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Year : 2023  |  Volume : 66  |  Issue : 1  |  Page : 91-95
Utility of morphologic assessment of bone marrow biopsy in diagnosis of lysosomal storage disorders

1 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

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Date of Submission15-Jul-2021
Date of Decision26-Nov-2021
Date of Acceptance28-Nov-2021
Date of Web Publication18-Jan-2023


Introduction: Lysosomal storage disorders (LSDs) are rare disorders and pose a diagnostic challenge for clinicians owing to their generalized symptomatology. In this study, we aim to classify LSDs into two broad categories, namely, Gaucher disease (GD) and Niemann–Pick/Niemann–Pick-like diseases (NP/NP-like diseases) based on the morphology of the storage cells in the bone marrow (BM) aspiration smears and trephine biopsy sections. Materials and Method: This retrospective study includes 32 BM specimens morphologically diagnosed as LSDs at our institute, in the last 10 years. Subsequently, they were subclassified into GD and NP/NP-like diseases. Further, we have compared and analyzed the clinical, hematological, and biochemical parameters for the two groups of LSDs. Results: Based on BM morphology, 59.4% (n = 19) cases were diagnosed as NP/NP-like diseases and 40.6% (n = 13) cases as GD. Abdominal distension and failure to thrive were the most common clinical manifestations in both groups of LSDs. Anemia and thrombocytopenia were frequently seen in either of the LSDs. On the assessment of metabolic profile, elevated total/direct bilirubin and liver enzymes were more commonly seen in NP/NP-like diseases when compared with GD. Conclusion: We have classified LSDs into GD and NP/NP-like diseases based on the morphology of the storage cells in the BM specimen. The hallmark findings on BM biopsy annexed with the comparative features of the two proposed categories can aid the clinician in clinching the diagnosis. Formulation of such a methodology will prove instrumental for patient care in an underresourced setting.

Keywords: Bone marrow biopsy, Gaucher disease, lysosomal storage disorders, morphology, Niemann–Pick/Niemann–Pick-like diseases

How to cite this article:
Nishith N, Siddiqui SH, R. Raja S K, Agrawal N, Phadke S, Sharma S. Utility of morphologic assessment of bone marrow biopsy in diagnosis of lysosomal storage disorders. Indian J Pathol Microbiol 2023;66:91-5

How to cite this URL:
Nishith N, Siddiqui SH, R. Raja S K, Agrawal N, Phadke S, Sharma S. Utility of morphologic assessment of bone marrow biopsy in diagnosis of lysosomal storage disorders. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Mar 20];66:91-5. Available from:

   Introduction Top

The lysosomal storage disorders (LSDs) are a diverse group of nearly 70 disorders, most of which are inherited in an autosomal recessive fashion. A defect in the cell's lysosome machinery causes abnormal storage and progressive accumulation of undigested macromolecules leading to cellular distortion and dysfunction. Classification of these storage disorders based on the undigested biochemical substrate (i.e., sphingolipidoses, mucopolysaccharidoses, oligosaccharidoses, gangliosidoses) enables efficient diagnosis and appropriate treatment.[1]

Among these, Gaucher disease (GD) is the most common LSD caused by a deficiency of enzyme β-glucocerebrosidase [encoded by GBA gene (locus 1q21)] and characterized by the accumulation of glucosylceramide and glucosylsphingosine. Type I GD is a chronic non-neurological and most prevalent form of the disease, which manifests as hepatosplenomegaly, bone involvement, and cytopenia. The acute and subacute Gaucher types II and III have an early onset and are typified by progressive neurological involvement. Niemann–Pick disease (NPD) is an uncommon LSD, which is subclassified into types A, B, and C based on the underlying pathogenesis.

