GAUCHER DISEASE AND A SLC26A6 VARIANT: UNEXPECTED BONE FRAGILITY
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Enzyme Replacement Therapy
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Secondary Categories:
- Enzyme Replacement Therapy
Introduction
Gaucher disease (GD) is a lisosomal storage disorder with an autosomal recessive inheritance caused by mutations in the GBA gene. This leads to deficient glucocerebrosidase (GCase) activity and substrate accumulation. GD is classified into three types, with GD2 and GD3 collectively known as neuronopathic Gaucher (nGD). The main clinical manifestations of this disease include: hepatosplenomegaly, cytopenia,chronic bone pain, pathologic fractures and in nGD, oculomotor apraxia and seizures.
Case Presentation
A 16-month-old female presented with hepatosplenomegaly, growth arrest, anemia, and thrombocytopenia, suggesting Gaucher disease. Testing revealed a homozygous pathogenic variant: GBA:c.1448T>C p.Leu483Pro and GCase activity of 0.31 nmol/mL, confirming the diagnosis. Three months later, imiglucerase alfa was initiated as enzyme replacement therapy (ERT). On the day of the initiation, she presented with her first pathologic fracture in the right wrist. As she continued receiving this therapy for 2 years, she suffered two additional fractures in the humerus and olecranon which required conservative management. Given this clinical outcome, the decision was made to switch to velaglucerase alfa. After treatment with this enzyme, she developed abdominal gaucheromas and continued presenting pathological fractures, despite a reduction in organomegaly and improvement hematological parameters with a normal Lyso-Gb1. Later, it was decided to switch her back to imiglucerase, without signs of improvement regarding her persistent bone fragility. This patient has a history of 11 pathologic fractures. Additional workup revealed hypercalcemia, and a kidney ultrasound reported bilateral renal microlithiasis.
Diagnostic Workup
As this patient was receiving ERT with improvement in her biomarker levels and clinical improvement on the other manifestations, except bone fragility, an exome sequencing was performed. A variant of uncertain significance (VUS) was found in SLC26A6:c.1985del p.Gly662Alafs*2, reported as a cause for nephrolithiasis (NL), hypercalcemia, and bone fragility. Follow-up testing revealed persistent hypercalciuria, hyperoxaluria, glomerular hyperfiltration and a kidney ultrasound that reported bilateral renal microlithiasis.
Treatment and Management
A referral to the nephrology department along with her clinical manifestations led to treatment with hydrochlorothiazide and citrate solution, in addition to ERT.
Outcome and Follow-Up
As part of the VUS reclassification, we intend to do familial segregation in both parents expecting a de novo variant (PM6), and when possible, perform functional studies.
Discussion
The SLC26A6 gene has been previously reportedin patients with clinical manifestations such as nephrolithiasis, hypercalcemia, and bone fragility. This condition is associated with an increased risk of bone demineralisation, fractures, and chronic kidney disease. As she has already presented nephrolithiasis, hypercalcemia, and hyperoxaluria, we believe this gene could also be associated with bone demineralisation in addition to Gaucher disease.
Conclusion
This case exemplifies a rare coexistence of two clinical entities, where a second cause of bone fragility was hidden behind a previously known condition. Exome sequencing should be performed whenever a clinical outcome of a condition does not follow the expected pattern, despite ERT and improvement in biomarkers.
Gaucher disease (GD) is a lisosomal storage disorder with an autosomal recessive inheritance caused by mutations in the GBA gene. This leads to deficient glucocerebrosidase (GCase) activity and substrate accumulation. GD is classified into three types, with GD2 and GD3 collectively known as neuronopathic Gaucher (nGD). The main clinical manifestations of this disease include: hepatosplenomegaly, cytopenia,chronic bone pain, pathologic fractures and in nGD, oculomotor apraxia and seizures.
Case Presentation
A 16-month-old female presented with hepatosplenomegaly, growth arrest, anemia, and thrombocytopenia, suggesting Gaucher disease. Testing revealed a homozygous pathogenic variant: GBA:c.1448T>C p.Leu483Pro and GCase activity of 0.31 nmol/mL, confirming the diagnosis. Three months later, imiglucerase alfa was initiated as enzyme replacement therapy (ERT). On the day of the initiation, she presented with her first pathologic fracture in the right wrist. As she continued receiving this therapy for 2 years, she suffered two additional fractures in the humerus and olecranon which required conservative management. Given this clinical outcome, the decision was made to switch to velaglucerase alfa. After treatment with this enzyme, she developed abdominal gaucheromas and continued presenting pathological fractures, despite a reduction in organomegaly and improvement hematological parameters with a normal Lyso-Gb1. Later, it was decided to switch her back to imiglucerase, without signs of improvement regarding her persistent bone fragility. This patient has a history of 11 pathologic fractures. Additional workup revealed hypercalcemia, and a kidney ultrasound reported bilateral renal microlithiasis.
Diagnostic Workup
As this patient was receiving ERT with improvement in her biomarker levels and clinical improvement on the other manifestations, except bone fragility, an exome sequencing was performed. A variant of uncertain significance (VUS) was found in SLC26A6:c.1985del p.Gly662Alafs*2, reported as a cause for nephrolithiasis (NL), hypercalcemia, and bone fragility. Follow-up testing revealed persistent hypercalciuria, hyperoxaluria, glomerular hyperfiltration and a kidney ultrasound that reported bilateral renal microlithiasis.
Treatment and Management
A referral to the nephrology department along with her clinical manifestations led to treatment with hydrochlorothiazide and citrate solution, in addition to ERT.
Outcome and Follow-Up
As part of the VUS reclassification, we intend to do familial segregation in both parents expecting a de novo variant (PM6), and when possible, perform functional studies.
Discussion
The SLC26A6 gene has been previously reportedin patients with clinical manifestations such as nephrolithiasis, hypercalcemia, and bone fragility. This condition is associated with an increased risk of bone demineralisation, fractures, and chronic kidney disease. As she has already presented nephrolithiasis, hypercalcemia, and hyperoxaluria, we believe this gene could also be associated with bone demineralisation in addition to Gaucher disease.
Conclusion
This case exemplifies a rare coexistence of two clinical entities, where a second cause of bone fragility was hidden behind a previously known condition. Exome sequencing should be performed whenever a clinical outcome of a condition does not follow the expected pattern, despite ERT and improvement in biomarkers.