A 5-year-old boy was brought for evaluation of ongoing thrombocytopenia before undergoing adenotonsillectomy for obstructive sleep apnea. The child had been given a diagnosis of "growing pains" after frequent evaluation for leg pain over the past 2 years. He also exhibited easy bruising and frequent epistaxis without other avenues of blood loss. There was no family history of a blood disorder, except for his maternal grandfather who had easy bruising of undetermined cause.
The child was born to Ashkenazi Jewish parents after a pregnancy complicated by 3 maternal transfusions for iron deficiency anemia that resolved postpartum; the delivery and neonatal stay were unremarkable.
As an infant, he had extensive eczema, abdominal pain, diarrhea, and poor weight gain attributed to allergic enteropathy; these conditions responded well to an elemental formula. As a toddler, he had 9 hospitalizations for asthma that became less frequent after age 2 years through standard controller therapy. His development was appropriate for age, and he had no history of regression.
Physical examination revealed a well-nourished boy with weight at the 50th percentile and height at the 16th percentile; vital signs were normal. Significant findings included coarse facial appearance; prominent forehead; multiple ecchymoses on the trunk and extremities (none on the mucous membranes); a firm, nontender liver about 5 cm below the costal margin; and a spleen 8 cm below the costal margin. There was no audible bruit over the liver, spleen, or abdomen; no pallor, jaundice, hemangioma, lymphadenopathy, rash, or bony tenderness; and no abnormalities of the genitalia or fundi.
During the 2 years of monitoring for asthma and leg pain, the white blood cell count ranged from 2.4 to 7.3 x 109/µL and the platelet count from 108 to 160 x 109/µL; the differential and peripheral smear were normal. Red cell indices showed a mean corpuscular volume of 81.4 to 87 fL, mean corpuscular hemoglobin concentration of 33.1 to 35.8 g/dL, and red cell distribution width of 12.7% to 14.8%, with a reticulocyte count of 0.7%. A coagulation profile, iron studies, electrolyte levels, liver function test results, lipid profile, sweat chloride test results, C-reactive protein level, erythrocyte sedimentation rate (ESR), and immunoglobulin levels were all normal. Serological titers of Epstein-Barr virus (EBV), HIV, Cytomegalovirus (CMV), hepatitis C virus (HCV), and mycoplasma were not elevated. CT scans of the chest and abdomen were normal, and chest radiographs revealed occasional infiltrates associated with asthma exacerbations.
TO WHAT DIAGNOSIS DO THESE FINDINGS POINT— AND WHAT ARE THE TREATMENT
ANSWER: GAUCHER DISEASE TYPE 1
The differential diagnosis for hepatosplenomegaly is extensive and must be refined based on the history and physical examination. This patient’s Ashkenazi Jewish background, "growing pains," marginal leukopenia, and bruising suggested a condition that diminished production of cellular elements in the marrow, consistent with the low reticulocyte count. Aplastic anemia would not explain the splenomegaly. In addition, there was no evidence of hepatocellular or cardiovascular disease, common immunological disturbances, chronic infections (normal titers for CMV, EBV, HCV, and HIV), or inflammatory conditions (normal antinuclear antibody and rheumatoid factor). The duration of symptoms, somewhat short stature, and normal laboratory values ruled out most of the causes of hepatosplenomegaly. Malignancy was unlikely because of the insidious onset of symptoms and the absence of blasts or abnormal cells in the peripheral smear. High in the clinical differential were nonmalignant infiltrative storage diseases that involve carbohydrates, gangliosides, or glycosaminoglycans.
Possible diagnoses included:
- Niemann-Pick disease (NPD) type A.
- Wolman disease.
- Oligosaccharidoses, such as fucosidosis.
- Mucopolysaccharidoses (MPS), such as Hunter disease.
- Glycogen storage diseases, such as Anderson disease type IV.
Most of these possibilities were excluded by the lack of a cherry-red spot (NPD), neurodegeneration (MPS, Wolman disease, oligosaccharidoses), and cirrhosis (Anderson disease).
The patient was referred for genetic consultation and underwent a skin biopsy for fibroblast lysosomal enzyme studies. The results revealed a lack of acid β-glucosidase activity, consistent with the diagnosis of Gaucher disease (GD). Levels of angiotensin-converting enzyme, a marker secreted by Gaucher cells, were elevated. DNA analysis did not reveal the 4 common mutations found in GD.
