Introduction
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iemann-Pick disease is a form of lipidosis and consists of six subtypes (A to F), that are inherited as autosomal recessive traits and result from allelic mutations within the acid sphingomyelinase (ASM) gene. These patients have a deficient activity of ASM, a lysosomal enzyme that hydrolyzes sphingomyelin (SPM) to phosphorylcholine and ceramid and results in the pathologic accumulation of SPM and other lipids in the monocyte-macrophage system, the primary site of pathology.1, 2
Case Report
A 10-year-old girl was admitted to the hospital because of abdominal pain and gross hematuria for 3 days. She was well until one week prior to admission, when she experienced otitis media and was placed on antibiotics. The parents are first cousins. She has two healthy sisters—3 and 5 years old—and her grandfather has a history of renal stones. On physical examination, vital signs were within normal limits. She was not ill or toxic and had no distress. Severe tenderness on both flanks, suprapubic region, and right upper quadrant of the abdomen were detected on palpation and percussion. Liver was palpable 4 cm below costal margin with a span of 12.5 cm. Spleen was also palpable 5 cm below costal margin.
Lymphadenopathy was not present. Examination of both eyes, including retinoscopy by ophthalmologist, did not show any abnormality. Laboratory findings and imaging studies suggested hemorrhagic cystitis and bilateral pyelonephritis, which were treated with antibiotics. Liver function tests were normal. A diffuse miliary pattern was detected on chest X-ray (Figure 1). The patient had BCG scar and the Mantoux test was negative after 72 and 96 hours. Ultrasonography of the abdomen and pelvis was normal except for hepato-splenomegaly (liver span 12.9 cm, spleen 13 cm).
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B
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Figure 1 (A and B). Chest X-ray showing bilateral diffuse miliary pattern. |
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Chest CT scan with double contrast showed a diffuse miliary pattern in both lungs. Abdominal CT was unremarkable. Bone survey showed hypo-density of bones and delayed bone age, 2.5 years on average. Whole body bone scan was normal.
Bone marrow aspiration and bone marrow and liver biopsies showed characteristic NPD foam cells (Figures 2 and 3) and revealed no findings in favor of metastatic lesions or granulomatous reaction. Polymerase chain reaction (PCR) performed on bone marrow and liver specimens were negative for tuberculosis.
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Figure 2. Bone marrow biopsy showing characteristic Niemann-Pick disease foam cells . |
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Figure 3. Liver biopsy showing characteristic Niemann-Pick disease foam cells. |
Discussion
Type A NPD, with Ashkenazi Jewish predilection, is a fatal disorder of infancy characterized by failure to thrive, hepatosplenomegaly, cherry red maculae, and rapidly progressive neurodegenerative course, presents as psychomotor and neuro-developmental regression, loss of motor function and intellectual capabilities, spasticity, and rigidity that leads to death by 2 – 4 years of age.2 Except for type B, other types of NPD also have a variable neurodegenerative course. Type B disease is panethnic and is characterized by hepatosplenomegaly, hyperlipidemia, and variable survival to adulthood. Cherry red spot or haloes are rarely seen in the maculae of type B patients. They do not have neurodegeneration and have normal IQ and intellectual capabilities. Most cases have decreased pulmonary diffusion due to infiltration of both alveoli and interstitium. Sea blue histiocytes become evident in late childhood. Progression happens by 15 – 20 years of age and may cause life-threatening bronchopneumonia and corpulmonale. In severe forms, liver involvement leads to life-threatening cirrhosis, portal hypertension, ascites, and pancytopenia due to hypersplenism that may require splenectomy. However, this should be avoided as splenectomy leads to the progression of pulmonary involvement.1
Liver dysfunction, pulmonary disease, retinal stigmata, and growth restriction may also be present, but are features that are more variable. Although the clinical manifestations in type A patients are uniform, there is marked variability in the phenotype among type B patients, ranging from severe disease in childhood to patients with milder course. Duchateau et al reported an asymptomatic 22-year-old man with NPD type B diagnosed by bone marrow biopsy and ASM assessment. Pulmonary involvement was discovered incidentally during the evaluation of a dry cough. Chest X-ray and CT scan showed smooth interlobular septa thickening and a subtle ground glass pattern.3 Gonzalez-Reimers et al also reported another asymptomatic 39-year-old male patient in whom pulmonary involvement became evident as the initial diagnosis.4 Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with type B disease; short stature and low weight are significantly correlated with large organ volumes, delayed bone age, and low insulin-like growth factor-1 (IGF-1) levels.
