Gaucher Disease in 20-Month-Old Ethiopian Boy with a Massive Splenomegaly and Failure to Grow: Challenges in Case Management

doi:10.21203/rs.3.rs-2343408/v1

Download PDF

Case Report

Gaucher Disease in 20-Month-Old Ethiopian Boy with a Massive Splenomegaly and Failure to Grow: Challenges in Case Management

https://doi.org/10.21203/rs.3.rs-2343408/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Gaucher disease is an autosomal recessive lipid storage disorder caused by genetic mutations in the GBA gene. Symptoms are variable, range from asymptomatic to perinatal lethality, and can occur at any age.

Case report: This report details a case of a 20-month-old male born in Harar and referred to Hiwot Fana Specialized University Hospital, Harar, Ethiopia for evaluation of severe acute malnutrition, hepatosplenomegaly, and Developmental regression since the age of 8 months. He was well known for receiving blood transfusions due to anemia with persistent thrombocytopenia multiple times. On clinical examination, there was no dimorphism but had pallor, multiple lymphadenopathies with enlarged Liver, and a massive spleen. His assessment showed anemia was associated with marked thrombocytopenia. Bone marrow biopsy revealed Gaucher cells, confirmatory test for Gaucher disease, B-glucocerebrosidase activity results showed low activity and mutation detected in homozygous condition c. 1448 T>C p. (Leu483Pro). Over a year his abdomen became progressively distended, and he began to have breathing problems. Unfortunately, while seeking donated medical treatment, he died suddenly in the hospital after serious bleeding mainly due to a delayed diagnosis and a lack of supplies of medicines.

This case was presented to demonstrate the challenges in diagnosing and treating Gaucher disease, especially in a resource-constrained environment like ours

Conclusions: This case demonstrates the need to include this disease in the differential diagnosis when dealing with unexplained thrombocytopenia, anemia, hepatomegaly, and splenomegaly

Gaucher disease

management challenges

massive splenomegaly

Ethiopia

Gaucher disease is pan-ethnic and the prevalence of the disease is 1 in 40,000 to 120,000 live births worldwide, but in Ashkenazi descent, it is more common 1 in 800 people of Jewish descent. GD was first described by French dermatologist Philippe-Charles-Ernest Gaucher in 1882. It is an autosomal recessive disease caused by pathogenic variants in glucocerebrosidase 1 (GBA1) located on chromosome 1q21, causing a deficiency of glucocerebrosidase (acid β-glucosidase), resulting in cytotoxicity in cellular lysosomes from abnormal accumulation of glycolipids.

It is the most common lysosomal storage disease and more than 380 mutations in the GBA gene have been identified. Although genotype-phenotype correlations are not perfectly consistent, disease onset, severity, and clinical manifestations vary by genotype. The c.1448T>C allele (L444P or p.L483P) accounts for 18% of the mutant alleles in the Gaucher registry and has a worldwide distribution. (1-8)

Three clinical subtypes of GD exist. Contrary to types 2 and 3, type 1 (GD1) lacks the characteristic involvement of the central nervous system (CNS) (GD2 and GD3). GD2 or GD3, depending on whether it is acute or chronic, is the name given to GD that involves the nervous system (neuropathic GD). Internal organs, bone marrow, and bones are all affected by GD. When compared to type 1 Gaucher disease (GD1), which is more prevalent in people of Ashkenazi Jewish heritage, Gaucher disease is pan-ethnic. Type 2 is a more uncommon form, whereas type 3 is the most prevalent form globally and primarily affects non-Jews. All three types of GD may be connected to the L444P mutation. While heterozygotes are more likely to experience GD type 1 or 2, homozygotes frequently have GD type 3. (2, 9, 10)

The presentation varies with the age of presentation, rate of progression, and organ involvement. The severity of the disease is based on the type and genetic mutations. Hepatosplenomegaly, anemia, and thrombocytopenia are common presenting manifestations.

All of these symptoms are nonspecific and overlap with more common disorders, such as leukemia, viral infections, or other malignancies, often resulting in a lengthy diagnostic odyssey. This disease is progressive and clinically significant manifestations may not be seen in children but will be severe when present. Early identification is crucial to improving the ultimate outcomes because early treatment can prevent the development of irreversible complications. (2, 10)

Bone involvement is variable and macrophages filled with lipid material known as Gaucher's cells are a cardinal feature of the disease. Diagnosis can also be confirmed by mutation analysis. Early identification is crucial to improving the ultimate outcomes because early treatment can prevent the development of irreversible complications. (12)

Treatment is based on the severity of the symptoms and the type of Gaucher disease that is present. For example, many cases of type 1 Gaucher disease may not require treatment due to very mild symptoms and due to the quick progression of type 2 Gaucher disease at an early age, there currently is no treatment for this type of disease. Enzyme replacement therapy is used in patients with GD for types 1 and 3.Another treatment option for the more severe cases of Gaucher disease is bone marrow transplantation. (2, 4, 10)

