|Year : 2017 | Volume
| Issue : 3 | Page : 442-445
Lysosomal storage disorders: Morphologic appraisal in Indian population
Dinesh Pradhan1, Neelam Varma1, Ashmita Gami2, Kanwaljeet Singh Hura3, Sambit K Mohanty4
1 Department of Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, Chhattisgarh, India
2 Department of Pediatrics, Grant Medical College, Mumbai, Chhattisgarh, India
3 Department of Pediatrics, Pt. JNM Medical College, Raipur, Chhattisgarh, India
4 Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, United States
|Date of Web Publication||31-Aug-2017|
660 Maryland Avenue, Pittsburgh, Pennsylvania-15232
Source of Support: None, Conflict of Interest: None
Background: Lysosomal storage disorders (LSDs) comprise a group of at least 50 distinct genetic diseases, each one resulting from the deficiency of a particular lysosomal enzyme involved in metabolism. We attempt to study and further subclassify pediatric LSDs into Gaucher's and non-Gaucher's category based on the morphologic variables seen in the bone marrow aspiration smears and trephine biopsy sections.
Materials and Methods: Pediatric (<12 years age) cases of LSDs diagnosed by bone marrow aspiration and trephine biopsy specimens, in the last 12 years period, were retrieved. The archival material and the relevant clinical as well as hematologic parameters were reviewed.
Results: From January 1997 to December 2008, 55 cases were diagnosed as LSDs. Based on bone marrow morphology, 56% (n = 31) cases were diagnosed as non-Gaucher's and the remaining 44% (n = 24) cases as Gaucher's disease, the ratio being 1.29:1. Anemia and thrombocytopenia were more commonly observed in Gaucher's disease (91.67 and 62.5%) as compared to non-Gaucher's group (74.19 and 19.35%). Neurologic symptoms and signs were more frequently present in non-Gaucher's cases (45.16%) as compared to Gaucher's group (29.17%).
Conclusion: LSDs can be classified into Gaucher's and non-Gaucher's subtypes based on the characteristic cytomorphology of the storage cells in Giemsa-stained bone marrow aspiration smears and on hematoxylin and eosin-stained trephine biopsy sections. This approach would be fairly adequate for therapeutic and prognostic purposes in resource.constrained settings, where enzyme studies and mutational analysis may not be easily available.
Keywords: Anemia, gaucher's, lysosomal storage disorders, non-Gaucher's, thrombocytopenia
|How to cite this article:|
Pradhan D, Varma N, Gami A, Hura KS, Mohanty SK. Lysosomal storage disorders: Morphologic appraisal in Indian population. J Can Res Ther 2017;13:442-5
| > Introduction|| |
Lysosomal storage disorders (LSDs) are caused by deficiencies of one or more enzymes required for the catabolism of a variety of structurally complex biomolecules, including proteins, nucleic acids, sphingolipids, neutral lipids, and glycogen; arising from the normal turnover of the cellular constituents. They are often classified according to the principal substrate of the deficient enzyme. Regardless of etiology, all LSDs share the common pathogenesis of accumulated metabolic substrate in the lysosome. The progressive accumulation of these products leads to cellular distortion and dysfunction.
Type 1 Gaucher's disease is the most prevalent of the LSDs. It is an autosomal recessive condition caused by the deficiency of glucocerebrosidase, resulting in accumulation of glucosylceramide, primarily in macrophages of the reticuloendothelial system. It is characterized clinically by hepatosplenomegaly, anemia, thrombocytopenia, and painful skeletal and pulmonary complications. Acute and subacute neuronopathic Gaucher's disease types 2 and 3, respectively, are characterized by primary brain involvement causing progressive neurodegeneration and early death. Diseases resulting from deficiencies of specific lysosomal enzymes might be treatable by intravenous infusion of normal enzyme.
Fabry disease is the second most common of the LSDs, after Gaucher disease. Almost all LSDs are inherited as autosomal recessive traits, except for the X-linked Fabry and Hunter (mucopolysaccharidosis (MPS) type II) diseases and Danon disease. Early diagnosis and intervention before the onset of irreversible pathology provides substantial benefit to the newborns, as well as providing the opportunity for parents to receive genetic counseling. The majority of patients are initially screened by enzyme assay, which is the most efficient method to arrive at a definitive diagnosis. In some families where the disease-causing mutation (s) is known and in certain genetic isolates, mutation analysis may be performed.