NPD type A and B are caused by a missense mutation in the SMPD1 gene while NPD type C occurs due to deficiencies in the lysosomal cholesterol export machinery. The clinical manifestation depends upon the subtype of the disease.[1],[2] Other LSDs such as Wolman's disease and Fabry disease may be regarded as Niemann–Pick-like diseases due to similar bone marrow (BM) cytomorphology.[3]

The generalized symptoms of hepatosplenomegaly and cytopenias often warrant BM examination to rule out hematolymphoid disorders. Consequently, the diagnosis of most LSDs is certainly challenging owing to their rarity. However, early detection and appropriate intervention before the onset of an irrevocable pathology provides a definite advantage to the patients. Diagnostic work-up of LSDs begins with screening for the group of disorders with similar clinical presentations, followed by enzyme assay and genetic testing.[1]

Majority of the LSDs are managed symptomatically as only some of them are curable. The various therapeutic modalities include hematopoietic stem-cell transplantation, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and chaperone therapy. The US Food and Drug Administration has approved ERT for non-neuronopathic GD, Fabry disease, Pompe disease, lysosomal acid lipase deficiency, and a few others. The main limitation of ERT is the lack of penetration to vital organs such as the heart, brain, and so on. These management approaches are quite expensive and not readily available to patients in developing countries. Currently, nucleic-acid-based medicines (such as gene replacement, antisense oligonucleotide therapies, or gene editing) are under trial to overcome the limitations of ERT and improve the clinical outcome of the patients.[1]

The available literature on LSDs from India is very limited. The present study was undertaken with the impetus to expand the knowledge of LSDs in the Indian population. We aim to classify LSDs into two broad categories, namely, GD and Niemann–Pick/Niemann–Pick-like diseases (NP/NP-like diseases) based on the morphology of the storage cells in the bone marrow aspiration (BMA) smears and trephine biopsy sections. Further, we have compared the clinical, hematological, and biochemical parameters between the two groups of LSDs.

   Material and Methods Top

This retrospective study includes 32 BM specimens, which were morphologically diagnosed as LSDs at our institute from January 2010 to December 2019. All cases were retrieved via an electronic data search in the Hospital Information System. All the patients provided informed consent before the procedure. Clinical details most pertinent to the study were recorded according to the prepared checklist which included age, gender, history of consanguineous marriage, sibling history, and clinical manifestations (abdominal distension, failure to thrive, developmental delay, hepatomegaly, splenomegaly, neurological, and ocular symptoms). Lab parameters like complete hemogram, coagulation profile, biochemical parameters, that is, total bilirubin, direct bilirubin, serum aspartate and alanine transaminases, serum alkaline phosphatase, and serum calcium, were retrospectively recorded from Hospital Information System. Giemsa-stained BMA smears and hematoxylin and eosin-stained sections of the trephine biopsy were examined for all the patients. These cases were morphologically diagnosed either as GD or NP/NP-like diseases based on the characteristic cytomorphology of the storage cell. Gaucher cells are large, round, or oval cells with a small, usually eccentric nucleus and voluminous weakly basophilic cytoplasm with a wrinkled pattern, resulting from elongation of lysosomes. On the other hand, NP/NP-like diseases were identified by the Niemann–Pick cells, which are large (exceeding 50 μm in diameter) with central to eccentric nucleus and pale blue cytoplasm filled with lipid droplets that impart a “soap bubble” appearance [Figure 1].[2],[4] Enzyme studies were performed for 18 cases, which included estimation of serum sphingomyelinase level (normal: 10–32 nmol/h/mg) and serum beta-glucosidase level (normal: 5.5–20 nmol/h/mg). The remaining 14 cases did not consent for enzymatic testing due to financial constraints.
Figure 1: Characteristic morphology of (a) Gaucher cell (bone marrow aspirate; 400 × MGG), (b) Gaucher cell (bone marrow biopsy; 400 × H&E), (c) Niemann–Pick cell (bone marrow aspirate; 400 × Giemsa), and (d) Niemann–Pick cell (bone marrow biopsy; 400 × H&E)

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Statistical analysis

The clinical, hematologic, and biochemical parameters among the two categories were compared using the Chi-square test. A P value of <0.05 was taken as statistically significant.

