Why is it important for Gaucher disease to be diagnosed early?

An early diagnosis of Gaucher disease is critical in initiating the appropriate patient assessment and management plans as soon as possible.1 Recognition of Gaucher disease enables patients to avoid inappropriate or unnecessary medical procedures or treatments. Early diagnosis of Gaucher disease can also reduce the likelihood of irreversible organ damage and serious complications, as well as chronic pain and disabling symptoms.2 Additionally, when a prompt diagnosis is made, many patients receive treatment early, which may reverse several of the initial disease signs and symptoms and therefore improve quality and duration of life.3

Patients with an enlarged liver or spleen, or a low blood count, are often referred to a haematologist for treatment. Haematologists are essential in identifying and diagnosing Gaucher disease, and are well positioned to consider the disease in their differential diagnosis. Nevertheless, the rarity of Gaucher disease means that most community-based haematologists are unlikely to encounter patients with the disease very often, if ever.2 One study showed that of 406 haematology–oncology specialists, only 20% would consider Gaucher disease Type 1 in their differential diagnosis for a patient presenting with common disease-related symptoms (anaemia, thrombocytopaenia, hepatomegaly, splenomegaly and bone pain).4 Since the management of Gaucher disease is complex, diagnosed patients should be referred to a centre specialised in treating patients with Gaucher disease. This health pathway ensures that other specialists, who are also familiar with the disease, are involved in the disease management process. Specialists in Gaucher disease may be in the best situation to manage the overall disease, discuss the prognosis, and provide education and supportive care recommendations based on the disease course and treatment.2

Overall, physicians need to maintain awareness of Gaucher disease to enable correct diagnosis, even if they will rarely encounter these patients. For example, when evaluating patients with unexplained splenomegaly, including Gaucher disease in a differential diagnosis is critical. It is important that clinicians also take a detailed family history to assess possible prior cases of familial Gaucher disease, for example, a family member who had a hip replacement at a very young age or unexplained bone problems.2 By tracing the family tree, the grandparents, parents, siblings, cousins and offspring of the patient with Gaucher disease can be identified.5 However, as Gaucher disease has an autosomal recessive pattern of inheritance (see genetic inheritance of Gaucher disease), family members of patients with Gaucher disease may be carriers of the disease, rather than affected themselves.6 Screening for Gaucher disease in partners or spouses is only useful in cases of consanguinity.5

Gaucher disease is more common in individuals of Ashkenazi Jewish ethnicity, with a birth incidence of approximately 1 in 850.7,8 Family history of Gaucher disease and Ashkenazi Jewish ethnicity are two major covariables identified by the Gaucher Earlier Diagnosis Consensus (GED-C) initiative (sponsored by Shire, now part of Takeda) that could be indicative of early Gaucher disease Type 1. Moreover, a family history of Gaucher disease is the one major covariable that could help early diagnosis of Gaucher disease Type 3.1

How can clinicians include Gaucher disease in their differential diagnosis?

The GED-C initiative aims to guide non-specialists and raise clinicians’ suspicions in identifying patients who may potentially have Gaucher disease. The signs and covariables as major indicators of early Gaucher disease Type 1 and early Gaucher disease Type 3 identified by 22 Gaucher disease specialists are presented in Table 1.1

Table 1.
Signs and covariables as major indicators of early Gaucher disease Type 1 and Gaucher disease Type 3 developed by the GED-C initiative1

Splenomegaly and hepatomegaly are common in patients with untreated Gaucher disease Type 1 and Type 3, and abdominal distension is one of the earliest health problems experienced by patients with Type 1.9,10 Moderate or severe bleeding and bruising, and frequent tiredness or fatigue, are other early health conditions that may be reported by patients with Gaucher disease Type 1.10 The most frequent symptom leading to diagnosis of Gaucher disease in 562 patients (85.0% with Gaucher disease Type 1) from the French Gaucher Registry was splenomegaly (70.3%), followed by thrombocytopaenia (49.1%) and hepatomegaly (22.0%).11 Plasma levels of ferritin are also elevated in patients with Gaucher disease Type 1, and correlate with increased liver volume and reduced haemoglobin levels.12 The symptoms of Gaucher disease are often first presented to haematologists and they are the most likely speciality to make a diagnosis.10