There are no cures for lysosomal storage diseases and treatment is mostly symptomatic, although bone marrow transplantation and enzyme replacement therapy (ERT) have been tried with some success. The US Food and Drug Administration has cleared enzyme-replacement therapy for type 1 Gaucher disease, Fabry disease, MPSI, MPS II, MPS VI, and Pompe disease. In addition, umbilical cord blood transplantation is being performed at some specialized centers. Substrate reduction therapy, a method used to decrease the accumulation of storage material, and chaperone therapy, a technique used to stabilize the defective enzymes produced by patients, is currently being evaluated for some of these diseases. Gene therapy may offer cure in the future.
These management approaches are very costly and not easily available to most patients in developing countries. Besides, the literature on LSDs from the Indian subcontinent deals mainly with single or few case reports.,,,,,,,,,,,,,, The present study aims at classifying LSDs into Gaucher's and non-Gaucher's category based on the morphology of the storage cells in the bone marrow aspiration smears and trephine biopsy sections, which might appear an oversimplification but a practical way of dealing these diseases, particularly in developing countries with limited resources. Also, in this study we attempt to provide a clinical and hematologic comparison among the Gaucher's and non-Gaucher's LSDs in north India.
| > Materials and Methods|| |
The department archive of a tertiary care institute was searched over a period of 12 years (from January 1997 to December 2008) and 55 cases were retrieved. All the patients were from northern part of India. The patients aged less than 12 years were included in the study. The clinical profile (hepatomegaly, splenomegaly, lymphadenopathy, and neurologic symptoms) and complete hemogram (to detect anemia (hemoglobin less than 11 g/dl), leukopenia (total leucocyte count less than 4.0 × 109/l), thrombocytopenia (platelet count less than 100.0 × 109/l), and leukocytosis (total leucocyte count more than 11.0 × 109/l)) were recorded in each case. May–Grünwald–Giemsa-stained smears of the bone marrow aspiration and hematoxylin and eosin-stained sections of the trephine biopsies were examined.
An attempt was made to designate storage cells morphologically as Gaucher's cells or non-Gaucher's cells. Gaucher's cells are large cells with 20–100 μm diameter and a characteristic cytoplasm with wrinkled-paper appearance resulting from intracytoplasmic substrate deposition [Figure 1], in contrast non-Gaucher's cells are mostly lipid-laden foam cells or Niemann–Pick cells, which have abundant cytoplasm with numerous vacuoles in the cytoplasm [Figure 2]. Enzyme assay was done in most cases and few cases had follow-up.
|Figure 1: Typical morphology of Gaucher's cells as seen in the bone marrow aspirate|
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|Figure 2: Typical morphology of non-Gaucher's cells (Niemann–Pick cells) as seen in the bone marrow aspirate|
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Various clinical and hematologic features among the groups were compared using Chi-square test and a P < 0.05 was taken as significant.
| > Results|| |
A total of 55 cases of LSDs were found during a 12-year period. Age ranged from 1 month to 12 years. The peak incidence of LSD was in the 1st and 2nd year (69% of cases, 38 of 55 cases). The overall male to female ratio was 3.2:1. In the Gaucher's disease category, the male to female ratio was 3:1; whereas in the non-Gaucher's category, it was 3.4:1. Of the 55 cases, 56% (n = 31) were non-Gaucher's and remaining 44% (n = 24) cases were of Gaucher's disease, the ratio being 1.29:1. Enzyme studies correlated with bone marrow diagnosis in cases in which enzyme assay was done. None of these patients could afford ERT. [Table 1] illustrates a comparative overview of the clinical and hematologic parameters among both the groups. In all the cases, abdominal distension due to hepatosplenomegaly (all cases had both hepatomegaly and splenomegaly) was the presenting complaint and neurologic symptoms in the form of developmental delay or seizure was seen in 35% (n = 21) of cases. The neurologic symptoms were more frequent in non-Gaucher's (45%, 14/31) cases as compared to Gaucher's disease (29%, 7/24), but difference was not significant (P = 0.225). None of the patients had lymphadenopathy. Anemia was noted in most of the cases (82%; n = 45). It was more often seen in Gaucher's disease (92%, 22/24) as compared to non-Gaucher's disease (74%, 23/31), though difference was not statistically significant (P = 0.095). Thrombocytopenia was noted in 38% (n = 21) of cases. It was more frequent in Gaucher's disease (63%, 15/24), and the difference was statistically significant (P = 0.001). In non-Gaucher's cases thrombocytopenia was seen in only six cases and leukopenia in only three cases. On the contrary, leukocytosis was noted significantly more frequently in non-Gaucher's cases (P = 0.005). Interestingly, myelofibrosis with reticulin staining (grade 3+) was noted in one case of Gaucher's disease. Additionally, pulmonary tuberculosis was present in two non-Gaucher's cases.