NPD is diagnosed by demonstrating foam cells in bone marrow and liver biopsies, which are characteristic NPD cells and are seen in all types. Type B is the only type with pulmonary involvement characterized by a micronodular or miliary pattern on chest X-ray and CT scan. ASM activity is also reduced in isolated leukocytes or cultured cells and two mutations within the ASM gene may be identified. Many ASM mutations have been identified in unrelated type A and B patients.5, 6 Three of these, R496L, L302P, and FsP330, account for 95% of the mutant alleles in Ashkenazi Jewish type A patients7 and a single mutation, Delta R608, has been reported to occur commonly in patients with type B disease. In contrast to patients with other mutations, individuals homozygous for the Delta R608 mutation had normal height and weight, markedly less hepatosplenomegaly, and bone age delay, as well as normal IGF-1 levels.8, 9
He X et al suggest that high performance liquid
chromatography (HPLC), using plasma instead of leukocytes, is a very reliable
and highly sensitive technique to determine ASM activity and that plasma is a
very reliable and simple source for the accurate diagnosis of NPD patients and
carriers based on ASM activity.10 Our patient showed similar
findings as in the literature. Genetic studies or ASM activity was not
performed. So far, there is no specific treatment for NPD type B nor for the
pulmonary involvement. Whole-lung lavage may be a potentially useful modality
of treatment for patients with pulmonary involvement.11 Prenatal
diagnosis of NPD type A and B is routinely accomplished by sphingomyelinase
assay.12 The only effective method for prevention of disease appears
to be the identification of heterozygotic
individuals and the prevention of marriage of such individuals with each other.
Acknowledgment
We thank Ms. M. Khadem-Hosseini for her diligent typewriting.
References
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2 Wasserstein MP, Larkin AE, Glass RB, Schuchman EH, Desnick RJ, McGovern MM. Growth restriction in children with type B Niemann-Pick disease. J Pediatr. 2003; 142: 424 – 428.
3 Duchateau F, Dechambre S, Coche E. Imaging of pulmonary manifestations in subtype B of Niemann-Pick disease. Br J Radiol. 2001; 74: 1059 – 1061.
4 Gonzalez-Reimers E, Sanchez-Perez MJ, Bonilla-Arjona A, et al. Pulmonary involvement in an adult male affected by type B Niemann-Pick disease. Br J Radiol. 2003; 76: 838 – 840.
5 Levran O, Desnick RJ, Schuchman EH. Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients. Blood. 1992; 80: 2081 – 2087.
6 Schuchman EH, Miranda SR. Niemann-Pick disease: mutation update, genotype/phenotype correlations, and prospects for genetic testing. Genet Test. 1997; 1: 13 – 19.
7 Li L, Caggana M, Robinowitz J, Shabeer J, Desnick RJ, Eng CM. Prenatal screening in the Ashkenazi Jewish population: a pilot program of multiple option testing for five disorders. Am J Hum Genet. 1997; 61(suppl): 24.
8 Levran O, Desnick RJ, Schuchman EH. Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients. J Clin Invest. 1991; 88: 806 – 810.
9 Vanier MT, Ferlinz K, Rousson R, et al. Deletion of arginine (608) in acid sphingomyelinase is the prevalent mutation among Niemann-Pick disease type B patients from northern Africa. Hum Genet. 1993; 92: 325 – 330.
10 He X, Chen F, Dagan A, Gatt S, Schuchman EH. A fluorescence-based, high-performance liquid chromatographic assay to determine acid sphingo-myelinase activity and diagnose types A and B Niemann-Pick disease. Anal Biochem. 2003; 314: 116 – 120.
11 Nicholson AG, Wells AU, Hooper J, Hansell DM, Kelleher A, Morgan C. Successful treatment of endogenous lipoid pneumonia due to Niemann-Pick type B disease with whole-lung lavage. Am J Respir Crit Care Med. 2002; 165: 128 – 131.
12 Vanier MT. Prenatal diagnosis of Niemann-Pick diseases types A, B, and C. Prenat Diagn. 2002; 22: 630 – 632.