Correct!
2. Bone marrow aspiration
Given the interlobular septal thickening, bronchoscopy with bronchoalveolar lavage and transbronchial biopsy could obtain diagnostic tissue, assuming the thickened septae contain abnormalities that would allow a specific diagnosis. However, as noted previously, the historical, physical examination, and laboratory features suggest a process infiltrating the bone marrow, and therefore examination of the bone marrow may have a higher likelihood of providing the actual diagnosis. Much like bronchoscopy with bronchoalveolar lavage and transbronchial biopsy, surgical lung biopsy would be capable of determining the cause of the interlobular septal infiltration, but is needlessly invasive when bone marrow aspiration may provide similar, or even superior, information. 68Ga citrate scanning would not provide diagnostically useful or management-altering information in this case. Pulmonary tracer at 68Ga citrate scanning uptake could represent either active pulmonary inflammation or neoplastic infiltration, but a pulmonary abnormality is already known; in contrast, the absence of tracer uptake within the lung parenchyma would not alleviate the need to establish a tissue diagnosis. Percutaneous transthoracic needle biopsy is typically employed for focal pulmonary abnormalities, not multifocal or diffuse interstitial abnormalities; the latter are difficult to target with and typically not amenable to percutaneous techniques.
Bone marrow aspiration showed the presence of lipid-laden, foamy cells (Niemann-Pick cells). Because these cells, while characteristic of Niemann-Pick disease, are not diagnostic of that disorder (they can also be seen in cholesterol ester storage disease, Wolman disease, lipoprotein lipase deficiency, and, occasionally, GM1 gangliosidosis type 2), further measurement of acid sphingomyelinase activity in peripheral white blood cells was performed and was found to be decreased to ˂10% normal activity. Genetic analysis showed the deltaR608 mutation affecting the SMPD1 gene, located on bands 11p15.1-p15.4, which normally codes for the lysosomal enzyme acid sphingomyelinase. These findings established the diagnosis of Niemann-Pick disease, type B.
Diagnosis: Niemann-Pick disease, type B.
Discussion
Niemann-Pick disease (NPD) is a rare, autosomal recessive lysosomal storage disorder due to a deficiency of acid sphingomyelinase, which results in the accumulation of sphingomyelin within the monocyte-macrophage system. Sphingomyelinase is a lysosomal enzyme encoded by the SMPD1 gene located on bands 11p15.1-p15.4. This accumulation produces a foam cell- the Pick cell- in affected tissues, which is the characteristic histopathologic finding of this disorder.
NPD is often divided into two distinct subtypes based on phenotype- NPD-A and NPD-B. An “NPD-C” is also described, but is a genetically distinct abnormality that results from defective intracellular handling of cholesterol, resulting in a secondary accumulation of glycosphingolipids. NPD-A often affects patients of Ashkenazi Jewish decent, although NPD may affect any race, and usually manifests in infancy as a severe neurodegenerative disorder characterized by failure to thrive, psychomotor deficiency, cherry-red macula, hepatosplenomegaly, with death usually resulting by the age of 3 years.
NPD-B may affect persons of any race, but often is seen in patients from North Africa, Saudi Arabia, and Turkey. NPD-B presents with a spectrum of severity related to the amount of residual acid sphingomyelinase activity, and is characterized by hepatosplenomegaly, thrombocytopenia, dyslipidemia, and interstitial lung disease; neurological involvement is usually absent or minimal. Pulmonary involvement in NPD-B is common and results from the interstitial accumulation of lipid-laden macrophages, notably within the alveolar septae, bronchial walls, and pleura. This accumulation results in a restrictive ventilatory abnormality which may range from practically asymptomatic to respiratory failure. On chest radiography, the interstitial infiltration produces a linear or reticular pattern that reflects the presence of thickened interlobular septae, sometimes accompanied by vague areas of increased attenuation and small, possibly calcified lung nodules. At thoracic CT, these abnormalities may produce a “crazy paving” pattern.” The interstitial abnormalities are typically more pronounced in the bases. Additional imaging findings in patients with NPD-B include coronary arterial calcification, reflecting premature coronary arterial atherosclerosis (which may be a notable finding given the relatively young age of affected patients), hepatosplenomegaly, osteopenia / osteoporosis, delayed skeletal maturation, and adrenal lesions. Recurrent pneumonias and cirrhosis with features of portal hypertension have been described.
The diagnosis of NPD is usually made by demonstrating reduced acid sphingomyelinase activity within peripheral leukocytes of cultured fibroblasts, or through the detection of characteristic mutations in the acid sphingomyelinase gene. Bone marrow aspiration may demonstrate the characteristic, lipid-laden foamy Niemann-Pick cell.
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