|Table 1: Comparison of clinicohematologic features among the two groups of the lysosomal storage disorders (Gaucher's and non-Gaucher's disease)|
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| > Discussion|| |
Classification of LSDs is important from the treatment and prognosis point of view. The main objective of this study was to classify LSDs into Gaucher's and non-Gaucher's based on the morphology of the storage cells in Giemsa-stained bone marrow aspiration material and on hematoxylin and eosin-stained trephine biopsy sections.
In the present study, all the cases were reviewed by two pathologists. Out of these 55 cases, clear distinction was possible into Gaucher's and non-Gaucher's in all the cases. Our data emphasizes the fact that morphology of storage cells in Giemsa-stained bone marrow aspirate material and hematoxylin and eosin-stained trephine biopsy sections is sufficient to classify all LSDs into two broad groups. However, help from enzyme assay may be required to further classify non-Gaucher's type of storage disorders.
Of these 55 cases, 31 were non-Gaucher's and 24 cases were of Gaucher's disease. This is comparable with the world literature, Gaucher's disease being the most common LSD, considering the fact that non-Gaucher's disorders include different entities. Age of the patients ranged from 1 month to 12 years and the peak incidence was in the 1st and 2nd year, wherein 38 out of 55 cases occurred. This is in accordance with western literature which highlights that LSDs occur in all ages, with a predilection for children. In this study, the sex ratio in Gaucher's disease is 3:1, whereas the disease has equal sex distribution according to the western literature. This may be explained by the gender bias which is prevalent in this part of the country; with the result people bring their male children for treatment to the hospital neglecting the female children.
In this study, hepatosplenomegaly was present in all the cases, which is comparable to the published literature indicating that it occurs in more than 50% of the cases. The neurologic symptoms in this study were more frequent in non-Gaucher's (14/31) cases as compared to Gaucher's disease (7/24). No such data is available for all types of storage disorders lumped together. Anemia was more often seen in Gaucher's disease. It was present in 22 out of 24 cases. In the non-Gaucher's group, anemia was present in 23 cases out of the total 31 cases. This data is comparable to the world literature, wherein anemia is present in most cases of lysosomal storage disease. Thrombocytopenia was present in 15 out of 24 cases of Gaucher's disease. In non-Gaucher's cases, thrombocytopenia was seen in only six cases. This data for thrombocytopenia was statistically significant and thrombocytopenia was found to be clearly more prevalent in Gaucher's disease. Western literature gives similar view that thrombocytopenia occurs more frequently in Gaucher's disease. Leukopenia was noted only in three cases in this study. Pulmonary tuberculosis was present in two non-Gaucher's cases and myelofibrosis was noted in one Gaucher's disease. These are not known associations in these LSDs and most probably may have been present by coincidence.
In summary, the LSDs can be classified into Gaucher's and non-Gaucher's based on the morphology of the storage cells in bone marrow aspiration smears and trephine biopsy sections. Gaucher cells are fairly specific for Gaucher's disease, whereas foam cells resembling those seen in Niemann–Pick disease may also be observed in generalized gangliosidosis and Erdheim–Chester disease. This approach would be fairly adequate in developing countries where it is not feasible to routinely perform enzyme studies and mutational analysis. Again, there is paucity of literature on LSDs from the Indian subcontinent which is inhabited by an ethnically diverse population, and only a few case reports are available from this part of the world.,,,,,,,,,,,,,, Single cases were reported in 10 studies; whereas, two or more cases were described in five studies. Kaur et al., have discussed clinical parameters of five Niemann–Pick cases, and has found hepatosplenomegaly as well as developmental delay in all the cases. Besides they have also discussed the previously reported 17 cases of Niemann–Pick disease. Kaur et al., have also reported 13 cases of Gaucher's disease and found hepatosplenomegaly as well as anemia in all the cases. ERT has also been assessed in very few cases. Shanti et al., earlier reported ultrastructural features of Niemann–Pick disease (single case). However, aforementioned studies did not compare the clinical manifestations in either type and these do not describe the degree of hematologic compromise in Gaucher's and non-Gaucher's group. Present study provides an overview of few important aspects of this heterogeneous group of disorders in Indian pediatric population.
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