It is common for Gaucher disease to manifest in childhood, and it may lead to poor growth and development with delayed puberty.13,14 One survey of 212 patients with Gaucher disease Type 1 showed that approximately half were diagnosed in childhood or adolescence (37% aged 0‒9 years and 12% aged 10‒18 years).10 In a study of 887 patients diagnosed with Gaucher disease Type 1 aged <18 years, the most common signs and symptoms reported were splenomegaly (95%), hepatomegaly (87%), bone disease as shown by radiological imaging (81%), thrombocytopaenia (50%), anaemia (40%), growth delays (34%), bone pain (27%) and bone crises (9%).14 Neurological manifestations such as oculomotor apraxia, supranuclear opthalmoplegia, extrapyramidal features, epilepsy, cerebellar ataxia and developmental delay are also common features of Gaucher disease Type 3 that could be recognised in childhood.15 Paediatricians are one of the first specialists that young patients with Gaucher disease commonly first present to with their symptoms, and can be involved in making the final diagnosis.10 Therefore, early recognition of Gaucher disease by paediatricians, including metabolic and endocrinology sub-specialities, is critical, as early intervention can reduce the risk of later complications.10

Skeletal problems are common in patients with Gaucher disease. In 413 patients enrolled in the Gaucher Outcome Survey (sponsored by Shire, now part of Takeda), 34.2% had ≥1 skeletal abnormality.16 Bone or joint pain is one of the earliest health problems experienced by patients with Gaucher disease. Other skeletal-related presenting features of Gaucher disease include growing pains, easy bone fracturing, avascular necrosis, slow growth or pubertal delay, abnormal X-ray and osteopaenia.10 The skeletal manifestations of Gaucher disease may progress slowly through childhood and only become apparent during the teenage years. Bone pain and bone crises are considered to progress with age in Gaucher disease; therefore, children who display evidence of Gaucher disease are sometimes incorrectly diagnosed with other growing pains.14 In 44 patients with paediatric-onset Gaucher disease (Type 1, n=41; Type 3, n=3), 73% had ≥1 major skeletal event in their clinical history, 45% of which occurred when they were children.17 Rheumatologists, radiologists or orthopaedists may be presented with patients with Gaucher disease-related symptoms.10 Therefore, it is important that Gaucher disease be considered in their differential diagnosis when presented with patients with bone involvement (e.g. avascular necrosis, bone infarction, bone crises, bone pain or osteomyelitis), particularly in combination with hepatosplenomegaly.17

Abdominal distension, caused by hepatosplenomegaly, is one of the earliest health problems experienced by patients with Gaucher disease.10 In untreated patients with Gaucher disease Type 1 and Gaucher disease Type 3, splenomegaly and hepatomegaly are common.9 Moreover, in 887 patients aged <18 years with Gaucher disease Type 1, splenomegaly and hepatomegaly affected 95% and 87% of children, respectively.14 In some instances, patients with Gaucher disease have first presented their symptoms to a gastroenterologist or hepatologist. Gastroenterologists could also be involved in diagnosing patients with Gaucher disease and in making the final diagnosis.10 Therefore, it is important that gastroenterologists are aware of Gaucher disease and its manifestations.

