How can Gaucher disease Type 1 be recognised clinically?
The overall phenotypic expression of Gaucher disease Type 1 is diverse; therefore, its clinical presentation can be variable.1 A diagnosis of Gaucher disease may be missed by clinicians, and patients may receive a range of initial misdiagnoses before being diagnosed years later.2
Results from the French Gaucher Registry of 562 patients (84.7% with Gaucher disease Type 1) found that the most common symptoms leading to a diagnosis were splenomegaly (70.3%), thrombocytopaenia (49.1%), hepatomegaly (22%), chronic bone pain (6.9%), bone crisis (3.4%) or other (35.3%).3 In line with these data, anaemia and/or thrombocytopaenia, but much less leukopaenia, are common findings among symptomatic patients with Gaucher disease Type 1.4 In general, patients who develop symptoms in adulthood are considered to have a milder form of the disease.5
In paediatric patients, anaemia and severe hepatomegaly and splenomegaly are frequently observed, growth retardation may occur, and puberty can be delayed.6,7 Children and young adults with Gaucher disease Type 1 may present with frequent episodes of epistaxis, bleeding gums or chronic fatigue of ‘unexplained cause’ which may be signs of anaemia and/or thrombocytopaenia.4 In patients aged <18 years with Gaucher disease Type 1, other common signs and symptoms may include bone manifestations which can be detected by imaging modalities, bone pain and bone crises.6
In elderly patients, non-classical symptoms of Gaucher disease Type 1, such as infectious complications following surgery, osteoporotic features, gallstones, or benign monoclonal gammopathy and multiple myeloma may also occur.1 Data published in 2015 from the International Collaborative Gaucher Group Gaucher Registry (sponsored by Sanofi Genzyme) indicated that 17% of patients had experienced onset of Gaucher disease Type 1 symptoms between the ages of 50 and 80 years. Approximately 75% of patients with Gaucher disease Type 1 with disease onset after they were 50 years old were homozygous for the N370S (c.1226A>G; p.Asp409Ser) mutation and may not have come to medical attention until later in life due to their mild disease manifestations.8
The Gaucher Earlier Diagnosis Consensus (GED-C) initiative
The GED-C Initiative (sponsored by Shire, now part of Takeda) aimed to identify clinical signs and covariables that would indicate early Gaucher disease Type 1 and Gaucher disease Type 3. In doing so, this would allow non-specialists to identify patients at risk for Gaucher disease and enable early diagnosis. An anonymous, three-round Delphi consensus was used amongst 22 Gaucher disease specialists from around the world (median experience, 17.5 years), with collective management of almost 3000 patients with Gaucher disease. During each round, data were gathered followed by importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds to define a priori.9
The seven major signs identified for early Gaucher disease Type 1 were9:
- Bone issues (including pain, crises, avascular necrosis and fractures)
- Elevated ferritin levels
- Gammopathy (monoclonal or polyclonal).
The two major covariables identified were family history of Gaucher disease and Ashkenazi Jewish ethnicity.9
How can Gaucher disease Type 2 be recognised clinically?
Symptoms of Gaucher disease that appear during the neonatal period are typically associated with Gaucher disease Type 2, although presentations may differ.5 An abnormal accumulation of fluid in ≥2 body areas, known as hydrops fetalis, has been described and may be present at birth or perinatally.5,10,11 Yet, Gaucher disease may not be considered until a couple experiences multiple spontaneous abortions or perinatal deaths.5
Other symptoms of Gaucher disease Type 2 may include:
- Apnoea (cessation of breathing)12 related to lengthy and frequent laryngeal spasms13
- Bulbar signs (severe swallowing disorders in particular)13
- Congenital ichthyosis5†
- Difficulty handling secretions5
- Impaired growth (in 30% of cases; may be the first sign of the disease)13
- Lockjaw and hypertonia with pyramidal and possibly extrapyramidal rigidity13,14
- Lung lesions13
- Myoclonic seizures resistant to anti-seizure medication13
- Neurological decline (e.g. brainstem dysfunction, impaired hearing, irritability, hypertonia, hypotonia, hypokinesia, ocular involvement [such as extraocular weakness, impaired vision, ocular apraxia,§ squint and supranuclear gaze palsy] and progressively impaired cognition)5,15
- Noisy breathing5
- Oculomotor paralysis13
- Petechaie,‡ blueberry muffin lesions, oozing or retinal bleeding, secondary to thrombocytopaenia5,16
- Poor suck5
- Rigidity of the neck and trunk13
- Systemic involvement with hepatosplenomegaly13
- Thrombocytopaenia (in 60% of cases).13
Patients with Gaucher disease Type 2 may die either from pneumopathy (any disease of the lungs) or from apnoea.14,17
How can Gaucher disease Type 3 be recognised clinically?
