Research Article
SAME BUT DIFFERENT: GAUCHER DISEASE Rare Cases of Gaucher in Two Siblings with the Same Genotype but Different Phenotype
https://doi.org/10.21203/rs.3.rs-3646133/v1
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Gaucher disease is a rare autosomal recessive lysosomal storage disease. More than 400 mutations have been identified. Although the disease has a genotype-phenotype relationship, the presence of cases with different phenotypes in the same genotype and phenotypic heterogeneity is noticeable. In this case report, we present 2 siblings with type 1 Gaucher disease carrying the same homozygous c.1226 A > G allele N370S (now called p.N409S) mutation with completely different phenotypes.
Gaucher disease
genotype phenotype relationship
N409S mutation
cirrhosis
osteoporosis
Gaucher Disease (GD) has three types. The most prevalent is type 1. Patients may present with different symptoms and signs due to phenotypic heterogeneity. The most frequent findings include hepatosplenomegaly (HSM), anemia, thrombocytopenia and bone lesions. Cirrhosis is very rare (Mahayani et al.2020). N409S is the most frequently detected mutation. There is a genotype-phenotype relationship, however, cases with the same genotype but different phenotype can be seen among siblings and even twins (Hruska et al.2007; Cassinerio et al. 2014). In a study of 32 cases with homozygous L444P mutation, neurologic symptoms were noted in all cases. However, the type and severity of neurologic symptoms as well as other accompanying findings were highly different among the patients and could not be attributed to the genotype. Among the cases, phenotypic heterogeneity was observed ranging from children who died at an early age to autism and even successful university students (Goker-Alpan et al 2005). Our two cases are rare type 1 GD patients with different phenotypes carrying homozygous N409S mutation.
A 34-year-old man with known splenomegaly (SM) (200 mm) for 18 years who had been followed up with a diagnosis of cryptogenic cirrhosis was examined for thrombocytopenia inconsistent with the liver disease clinical picture. Laboratory tests were normal except leukocytes 2900/mm3, platelets 37000/mm3 and ferritin 426 mg/L. Peripheral smear showed no findings except thrombocytopenia. In bone marrow aspiration and biopsy, Gaucher cells were detected (Fig. 1).The tests performed upon this observation revealed β-glucosidase 0.3 nmol/mg/h (normal range for adults: >1), chitotriosidase 748.2 μmol/L/h (normal range for adults: <200) and Lyso-Gb1 154 ng/mL (normal range for adults: 0-14). In addition, genetic studies showed homozygous mutations N409S and confirmed the type 1 GD diagnosis. Among the examinations of other systems, bone density scan revealed osteopenia. The patient was started treatment with imiglucerase. At 6 months of treatment, SM decreased to 177 mm, platelet count increased to 63.000/mm3, leukocyte and ferritin values were normalized. Family screening revealed that his brother was homozygous positive for the same mutation.
The 37-year-old brother of the first case was also diagnosed as N409S homozygote positive type 1 GD in family screening. The patient, who had onset of bone pain at the age of 20, underwent surgery for vertebral fracture after a fall at the age of 27 and was diagnosed with osteoporosis. The patient whose pain increased over the years and who developed difficulty in walking in 10 years stated that he could not work in any job requiring physical strength. Muscle atrophy and thinning in the lower extremities due to disuse were also present. The patient's signs and symptoms were entirely different from those of his brother who carries the same mutation. Laboratory tests showed ferritin 651mg/L, high density lipoprotein (HDL) 29mg/dL (normal range for adults: 40-60) and β-glucosidase 0.4 nmol/mg/hour. Bone density scan was consistent with osteoporosis (L1-4 vertebrae total T score: - 2.7). He had no cytopenia and organomegaly. With all these findings, it is a rare case of type 1 GD in the literature. Enzym replacement treatment (ERT) was started.
GD is a chronic progressive multisystemic disease. Diagnosis is made by mutation analysis of the β-glucosidase (GBA1) gene. The most prevalent mutations are N409S and L444P. There is a genotype-phenotype relationship. The best-known mutation is N409S, and this mutation has been associated with type 1 GD (Goker-Alpan et al. 2005; Hruska et al. 2007; Cassinerio et al. 2014; Stirnemann et al. 2017; Carubbi et al. 2020). Significant phenotypic heterogeneity is observed. Genotype may not account for all phenotypic findings. The phenotype may be very different in the same genotype, even in siblings or twins. Accompanying molecular co-abnormalities and environmental factors contribute to this difference (Goker-Alpan et al. 2005; Hruska et al. 2007; Stirnemann et al. 2017). Both of our cases were diagnosed with type 1 GD based on homozygous N409S mutation. It is interesting that our cases were two siblings with completely different phenotypes in the same genotype.
In type 1 GD, HSM, anemia, thrombocytopenia and bone lesions are the most frequent signs. Cirrhosis is quite rare. The prevalence of bone pain, osteopenia and bone fractures are 67%, 55% and 7%, respectively (Goker-Alpan et al. 2005; Hruska et al. 2007; Cassinerio et al. 2014; Stirnemann et al. 2017; Carubbi et al. 2020; Mahayani et al.2020). Our first case presented with SM, thrombocytopenia, and cirrhosis. 15 years of known SM and deep thrombocytopenia inconsistent with the stage of cirrhosis warranted investigation of hematologic causes. Our second case, unlike his brother, is a rare case with the absence of hematologic findings, the presence of osteoporosis and lumbar vertebral fracture.
Hyperferritinemia and low HDL levels may be observed in GD due to chronic inflammation. Hyperferritinemia is positive in 87% of cases and is associated with the severity of the disease (Carubbi et al. 2020). Hyperferritinemia was present in both of our patients and improved on treatment in the first patient.
GBA1 mutations are of prognostic relevance. The most frequent mutation, N409S, is protective against neurologic symptoms. However, it is not predictive of the severity of bone and visceral symptoms. Interestingly, 50% of cases of homozygous N409S are asymptomatic throughout life (Goker-Alpan et al. 2005; Grabowski 2008; Stirnemann et al. 2017; Hosoba et al. 2018; Carubbi et al. 2020). No neurologic findings were observed in our cases. Both of our patients had bone lesions with varying severity. Other phenotypic features in the same genotype are completely different.
Delay in diagnosis can lead to complications, some of which are life-threatening. Our patients had serious complications such as cirrhosis and bone fractures. ERT dramatically improves hematologic and visceral symptoms and quality of life. However, its effect on bone lesions appears in about 5 years. On the other hand, cirrhosis is irreversible (Hughes et al. 2019; Carubbi et al. 2020). The presence of serious complications in our cases demonstrate once again the importance of early diagnosis. And this is only possible if the disease is recalled at the time of diagnosis. In case of many unexplained symptoms GD with nonspecific findings should be considered.
We don’t have any funds, grants, or other support were received during the preparation of this manuscript.
We have no relevant financial or non-financial interests to disclose.
Our cases participants provided informed consent for publication of the images in Figure 1a, 1b and 1c.
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