It is also important that clinicians are careful to distinguish Gaucher disease Type 1 from other lysosomal storage diseases that have similar symptomatology, for example, Niemann-Pick disease, Tay-Sachs disease and Pompe disease.3 Symptoms of Gaucher disease should also be differentiated from haematological malignancies (e.g. B-cell lymphoma, leukaemia and myeloma).3,18,19 Hepatomegaly and polyclonal gammopathy without neutropaenia can be a useful set of symptoms in differentiating Gaucher disease from haematological malignancies; however, it is important to note that Gaucher disease can coexist with malignancy.3 A differential diagnosis approach to guide clinicians is presented in Table 2.1,20-29


Table 2. Differential diagnosis approach to Gaucher disease.1,20-29

The patient and physician journey to a Gaucher disease diagnosis

Diagnosis of Gaucher disease can be challenging for clinicians who do not specialise in the disease. This is generally attributable to the fact that there is patient variability in age, severity, Gaucher disease type and a range of clinical manifestations.10 Clinicians may also not be familiar with Gaucher disease and some features of the disease can be general and non-specific, such as nosebleeds, fatigue and pain.4,10 One study aimed to investigate the patient journey to a diagnosis of Gaucher disease from both an expert and patient perspective.10

In total, 16 experts from 14 specialist Gaucher disease centres across 12 countries (Australia, Brazil, France, Germany, Ireland, Israel, Italy, Japan, Russia, Spain, the UK and the US) participated in the survey (sponsored by Shire, now part of Takeda). The survey was conducted between 25 February and 22 March 2015 and, at this time, these experts were managing 1595 patients with Gaucher disease (94% of these patients had Gaucher disease Type 1). Data were available for 1540 patients, 88% of whom were aged ≥18 years and 55% were of Ashkenazi Jewish ethnicity (these patients were primarily from sites in Israel [93%], the US [60%], France [55%] and the UK [45%]).10

Haematologists or haematologists–oncologists, followed by paediatricians and primary care physicians, were the most cited specialities to which patients first presented with Gaucher disease-related clinical features. Internists or general physicians, hepatologists, gastroenterologists, geneticists, orthopaedists, rheumatologists, or radiologists were also specialities where patients first sought help. Since the disease-specific early-presenting features of Gaucher disease are often haematological, this finding may explain why patients are often initially referred to haematologists. In this survey, haematologists or haematologists–oncologists were also most likely to refer patients to expert Gaucher disease centres.10

Gaucher disease experts reported that splenomegaly was typically the main presenting symptom of Gaucher disease, followed by thrombocytopaenia, anaemia, hepatomegaly, bone or joint pain, or ‘growing pains’, bruising, epistaxis or bleeding tendency, easy bone fracturing, avascular necrosis, slow growth or pubertal delay, abnormal X-ray, abdominal symptoms, leukopaenia or osteopaenia. Lack of awareness of Gaucher disease or misdiagnosis were the most common reasons for diagnostic delay. Phenotypic heterogeneity, non-specific symptoms, or mild symptomatology were also reasons for diagnostic delay.10

A total of 212 patients or their parents participated in the survey, all of whom were based in the US. The median age of participants was 50 years (range, 5‒92 years). The most common earliest health problems experienced by patients with Gaucher disease were abdominal distension, moderate or severe bleeding, bone or joint pain, moderate-to-severe bruising, and frequent tiredness or fatigue. Additional early health problems were growth retardation, delays in puberty and broken bones. An abnormal result on a blood test was the first health problem reported by some patients, and for others, they were only screened because a family member had Gaucher disease despite having no health problems themselves.10

Most patients first sought help for their symptoms from paediatricians, haematologists or haematologists–oncologists, or primary care physicians. Typically, patients who presented their symptoms to a primary care physician were then referred to a haematologist or haematologist–oncologist. In this survey, in most cases, Gaucher disease was eventually diagnosed by a haematologist or haematologist–oncologist.10 A diagnosis of Gaucher disease was made during childhood or young adulthood for the majority of patients, and they were often diagnosed within 1 year of first visiting a physician. However, for 1 in 7 patients, reaching a diagnosis of Gaucher disease took ≥7 years.10

Some patients noted that misdiagnosed Gaucher disease affected their lives. For example, patients reported a reduced quality of life due to bone pain and chronic fatigue, emotional distress due to initial suspicions of cancer, and depression and suicidal thoughts as a result of having no explanation of their symptoms. Some patients also felt that there was lack of physician awareness of Gaucher disease and rare diseases.10