Despite the presence of visceral manifestations, neurological signs of Gaucher disease Type 3 may present several years later and after a patient has been misdiagnosed with Gaucher disease Type 1.13 Therefore, a diagnosis of Gaucher disease Type 3 can be missed in the early stages of the disease or in patients with milder forms.1 Clinicians should observe patients for the presence of frequent movements of the head instead of the eyes, known as horizontal supranuclear gaze palsy.5,18 Slowing, looping or absence of the horizontal saccades characterise these eye-movement abnormalities.5 In addition, clinical features such as early disease onset, aggressive visceral disease and falling or low IQ scores can also be suggestive of Gaucher disease Type 3.1 In childhood, patients do meet developmental milestones; however, their ability to crawl and walk can be hindered by massive organomegaly. Neurodegeneration is markedly slower in patients with Gaucher disease Type 3 than in those with Gaucher disease Type 2.5
In childhood and adolescence, Gaucher disease Type 3 is characterised by anaemia, bone crises, splenomegaly, thrombocytopaenia or kyphosis (extreme curvature of the upper back), with neurological manifestations.5,19 Horizontal supranuclear gaze palsy is the most common neurological manifestation of Gaucher disease Type 3, and in some cases, the only neurological symptom.18 Some patients may also have cerebellar ataxia, developmental delay and generalised or myoclonus epilepsy.20
Gaucher disease Type 3 can be further classified into subtypes15,21,22:
- Gaucher disease Type 3a: dominant neurological manifestations and mild visceral disease
- Gaucher disease Type 3b: dominant visceral disease and skeletal manifestations with mild neurological signs
- Gaucher disease Type 3c: visceral disease associated with cardiac involvement (also known as cardiovascular Gaucher disease)
- Norrbottnian clinical variant: early-onset significant hepatosplenomegaly and neurological involvement generally within the first or second decade of life.
The GED-C initiative
From the GED-C initiative, the following nine major signs of early Gaucher disease Type 3 were identified by the expert panel9:
- Oculomotor disturbances
- Myoclonus epilepsy
- Bone pain
- Motor disturbances
The one major covariable identified was a family history of Gaucher disease.9
*Weight loss, wasting of muscle, loss of appetite, and general debility23
†Skin disease represented by thick, scaly skin24
‡Small, purplish haemorrhagic spots on the skin due to platelet deficiencies (e.g. thrombocytopaenia)25
§Inability to fixate on certain points in the peripheral visual field despite intact eye movements26
C-ANPROM/INT//7567; Date of preparation: September 2020
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- Norton ME, Chauhan SP, Dashe JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. Am J Obstet Gynecol 2015; 212: 127-139.
- Mignot C, Gelot A, Bessieres B, et al. Perinatal-lethal Gaucher disease. Am J Med Genet A 2003; 120a: 338-344.
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- Merriam-Webster Medical Dictionary. Pneumopathy. Available at: https://www.merriam-webster.com/medical/pneumopathy. Accessed September 2020.
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- The Free Dictionary. Kyphosis. Available at: https://medical-dictionary.thefreedictionary.com/kyphosis%2c. Accessed September 2020.
- Tylki-Szymańska A, Vellodi A, El-Beshlawy A, et al. Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. J Inherit Metab Dis 2010; 33: 339-346.
- Dreborg S, Erikson A, Hagberg B. Gaucher disease--Norrbottnian type. I. General clinical description. Eur J Pediatr 1980; 133: 107-118.
- Sestito S, Filocamo M, Ceravolo F, et al. Norrbottnian clinical variant of Gaucher disease in Southern Italy. J Hum Genet 2017; 62: 507-511.
- The Free Dictionary. Cachexia. Available at: https://medical-dictionary.thefreedictionary.com/Cachexia. Accessed September 2020.
- The Free Dictionary. Ichthyosis. Available at: https://medical-dictionary.thefreedictionary.com/ichthyosis. Accessed September 2020.
- The Free Dictionary. Petechiae. Available at: https://medical-dictionary.thefreedictionary.com/petechiae. Accessed September 2020.
- The Free Dictionary. Ocular apraxia. Available at: https://medical-dictionary.thefreedictionary.com/Ocular+apraxia. Accessed September 2020.