   Results Top

A total of 19,817 BM aspirates were performed during the study period, of which 32 (0.16%) were diagnosed as LSDs. The age of the patients ranged from 1 month to 8 years with a mean and standard deviation of 2.75 ± 2.3 years. The peak incidence of LSD was in the initial two years (17/32, 53.1%). The male-to-female ratio in the category of GD and NP/NP-like diseases was almost similar, that is, 1.6:1 and 1.4:1, respectively. The overall sex ratio was 1.5:1. [Table 1] shows a comparative analysis of the clinical, hematologic, and biochemical parameters among the two groups of LSDs. Majority of the patients in both these categories presented with abdominal distension (due to hepatosplenomegaly) and failure to thrive. Developmental delay in reaching motor milestones was observed in eight cases of NP/NP-like diseases and three cases of GD. Neurological manifestation was noted in one case of each of these groups. The case of NP/NP-like diseases exhibited marked hypotonia while the patient with GD had exaggerated deep tendon reflexes. Also, more than one-third of the patients (7/19; 36.8%) with NP/NP-like diseases had pulmonary involvement, which was evident radiologically as bilateral reticulonodular infiltrates or ground-glass opacity. In contrast, none of the patients with GD had pulmonary complaints. Cardiovalvular abnormality in the form of ostium secundum atrial septal defect was exclusively noted in two cases (10.5%) of NP/NP-like diseases. On fundoscopic examination, six cases (31.6%) of NP/NP-like diseases had bilateral cherry-red spots, while the case of GD had squint.
Table 1: Comparison of clinical, hematological, and biochemical characteristics between the two groups of LSDs (NP/NP-like diseases and GD)

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Anemia and thrombocytopenia were the most common hematological findings in both groups of LSDs. Anemia and increased prothrombin time were more often seen in NP/NP-like diseases as compared to GD, although the difference did not reach statistical significance. On the contrary, thrombocytopenia was more frequently seen in GD in comparison to NP/NP-like diseases, and the difference was statistically significant (P-value = 0.01).

On the assessment of metabolic profile, 28 cases (81.2%) showed deranged liver function tests and hypocalcemia in 8 patients (25.0%). Elevated total/direct bilirubin and liver enzymes were more commonly seen in NP/NP-like diseases when compared with GD (P-value <0.05). No significant difference was observed for decreased serum calcium in the two categories of LSDs. Of the 18 cases for which enzyme analysis was performed, 11 had a deficiency of sphingomyelinase and hence were diagnosed with NPD. The remaining seven subjects revealed decreased levels for beta-glucosidase and consequently suffered from GD. Results of enzyme assays correlated with BM diagnosis in cases for which the tests were done. The advent of ERT has proved beneficial against a small subset of LSDs. Yet, merely three cases with a confirmed diagnosis of GD had received ERT as the treatment of these rare diseases demands a huge expenditure.

   Discussion Top

LSDs are a congregate of clinically and genetically heterogeneous disorders. Therefore, it is necessary to subclassify them for appropriate management and prognostication. In the present study, we have categorized LSDs into two broad groups, namely, NP/NP-like disease and GD based on the morphology of the storage cells in the Giemsa-stained BMA smears and trephine biopsy sections. Nonetheless, enzyme assay remains the gold standard for the diagnosis of LSDs.

