Because Gaucher disease is inherited as an autosomal recessive trait, the proband is commonly the first affected individual in the family.
Type 1 Gaucher disease
At onset, patients with type 1 Gaucher disease commonly present with painless splenomegaly, anemia, or thrombocytopenia. They may also have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds, bruising, or both.
In symptomatic patients, splenomegaly is progressive and can become massive. Children with massive splenomegaly may be short in stature because of the energy expenditure required by the enlarged organ.
Most patients with type 1 Gaucher disease have radiologic evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal femur, which is an early skeletal change. Clinically apparent bony involvement, which occurs in more than 20% of patients with Gaucher disease, can present as bone pain or pathologic fractures. In patients with symptomatic bone disease, lytic lesions can develop in the long bones, ribs, and pelvis, and osteosclerosis or osteopenia may be evident at an early age. Bone crises with severe pain and swelling can occur in individuals with type 1 Gaucher disease and are frequently mistaken for synovitis or osteomyelitis until other symptoms become apparent.
Occasional patients with type 1 Gaucher disease develop pulmonary involvement, parkinsonism, multiple myeloma, or portal hypertension.
Patients with milder presentations of Gaucher disease are diagnosed later in life during evaluations for hematologic or skeletal problems or are found to have splenomegaly during routine examinations. Some patients are asymptomatic, and a diagnosis is made incidentally after evaluation for other medical problems.
Type 2 Gaucher disease
Type 2 disease is rare and is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life.
Patients with this type may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly. Disruption of the epidermal layers of the skin, observed on skin biopsy findings, may manifest before the onset of neurological symptoms, but this may not always be clinically apparent.
Failure to thrive, swallowing abnormalities, oculomotor apraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease.
The progressive psychomotor degeneration and brain stem involvement leads to death, usually caused by aspiration and respiratory compromise.
A severe neonatal form can present in utero or perinatally with hydrops fetalis, congenital ichthyosis, or both.
Type 3 Gaucher disease
This form of Gaucher disease widely varies and can present in infancy or childhood.
In addition to organomegaly and bony involvement, individuals with type 3 disease have neurologic involvement. However, in some patients, visceral involvement can be extreme.
The slowing of the horizontal saccades, an oculomotor finding, is often the sole neurologic manifestation. Some patients develop myoclonic epilepsy, exhibit learning disabilities, or develop dementia.
One rare subgroup of patients with type 3 Gaucher disease present with oculomotor findings, calcifications of the mitral and aortic valves, and corneal opacities. The phenotype is associated with homozygosity for the D409H mutant allele.
Another rare subgroup of patients with type 3 Gaucher disease is a genetic isolate from the Norrbottnian region of Sweden, homozygous for the L444P mutation. These individuals present in early childhood with visceral and skeletal involvement and oculomotor abnormalities and may develop seizures, cognitive disabilities, and dementia.
Some specific learning disabilities are common in children with type 3 Gaucher disease.
Type 2-3 intermediate Gaucher disease
Some patients present with severe neurovisceral manifestations in infancy or early childhood but survive past the second year of life, with death occurring in mid childhood (age 3-7 y). These patients are considered to fall within the phenotypic continuum between types 2 and 3.
Physical examination findings in type 1 disease usually include hepatosplenomegaly. Splenomegaly may be dramatic, with the splenic tip extending to the pelvis. Bruising along the anterior aspect of the shins and petechiae may be evident in patients with thrombocytopenia. Short stature and wasting are occasionally found in patients with massive organomegaly. In addition to these findings, patients with types 2 and 3 disease may have developmental delay, oculomotor abnormalities, and abnormal neurologic examinations.
Patients present with highly variable degrees of splenomegaly, with a size increase that ranges from 5-fold to more than 80-fold when adjusted for body weight (average spleen is approximately 0.2% of body weight). The absolute size of the spleen has been known to vary between 300 g to more than 10 kg, accounting for up to 25% of body weight.
Enlargement of the spleen appears to be most rapid in children with Gaucher disease. Rapid enlargement of the spleen in an adult with the disease should prompt suspicion of an associated disorder that may increase glycolipid turnover, such as hematologic malignancy, immune thrombocytopenia, or autoimmune hemolytic anemia.
Nodules on the surface of the spleen may represent regions of extramedullary hematopoiesis, collections of Gaucher cells, or resolving infarcts. Evidence of old infarcts is common in spleens that are enlarged more than 20-fold. Most splenic infarcts are asymptomatic, but subcapsular infarcts can present as localized abdominal pain. Intracapsular bleeding may also occur.
