteoarthritis at the dorsal spine. It was decided to perform a bone marrow biopsy, demonstrating abundant cells between the bone trabeculae, consisting of hematopoietic tissue, with a marked decrease in megakaryocytes of hypolobular nuclei, and myeloid-erythroid relationship conserved. In the inter and paratrabecular spaces, abundant clusters of macrophages of the typical broad cytoplasm are observed like “crumpled paper” with small, regular nuclei displaced to the periphery [Figure 2]. The morphological picture is suggestive of lysosomal storage disease, and with the suspicion of GD, quantification of the enzymatic activity of β-glucocerebrosidase was performed, confirming its deficit with a result of 0.27 µmol/L/h (normal range: 2.3 – 12 nmol/h/Ml). Sequential analysis of the GBA gene showed the presence of an apparently homozygous pathogenic alteration in the GBA gene (Nucleotide change: c.1226A>G; Amino acid change: G p.Asn409Ser).

Figure 1. Upper abdomen ultrasonography where hepatosplenomegaly is observed.

Figure 2. Bone marrow biopsy: Cuts show bony trabeculae, including extensive medullary replacement by histiocytic reticulum-like cells, with eosinophilic, pale cytoplasm and eccentric nuclei, some cells have a vacuolated cytoplasm with folded appearance on crumpled paper.

Unfortunately, enzymatic replacement or substrate reduction therapy are not available in our Hospital. At the time of writing the patient is regularly monitored at the Isidro Ayora General Hospital, Loja until the enzymatic medication can be obtained. Currently, the patient persists in good general conditions, without worsening clinical condition. It should be mentioned that she continues with bicytopenia and hepatosplenomegaly, her conditions are expected to be remit once the enzymatic treatment has been administered.

Discussion

This clinical case is a representative example of the clinical, biochemical and genetic characteristics of GD type 1⁹, characterized by the variability in the signs, symptoms, severity and progression of the disease¹⁰. The most common signs and symptoms are: splenomegaly [95%], hepatomegaly [87%], radiological bone disease [81%], thrombocytopenia [50%], anemia [40%], bone pain [27%]¹¹.

GD is caused by mutations in the GBA gene, located on chromosome 1 (1q21), leading to markedly decreased activity of the lysosomal enzyme, β-glucocerebrosidase, which hydrolyzes the glycolipid glucocerebroside into ceramide and glucose¹². In the case studied, it was possible to observe a decrease in the enzymatic activity of β-glucocerebrosidase, in addition to alteration of the gene GBA. The consequence of this deficiency is attributed to the accumulation of glucosilcerebroside in macrophages, inducing its transformation in Gaucher cells, which under optical microscopy are usually presented as enlarged cells with eccentric nuclei and condensed chromatin and cytoplasm with heterogeneous appearance as “crumpled paper”¹³, similar characteristics to the bone marrow biopsy performed in our patient. However, the presence of this type of histological pattern has occasionally been described in several hematological malignancies¹⁴ In our patient, the basic aspects that guided the diagnosis of GD were the finding of a bicitopenia in a routine laboratory examination, in addition to the presence of unexplained hepatosplenomegaly. Determining the enzymatic activity of reduced β-glucocerebrosidase or absence is therefore the gold standard for the diagnosis of all GD variants. In the present study a clearly reduced activity of this enzyme was evident, in addition to an apparently homozygous pathogenic alteration of the GBA gene (Nucleotide change: c.1226A>G; Amino acid change: G p.Asn409Ser), allowing us to establish a definitive diagnosis of GD.

Without considering the GD in the differential diagnosis of the patient with this type of symptomatology, the definitive diagnosis can be missed or delayed, because the signs and symptoms frequent other more common conditions, including the malignant neoplasms of hematological origin¹⁵. Therefore, it is essential to strengthen the knowledge about GD, allowing to reduce the threshold for diagnostic tests and reduce the rate of erroneous diagnoses, in addition to promoting the earliest start of treatment when it is indicated.

Conclusion

GD should be considered in the differential diagnosis of patients with unexplained pancytopenia or hepatosplenomegaly. A high index of suspicion together with enzymatic and genetic testing are essential for an early specific diagnosis, which will allow the administration of timely treatment and avoid irreversible complications in order to reduce morbidity and improve the clinical aspects of the patient.

Consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Data availability