Out of 32 cases, 19 were morphologically diagnosed as NP/NP-like diseases and 13 cases were of GD. This is comparable with the global literature that affirms Fabry's disease to be the commonest LSD, followed by GD, metachromatic leukodystrophy, and Pompe disease.[5] However, our results were incongruent to the Indian data that reports GD to be crowning the list of LSDs, followed by mucopolysaccharidosis.[6],[7] This incongruity may be attributed to the fact the category of NP/NP-like diseases is not a single entity, rather an umbrella term that encompasses entities which show Niemann–Pick cells on BM aspirate and trephine biopsy. Research on the Indian and Western populations highlights the occurrence of storage disorders in the pediatric population, as was also noted in our study.[2],[4] There are very few investigators who have dealt with gender distribution in LSDs. The overall male-to-female ratio in this study was 1.5.1, as has been documented by fellow Indian researchers as well.[4],[6],[8] This predisposition was regarded as gender bias by Pradhan et al., which results in the treatment of affected male patients and negligence toward the opposite sex in India.[4]

Although children with LSDs can present with a multitude of clinical manifestations, published literature, and our study have found the majority of patients victim to hepatosplenomegaly and failure to thrive.[1],[4] Developmental delay as a significant manifestation of neurological abnormality has been purported by several authors.[4],[9],[10] In the present study, children with NP/NP-like diseases had higher rates of developmental delay than those with GD, which was in accordance with the findings of Pradhan et al.[4] Ocular pathology was evident as bilateral cherry spots in patients with NP/NP-like diseases (6/19; 31.6%) in our study. This has been substantiated by other researchers as well.[2],[9],[11] In addition, Sheth et al.[11] highlighted that the clinical phenotype of Indian children with neuroregressive LSD would usually include macular cherry-red spot.

Hematological imbalances are often seen with LSDs and are a consequence of hypersplenism and/or BM infiltration by storage cells.[1],[2],[12] We observed thrombocytopenia to be more common in GD as compared to NP/NP-like diseases and the difference was statistically significant. This was analogous to prior national and international studies.[4],[12],[13] On the other hand, anemia and prolonged prothrombin time were relatively more frequent in patients with NP/NP-like diseases in our study. This was dissimilar to the results of previous studies that impressed on anemia, thrombocytopenia, and coagulopathy to be the defining hematological characteristics of GD.[2],[4],[12],[14] These parameters act as therapeutic goals while constructing a comprehensive treatment regimen for a patient with GD.[15]

The available literature indicates that the biochemical profile of LSDs (particularly NPD and GD) is depicted by deranged liver function tests in the form of raised bilirubin and liver enzymes. The results of the current study were concordant with the existing findings.[2],[16],[17],[18] On evaluating the metabolic profile of the two broad disease categories of LSDs, hyperbilirubinemia, elevated transaminases, and alkaline phosphatase were noted largely in patients of NP/NP-like diseases as opposed to GD and the difference was statistically significant. Serum calcium is another important biochemical parameter that has been recommended as a baseline investigation in GD as the alteration in intralysosomal Ca2+ homeostasis has been hypothesized in the various LSDs.[19],[20] In the present study, one-fourth of the patients presented with hypocalcemia; however, no significant difference was observed between the two categories. Further, Bembi et al.[21] documented that approximately 30% patients of GD treated with ERT suffered from transient hypocalcemia 10–12 days after the initiation of treatment. Thus, the timing of serum calcium measurements is vital as it will help in averting transient fall in serum calcium following ERT.[21] Therefore, estimation of serum Ca2+ level becomes crucial at presentation and posttreatment.