Due to a dearth of diagnostic resources, it is unknown how common GD is in Ethiopia. Here, we describe the first documented case of Gaucher's disease, which manifested as failure to thrive, massive splenomegaly, concomitant thrombocytopenia, and anemia. We also stress the importance of including this condition in a child's differential diagnosis. Despite the fact that in the majority of patients, disease symptoms and signs first show in infancy, diagnosis is frequently protracted for many years, oftentimes even until maturity. In order to avoid the development of irreversible consequences and improve quality of life, a child with this uncommon disease must be identified and treated as soon as possible. This article explains the presentation and challenges in the management of a toddler with this rare genetic condition, which calls for prompt diagnosis and care to improve outcomes and prevent the onset of irreversible consequences. It is well known that Gaucher's disease progresses over time and that, if ignored, it can cause growth failure, infection, hypertension, liver problems, and early death from bleeding problems. Diagnosis was delayed for our patient because to it is not being included early in the differential diagnosis. After all, there were no known cases, and there were no diagnostic testing facilities in the nation. The necessity of early identification and management to stop death is illustrated by this case.

A 20-month-old firstborn child was born to non-consanguineous couples. His mother had an uneventful pregnancy and an uncomplicated delivery at term referred to Hiwot Fana Specialized University Hospital, Harar, Ethiopia for evaluation of severe acute malnutrition and hepatosplenomegaly with developmental regression. He presented initially at 8 months with abdominal swelling with a progressive increase in abdominal girth associated with cough, significant weight loss, LGIF, and a drenching type of sweating. He was also noted for a history of frequent blood transfusions with persistent thrombocytopenia.

On physical examination, he had no dysmorphism. Weight was 6.1 kg length= 61 cm, MUAC = 8 cm (severe wasting) HC= 46 cm WFL= b/n -2 and -3 (moderate wasting) LFA < -3 (severe stunting) WFA < -3 (severe underweight). He had conjunctival pallor, there are multiple sites LAP: anterior and posterior cervical LN measuring 2x1cm bilaterally, bilaterally Axillary LN measuring 2x1cm and bilaterally inguinal LN measuring 2x3cm. The abdomen was grossly distended (Figure 1) and Liver was 10 cm palpable below the right costal margin and the total liver span is 13 cm with a smooth surface, round border, and non-tender. The spleen is 16 cm palpable below the left costal margin along the line of growth, smooth surface, and non-tender. No sign of fluid collection. The child was Irritable, pupil- mid-size and reactive bilaterally cranial nerve (III/IV/VI) eyeball moving in all directions. At the time of referral to our hospital, the patient had already undergone multiple investigations, including chest X-ray and gastric aspirate, considering disseminated tuberculosis, which is endemic in the country despite the lack of contact history. The result was non-reveling. Bone marrow and PM were not suggestive of hematologic malignancy. Later, he was sent to BLH for better care which bone marrow biopsy report shows mainly superficial biopsy with few inadequate trabecular spaces containing few myeloid erythroid series with maturation and megakaryocyte sheets of histiocytic with abundant fibrillary cytoplasm were seen as suggestive of Gaucher cells. Following this, the patient was told to go abroad for diagnosis and care. Unfortunately, the patient can't afford it and came back to our hospital. We repeated Abdominal Ultrasound imaging reveals liver measures of 13.2 cm along the midclavicular line which suggests hepatomegaly for his age. Otherwise, no focal liver lesions are seen. (Figure 2) The spleen measured 16.4 cm along the line of growth. There are also multiple round hypo-echoic lesions with intervening normal splenic tissue seen in the upper pole of the spleen, which suggests acute splenic infarct. (Figure 3) and he was transfused multiple times because of anemia and persistent thrombocytopenia. Echocardiography and Bone scan were normal while confirmatory testing based on Dried Blood Spot with Enzyme Assay and Genotype, the result of B-Glucocerebrosidase activity demonstrated a low activity B-Glucocerebrosidase=0.7 umol/L/h (below the cut-off value > 1.5) suggesting Gaucher disease so further genetic testing with quantitative measurement of lyso-GL-1 (lyso-Gb1; glucosylsphingosine) showed an elevated Lyso-GL-1=2626.8 ng/ml (Cut-off value 0.0 - 14.0) and the following mutation was detected in the homozygous state: c. 1448 T>C (p.(Leu483Pro) which established a diagnosis of Gaucher disease.

Over a 1 year, his symptoms ongoing with a severely distended abdomen, and he developed respiratory problems was referred to for which bone marrow showed Gaucher cells, and then upon confirmatory testing based on Dried Blood Spot with Enzyme Assay and Genotype was requested through a charity organization which established a diagnosis of Gaucher disease. Based on the presentation disease type 3 was our final diagnosis. Unfortunately, the patient passed away in the hospital because of severe bleeding due to a delayed diagnosis and no supply of medication in the country while waiting for treatment from donations

GD is a rare pan-ethnic disease that is important to consider in the differential diagnosis of massive splenomegaly. The disease may occur at any age and severity can vary widely. GD is categorized into three clinical types that are distinguished by their clinical features, course, and ethnic predilection.