INCIDENCE, GENETICS, AND PATHOPHYSIOLOGY
GD is the most common lysosomal storage disorder, with increased incidence among the Ashkenazi Jewish population (carrier frequency 1:17).1 Its worldwide distribution is around 1 in 75,000 births.
GD is inherited as an autosomal recessive disorder caused by deficiency of lysosomal glucocerebrosidase (also known as acid β-glucosidase). More than 100 different mutations have been discovered, including 4 common mutations that account for 95% of GD in Ashkenazi Jews and 70% of GD in non-Jewish populations.2 This limited sensitivity may explain the negative result of DNA analysis in this patient.
In affected patients, the deficiency of glucocerebrosidase leads to accumulation of glucocerebroside and other glycolipids within the lysosomes of macrophages. Macrophages filled with the lipid material are known as Gaucher cells and are a cardinal feature of the disease (Figure). They have a characteristic histological appearance of wrinkled tissue paper. The clinical manifestations of GD result from the accumulation of Gaucher cells in the spleen, liver, bone marrow, and bone.2
CLINICAL AND RADIOLOGICAL FEATURES
GD is a multisystem lipidosis characterized by organomegaly, hematological manifestations, and skeletal involvement. The 3 clinical subtypes of GD are:
- Type 2, the infantile acute neuronopathic form.
- Type 3, the juvenile form, which can involve subsequent insidious neurological dysfunction.
Skeletal manifestations are probably the most disabling aspects of GD. (For a list of features that are helpful in distinguishing benign from serious musculoskeletal conditions, see Malleson and Beauchamp.3) Patients commonly have bone pains, some have bone crises, and up to 20% have impaired mobility.4 Radiological findings include Erlenmeyer flask deformity, osteopenia, osteosclerosis, osteonecrosis, fractures, and bone marrow infiltration.4 Often, bone pains are inaccurately labeled as "growing pains." The prevalence of musculoskeletal pain in children ranges from 5% to 30%; growing pains account for 8% of cases.5,6
A child with bone pains should have a thorough history and physical examination followed by a complete blood cell count, ESR, and radiographs of the involved part to evaluate possible infective, inflammatory, and malignant conditions.
HEMATOLOGICAL MANIFESTATIONS
Anemia and/or thrombocytopenia are nearly universal findings in symptomatic patients with GD.1 Leukopenia is also seen, but much less frequently. The basic cause of anemia and/or thrombocytopenia in GD is hypersplenism; however, bone marrow infiltration by Gaucher cells could also cause pancytopenia. If a patient with GD (without splenectomy) presents with significant anemia but a normal or near-normal platelet count, then another cause is probable. The spleen is proportionately more enlarged than the liver in mild or severe GD, and disproportionate enlargement of the liver relative to the spleen in GD mandates evaluation for other causes of hepatomegaly. One study reported no correlation between degree of splenomegaly and signs of hypersplenism.7 Defective platelet function as well as thrombocytopenia causes bleeding tendency in GD.
BIOCHEMICAL MARKERS
Traditional markers for GD include increased levels of angiotensin-converting enzyme and serum acid phosphatase; in addition, the enzyme chitotriosidase can be assayed to quantify the degree of macrophage activation.8 The chemokine CCL18 is a valuable marker, but assays are not readily available.9 However, the newly identified human chemokine PARC (pulmonary and activation-regulated chemokine) is a reliable biomarker for quantitative evaluation and monitoring of GD.10
MANAGEMENT
Enzyme replacement therapy (ERT) with imiglucerase has considerably improved the management of GD by reversing the organomegaly and hematological abnormalities. Treated patients have more normal growth and fewer skeletal manifestations (although some patients still need medication for bone pain, and a few patients need splenectomy).11 ERT is now the treatment of choice for the non-neuronopathic form of GD.
More recently, an enzyme inhibitor (miglustat) that decreases the production of the substrate was introduced. This substrate reduction therapy has the advantage of being administered orally.12
Future therapies include chemical chaperones that correct protein misfolding or abnormal protein trafficking by binding to glucosidase enzyme, and, in the distant future, gene therapy.
PEARLS FOR PEDIATRICIANS
- Ancestry figures prominently in the evaluation of infiltrative conditions.
- Do not underestimate leg pains, especially when associated with organomegaly or hematological changes.
- Consider Gaucher disease in the differential diagnosis of any child with thrombocytopenia, hepatosplenomegaly, and bone pain, especially if the child is of Jewish descent.