   Conclusion Top

The sporadic occurrence of LSDs along with their protean manifestations creates diagnostic dilemmas in the absence of mandatory tests. In this study, we have classified lysosomal storage disorders into GD and NP/NP-like diseases based on cytomorphological features and analyzed the associated clinical, hematological, and biochemical parameters. The hallmark findings on BM biopsy annexed with the comparative features of the two proposed categories can aid the clinician in clinching the diagnosis. Formulation of such a methodology will prove instrumental for patient care in an under-resourced setting. Furthermore, insights from such a large demographic population can be extrapolated to guide further research on this genetic rarity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Lysosomal storage diseases. Nat Rev Dis Primers 2018;4:27.  Back to cited text no. 1
Ferreira CR, Gahl WA. Lysosomal storage diseases. Transl Sci Rare Dis 2017;2:1-71.  Back to cited text no. 2
Bain B, Clark D, Wilkins B. Bone Marrow Pathology. 5th ed. Newark: John Wiley & Sons, Incorporated; 2019.  Back to cited text no. 3
Pradhan D, Varma N, Gami A, Hura KS, Mohanty SK. Lysosomal storage disorders: Morphologic appraisal in Indian population. J Cancer Res Ther 2017;13:442-5.  Back to cited text no. 4
US National Library of Medicine, Genetics Home Reference. 2018. NIH. Available from:  Back to cited text no. 5
Sheth J, Mistri M, Sheth F, Shah R, Bavdekar A, Godbole K, et al. Burden of lysosomal storage disorders in India: Experience of 387 affected children from a single diagnostic facility. JIMD Rep 2014;12:51-63.  Back to cited text no. 6
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Al-Maawali AA, Joshi SN, Koul RL, Al-Maawali AA, Al-Sedari HS, Al-Amri BM, et al. Spectrum of paediatric lysosomal storage disorders in Oman. Sultan Qaboos Univ Med J 2012;12:295-9.  Back to cited text no. 8
Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage disorders in the newborn. Pediatrics 2009;123:1191-207.  Back to cited text no. 9
Pastores GM, Maegawa GH. Clinical neurogenetics: neuropathic lysosomal storage disorders. Neurol Clin 2013;31:1051-71.  Back to cited text no. 10
Sheth J, Mistri M, Bhavsar R, Sheth F, Kamate M, Shah H, et al. Lysosomal storage disorders in Indian children with neuroregression attending a genetic center. Indian Pediatr 2015;52:1029-33.  Back to cited text no. 11
Zimran A, Altarescu G, Rudensky B, Abrahamov A, Elstein D. Survey of hematological aspects of Gaucher disease. Hematology 2005;10:151-6.  Back to cited text no. 12
Sharma S, Pujani M, Malhan P, Harbhajanka A, Jain M. Clinico-hematological profile of lysosomal storage disorders-a report of three cases. Indian J Hematol Blood Transfus 2008;24:72-4.  Back to cited text no. 13
Thomas AS, Mehta A, Hughes DA. Gaucher disease: Hematological presentations and complications. Br J Hematol 2014;165:427-40.  Back to cited text no. 14
Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol 2004;41 (4 Suppl 5):4-14.  Back to cited text no. 15
Wasserstein MP, Desnick RJ, Schuchman EH, Hossain S, Wallenstein S, Lamm C, et al. The natural history of type B Niemann-Pick disease: Results from a 10-year longitudinal study. Pediatrics 2004;114:e672-7.  Back to cited text no. 16
Wang RY, Bodamer OA, Watson MS, Wilcox WR, ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. Genet Med 2011;13:457-84.  Back to cited text no. 17
James SP, Stromeyer FW, Chang C, Barranger JA. LIver abnormalities in patients with Gaucher's disease. Gastroenterology 1981;80:126-33.  Back to cited text no. 18
Puri RD, Kapoor S, Kishnani PS, Dalal A, Gupta N, Muranjan M, et al. Diagnosis and Management of Gaucher disease in India consensus guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics. Indian Pediatr 2018;55:143-53.  Back to cited text no. 19
Lloyd-Evans E, Platt FM. Lysosomal Ca (2+) homeostasis: Role in pathogenesis of lysosomal storage diseases. Cell Calcium 2011;50:200-5.  Back to cited text no. 20
Bembi B, Zanatta M, Carrozzi M, Baralle F, Gornati R, Berra B, et al. Enzyme replacement treatment in type 1 and type 3 Gaucher's disease. Lancet 1994;344:1679-82.  Back to cited text no. 21

Correspondence Address:
Seema Sharma
C-Block, Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_725_21

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