The prevalence of GD in Ethiopia is not known, mainly due to a lack of diagnostic facilities. Here we report the first case of confirmed Gaucher's disease presenting with failure to thrive and massive splenomegaly associated thrombocytopenia and anemia and emphasize the importance of considering this illness in the differential diagnosis of a child. Even though symptoms and signs of the disease appear during childhood in most patients, diagnosis is often delayed for many years, even until adulthood. This occurs partly because physicians do not always consider this disease in their differential diagnoses.

Lesson Learned:

To recognize clinical features for the diagnosis of GD.
Learn about the appropriate investigation of splenomegaly of unknown causes.
The importance of early identification before irreversible complication.
Understanding the management plan of this rare disease for better outcomes.
To recognize clinical features for the diagnosis of GD.
Learn about the appropriate investigation of splenomegaly of unknown causes.
The importance of early identification before irreversible complication.

Understanding the management plan of this rare disease for better outcomes.

Gaucher's disease can be treatable. However, there are many challenges, particularly in resource-limited settings. Diagnostic delay with severe complications such as growth failure is common among children with GD. This is particularly true in our case because there were no reported cases from our country. So physicians should consider this disease in their differential diagnosis. Further challenges were to confirm the diagnosis because the family could not afford to do confirmatory tests which are not available in the country. Fortunately, we managed to do this test with help of a charity organization abroad taking more time. Although the diagnosis was delayed in this case, further challenges were providing expensive treatment as imiglucerase was another challenge as it was not available in the country. This is an expected problem in low-income countries and civil and armed conflict. Finally, the education of pediatricians is essential to improve the early detection of patients with GD and facilitate the optimal management of this treatable disorder.

Ethics approval and consent to participate:

No prior ethics are required in our institution for single case reports, or short case reports provided the patient provided written informed consent on an anonymous basis.

Consent for publication

Written informed consent for publication was taken from parents.

Availability of data and materials

All materials and data are available from the corresponding author on reasonable request.

Competing interests: there are no conflicts of interest in this case report.

Funding: No funding was obtained.

Authors' contributions:

OH, HA and TG were involved in the patient’s clinical care, conception and drafting of the main manuscript text.

D.W. prepared figures 2-3.

All authors reviewed and approval of the final manuscript.

Acknowledgments:

We would like to thank child’s parents for their willingness to share this case. We are also grateful towards Dr. Abeer Ezzat and the Sanofi Genzyme team from Egypt for helping to diagnose my patient and Direct Relief and the Takeda Charitable Access Program for agreeing to donate the medicine. And finally, I would like to thank Dr. Nega Assefa for editing the paper.

Ginzburg L, Kacher Y, Futerman AH. The pathogenesis of glycosphingolipid storage disorders. Seminars in cell & developmental biology. 2004;15(4):417-31.
Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci. 2017;18(2).
Ida H, Rennert OM, Iwasawa K, Kobayashi M, Eto Y. Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutation. Human genetics. 1999;105(1-2):120-6.
Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet (London, England). 2008;372(9645):1263-71.
Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Human mutation. 2008;29(5):567-83.
Andrade-Campos M, Alfonso P, Irun P, Armstrong J, Calvo C, Dalmau J, et al. Diagnosis features of pediatric Gaucher disease patients in the era of enzymatic therapy, a national-base study from the Spanish Registry of Gaucher Disease. Orphanet J Rare Dis. 2017;12(1):84.
Schiffmann R, Sevigny J, Rolfs A, Davies EH, Goker-Alpan O, Abdelwahab M, et al. The definition of neuronopathic Gaucher disease. J Inherit Metab Dis. 2020;43(5):1056-9.
Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Archives of internal medicine. 2000;160(18):2835-43.
Dahl N, Lagerström M, Erikson A, Pettersson U. Gaucher disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene. American journal of human genetics. 1990;47(2):275.
Weinreb NJ, Goker-Alpan O, Kishnani PS, Longo N, Burrow TA, Bernat JA, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab. 2022;136(1):4-21.
Grabowski GA, Zimran A, Ida H. Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry. American Journal of Hematology. 2015;90(S1):S12-S8.
Mehta A, Kuter DJ, Salek SS, Belmatoug N, Bembi B, Bright J, et al. Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative. Intern Med J. 2019;49(5):578-91.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Gaucher Disease in 20-Month-Old Ethiopian Boy with a Massive Splenomegaly and Failure to Grow: Challenges in Case Management

Status:

Version 1

Abstract

Figures

Introduction

Case Presentations

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1