Results from this survey highlight an ongoing need for Gaucher disease awareness among non-specialists. A lack of physician awareness of the early signs and symptoms of Gaucher disease among non-specialists may lead to misdiagnosis, diagnostic delays and, ultimately, the development of irreversible complications for patients. This survey also reinforces that haematologists are not only the most cited specialists to whom patients with Gaucher disease first present their symptoms, but that haematologists are also most likely to make the diagnosis of Gaucher disease and refer patients to expert disease centres. In this survey, patients with Gaucher disease were typically diagnosed during childhood or young adulthood and often visited a paediatrician due to their early health problems.10 This highlights that paediatricians also need to maintain awareness of Gaucher disease and include the disease in their differential diagnosis when presented with younger patients with Gaucher disease-related symptoms. Finally, as the symptoms of Gaucher disease may be first presented to rheumatologists, orthopaedists and gastroenterologists, who may be involved in making the final diagnosis,10 these specialities also need to maintain awareness of the disease. Moreover, it is important that Gaucher disease be included in their differential diagnosis when presented with patients having skeletal abnormalities or abdominal distention.

Case series illustrating the severe complications of delay in Gaucher disease diagnosis

Patients with Gaucher disease were surveyed to investigate the length and impact of diagnostic delays. Of the 136 patients (51% male) included in this survey (sponsored by Genzyme Corporation, now part of Sanofi Genzyme), 98 were from the US and 38 were from Australia and New Zealand; the mean (standard deviation [SD]) age of diagnosis was 28.9 (21.2) years and 24.4 (12.1) years, respectively. For patients in the US, the mean (SD) time from first symptoms and/or signs of Gaucher disease to diagnosis was 49 (124) months, and 36 (73) months for patients in Australia or New Zealand.4

Overall, patients consulted up to eight different physicians (mean [SD], 3.0 [1.2]) concerning their condition, including gastroenterologists, geneticists, haematologists–oncologists, internists, neurologists, obstetricians or gynaecologists, orthopaedists, paediatricians and rheumatologists. The majority of patients had consulted haematologists–oncologists (86% in the US and 73% in Australia or New Zealand), and 38% of patients in the US indicated their condition was currently managed by these specialists, as did 68% of patients in Australia or New Zealand.4 

In 51.1% of 92 patients who responded, the first signs and symptoms of Gaucher disease were easy bruising or bleeding. These symptoms were followed by enlarged abdomen (46.7%), fatigue (31.5%), pain in bone and joints or bone fractures (26.1%), delayed growth (17.4%) and other (29.3%), which included anaemia, chronic infection, enlarged liver and/or spleen, epitasis, leg pain and thrombocytopaenia.4

In this survey, 14 patients were identified who experienced diagnostic delays of between 1‒10 years in confirming a diagnosis of Gaucher disease. Initial diagnoses included cirrhosis with portal hypertension, coagulopathy, collagenosis, ‘frozen shoulder’, haemophilia, haemochromatosis, liver disease, malignancy and pituitary adenoma.4 

Several instances of unnecessary invasive investigations also occurred before a correct diagnosis was made. For example, three patients had percutaneous liver biopsies (in the presence of thrombocytopaenia), four had bone marrow biopsies (one complicated by severe haemorrhage) and one instance each occurred in which Gaucher disease diagnosis was made upon examination of a splenectomy specimen or autopsy material after death due to post-surgical sepsis.4

Failure to make a prompt diagnosis of Gaucher disease also led patients to experience chronic bone pain, growth failure, life-threatening bleeding complications, pathological fractures, progressive liver disease and severe sepsis. Results from this study highlight that an earlier diagnosis of Gaucher disease, and increased disease awareness among clinicians, may reduce the likelihood of patients developing debilitating or irreversible complications.4

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