Hepatomegaly occurs in more than 50% of patients with type 1 Gaucher disease. In a series of 88 patients, liver volumes ranged from within the reference range to 8.7-fold more than the predicted normal weight (normal is 2.5% of body weight), with a median of 1.75%.
Hepatic glucocerebroside levels are elevated from 23-fold to 389-fold above the reference range.
The massively enlarged liver is usually firm to palpation, with an irregular surface. Cirrhosis and portal hypertension are uncommon but occur in a small number of patients with Gaucher disease. Compression of the sinusoids by Gaucher cells can accentuate portal hypertension.
Death from variceal bleeding has been reported, especially prior to enzyme replacement therapy. Minor elevations of liver enzyme levels are common, even in patients who are mildly affected, but the presence of jaundice or impaired hepatocellular synthetic function is a poor prognostic indicator. Jaundice in a patient with Gaucher disease is usually a result of infection, the development of chronic hepatitis, or, rarely, hepatic decompensation in the late stages. The presence of unconjugated hyperbilirubinemia is more suggestive of hemolysis.
Elevated levels of serum ferritin are occasionally found in individuals with Gaucher disease; however, transferrin saturation is usually normal. Glycolipid-laden Gaucher cells are evident in the sinusoids on liver biopsy findings, but the hepatocytes do not manifest overt glycolipid storage, presumably because of biliary excretion of glucocerebroside and the fact that exogenous glycolipid turnover is handled by the mononuclear phagocytes. Sparing of hepatocytes is consistent with the low incidence of liver failure in individuals with Gaucher disease.
Skeletal manifestations of Gaucher disease vary, ranging from asymptomatic Erlenmeyer flask deformity of the distal femora to pathologic fractures, vertebral collapse, and acute bone crises that can be confused with acute osteomyelitis.
Painful bone crises result from episodes of bone infarction, leading to osteosclerosis analogous to that occurring in sickle cell disease.
In children with Gaucher disease, acute hip lesions can be misinterpreted as Legg-Calvé-Perthes disease, and avascular necrosis of the hips is a common complication in individuals of all ages.
Hematologic manifestations of Gaucher disease include cytopenia and acquired coagulopathy due to factor XI deficiency. However, genetic factor XI deficiency is common in individuals of Ashkenazi descent and may be present in some patients with Gaucher disease.
Cytopenia that develops in patients who have undergone splenectomy reflects advanced marrow infiltration by Gaucher cells. Bone marrow failure and myelofibrosis occur in a small number of these patients.
Numerous immunologic abnormalities are common in individuals with Gaucher disease, including hypergammaglobulinemia, T-lymphocyte deficiency in the spleen, and impaired neutrophil chemotaxis.
All three forms of Gaucher disease are caused by glucocerebrosidase activity deficiency due to mutations in GBA1, the structural gene that encodes the enzyme. Widespread accumulation of glucosylceramide-laden macrophages results from the enzyme deficiency.
More than 300 different mutant GBA1 alleles have been identified in patients with Gaucher disease. Screening for the 6 most common GBA1 mutations in patients of Ashkenazi Jewish descent has enabled the identification of 90%-95% of the mutant alleles in this population, but a large number of other mutations have been described in other populations, making screening impractical.
Some mutations derive from recombination with the glucocerebrosidase pseudogene, a sequence 15 kb downstream that shares 96% sequence homology to glucocerebrosidase. Complex alleles with regions of pseudogene sequence, in which simple polymerase chain reaction (PCR)–based mutation detection screening is inadequate, have been identified in some patients.
Genotype and phenotype correlations have been noted in some specific Gaucher presentations. For example, patients with type 1 Gaucher disease who are homozygous for the N370S mutation tend to have a later onset and a relatively mild course, and patients with type 3 Gaucher disease who are homozygous for the D409H mutation exhibit a rare phenotype that involves cardiac calcifications, oculomotor abnormalities, and corneal opacities. However, clinical presentation in patients with Gaucher disease widely varies and frequently cannot be fully explained by the underlying mutations because severity can vary even among siblings who have identical genotypes.
Similarly, the amount of residual enzymatic activity does not accurately predict disease subtype and severity, with the exception that many of the mutations identified in patients with severe type 2 Gaucher disease express little, if any, enzymatic activity in vitro. These are frequently nonsense, frame-shift, or recombinant alleles that cannot form a complete protein and are essentially null alleles.
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