Early diagnosis of Gaucher disease is essential in initiating the appropriate patient assessment and management plans as soon as possible.To aid clinicians in reaching a diagnosis of Gaucher disease, diagnostic algorithms and guidance for diagnoses have been published.2-4

Diagnostic algorithm for paediatric patients with Gaucher disease 

Two-thirds of all patients with Gaucher disease are reported to experience clinical manifestations in childhood; therefore, a group of Italian paediatric haematologists and metabolic disease specialists with experience in Gaucher disease developed an algorithm (sponsored by Genzyme Corporation, now part of Sanofi Genzyme) for diagnosis of Gaucher disease in paediatric patients.2 Initially, the expert panel outlined the general structure of the algorithm and its core flow of information based on their clinical experience and published data, in addition to information from the International Collaborative Gaucher Group Registry (sponsored by Sanofi Genzyme).2,5 Clinical rationale was identified for each step of the algorithm to increase the likelihood that the scheme would be applicable to clinical practice.2 The proposed algorithm for early diagnosis of Gaucher disease in paediatric patients is outlined in Figure 1.

Figure 1.
Diagnostic algorithm for early diagnosis of Gaucher disease in paediatric patients. Reproduced with permission from Di Rocco M et al. Pediatr Blood Cancer 2014; 61: 1905-1909.2

In children, the key presenting sign of Gaucher disease is splenomegaly, and other symptoms included in the diagnostic algorithm for adults are not considered (e.g. gallstones, post-partum haemorrhage, monoclonal gammopathy of undetermined significance, pregnancy-associated thrombocytopaenia or splenic nodules). Taking radiological evidence of bone disease into account (mainly Erlenmeyer flask deformity, growth retardation, oculomotor abnormalities, and ferritin or tartrate-resistant acid phosphatase levels) can shorten the pathway to a diagnosis of Gaucher disease in children. In the absence of these symptoms, however, a bone marrow biopsy is mandatory to exclude malignancies or other haematological disorders. This algorithm leads to a diagnosis of Gaucher disease, even if Gaucher cells are not found in the bone marrow, as although Gaucher cells are a key finding for diagnosing the disease, Gaucher disease cannot be excluded if Gaucher cells have simply not been detected. If a diagnosis of Gaucher disease is confirmed, genetic molecular diagnosis is compulsory to identify the risk of Gaucher disease Type 3 and thus the appropriate follow-up.2

Although diagnosis of Gaucher disease Type 2 is challenging, it is important that an accurate and timely diagnosis is made, enabling appropriate disease management, genetic counselling and family planning that can inform future pregnancies. The visceral and neurological manifestations are fairly consistent in Gaucher disease Type 2; however, the signs and symptoms are heterogeneous. The recommended diagnostic work-up for Gaucher disease Type 2, as developed by a group in the US, is outlined in Figure 2. The most reliable diagnostic methods are glucocerebrosidase testing and direct sequencing of the GBA1 gene. Nevertheless, Gaucher disease Type 2 can be difficult to distinguish from Gaucher disease Type 1 and Type 3 based solely on glucocerebrosidase testing, although complete absence of this enzyme is associated with early lethality.3

Figure 2.
Recommended diagnostic work-up for establishing a diagnosis of Gaucher disease Type 2. Reproduced with permission from Weiss K et al. Mol Genet Metab 2015; 114: 110-122.3

Diagnostic algorithm for adult patients with Gaucher disease

Physicians with experience in Gaucher disease developed diagnostic and disease management algorithms (sponsored by Genzyme Corporation, now part of Sanofi Genzyme) in response to the need for greater awareness and early diagnosis of the disease.4,6 The participating physicians represented 10 countries: Argentina, Colombia, Germany, Israel, Italy, Russia, Spain, Switzerland, Turkey and the US. The physicians assessed relevant peer-reviewed medical literature, and discussed their experiences of patterns of misdiagnoses as well as the signs and symptoms of Gaucher disease from their clinical practice. Key diagnostic features of Gaucher disease Type 1 were identified which formed the basis of the diagnostic algorithms. These algorithms were then further developed and consensus was reached by the physicians.4

Diagnostic algorithm for Gaucher disease Type 1 in adult patients of Ashkenazi Jewish ethnicity

The prevalence of Gaucher disease Type 1 is higher in individuals of Ashkenazi Jewish ethnicity compared with the general population.7,8 From the consensus meeting, the physicians agreed that a diagnosis of Gaucher disease Type 1 should be considered in any individual of Ashkenazi Jewish ethnicity presenting with mild, moderate or severe splenomegaly. When splenomegaly is not present, Gaucher disease Type 1 should be considered if there is even mild thrombocytopaenia, bleeding tendency, unexplained high levels of ferritin with normal transferrin saturation, or increased levels of inflammatory markers (Figure 3).4

Figure 3.
Diagnostic algorithm for Gaucher disease Type 1 in adult Ashkenazi Jewish populations. Figure reproduced with permission from Mistry PK et al. Am J Hematol 2011; 86: 110-115.4

In patients with bleeding diatheses, coagulopathies such as factor XI deficiency is common in individuals of Ashkenazi Jewish descent9 and should be excluded.4

Diagnostic algorithm for Gaucher disease Type 1 in adult patients of non-Ashkenazi Jewish ethnicity

In non-Ashkenazi Jewish populations, Gaucher disease Type 1 is less frequent compared with haematological malignancies. Therefore, it is more appropriate to consider Gaucher disease in the differential diagnosis once malignancies have been ruled out. In these cases, it is reasonable for a bone marrow biopsy to be performed in initial investigations. If Gaucher cells are found within the bone marrow aspirate, then this finding is suggestive of Gaucher disease; however, Gaucher disease and malignancy are not mutually exclusive (Figure 4).4 Pseudo-Gaucher cells have also been observed in malignant conditions even in the absence of Gaucher disease.4,10

Figure 4.
Diagnostic algorithm for Gaucher disease Type 1 in adult non-Ashkenazi Jewish populations. Figure reproduced with permission from Mistry PK et al. Am J Hematol 2011; 86: 110-115.4

C-ANPROM/INT//7567; Date of preparation: September 2020