Two Siblings With Interstitial Lung Disease

Abstract

A 52-year-old white woman and her 61-year-old white brother separately presented with gradually worsening dyspnea on exertion and cough, and evidence of interstitial lung disease on chest imaging.

Case Presentations

The woman presented with a several-year history of progressive dyspnea and evidence of interstitial lung disease (ILD) on imaging. She had owned pet cockatiels 3 years prior to the start of her symptoms and had a history of exposure to a moldy environment at work. She had no history of smoking or other relevant respiratory exposures, and had no symptoms to suggest a connective tissue disease or exposure to medications associated with ILD. The patient had a history of hormonally inactive bilateral adrenal hyperplasia and mild splenomegaly, both discovered incidentally on imaging, as well as osteopenia and several foot fractures after minor trauma. Her physical examination was unrevealing. Results of the patient’s pulmonary function tests revealed an FVC of 3.09 L (94% of predicted), an FEV₁ of 2.59 L (99% of predicted), an FEV₁ to FVC ratio of 84%, total lung capacity of 4.62 L (93% of predicted), reserve volume of 1.46 L (88% of predicted), and diffusion capacity for carbon monoxide of 11.31 mL/min/mm Hg (49% of predicted), which we interpreted as normal lung volumes with moderately impaired gas transfer.

The woman's brother presented with 1 year of progressive dyspnea on exertion and a cough productive of scant clear sputum. His medical history was notable for two spontaneous pneumothoraces at 29 years of age (for which he underwent doxycycline pleurodesis) and idiopathic thrombocytopenia. He had never smoked cigarettes or used recreational substances but had a history of exposure to asbestos in his 20s during construction work. As with his sister, he had no history that would suggest a connective tissue disease or exposure to medications associated with an ILD. On examination, the patient had crackles over both lower lobes and hypoxia to 84% after walking 450 m on room air. His laboratory studies were notable for a platelet count of 140,000/μL but otherwise normal blood counts. Results of the patient’s pulmonary function tests revealed an FVC of 3.77 L (89% of predicted), an FEV₁ of 2.66 L (83% of predicted), an FEV₁ to FVC ratio of 71%, total lung capacity of 5.79 (88% of predicted), reserve volume of 1.88 L (80% of predicted), and diffusion capacity for carbon monoxide of 11.31 mL/min/mm Hg (39% of predicted). Thus, similar to his sister, the patient had normal lung volumes with moderately impaired gas transfer. Results of tests for plasma α₁-antitrypsin level were normal. Both siblings had otherwise normal laboratory studies with no serologic evidence to support autoimmune diseases.

High-resolution chest CT imaging of the female sibling (Fig 1A) showed interlobular septal thickening bilaterally with a craniocaudal gradient, with no honeycombing, ground-glass opacities, nodules, bronchiectasis, lymphadenopathy, or axial gradient. High-resolution chest CT imaging of the male sibling revealed upper lobe-predominant paraseptal emphysema and basilar-predominant reticulation, honeycombing, ground-glass opacities, and traction bronchiectasis, with no nodules, or lymphadenopathy (Fig 1B). In addition, abdominal imaging showed bilateral adrenal enlargement, splenomegaly, and coarse hepatic echotexture.

Figure 1.

Imaging and histologic findings of the (A, C) female and (B, D) male siblings. A, B, representative high-resolution chest CT imaging of upper lobes, level of the carina, and lower lobes (from left to right) of the right lung in both subjects. C, D, hematoxylin and eosin stains of lung histopathology; original magnifications were 100× (main panels) and 400× (insets). The text provides a narrative description of the findings.

Lung histopathologic analyses in both siblings revealed marked accumulation of histiocytes containing foamy material within the alveoli (Fig 1C). In the female subject, there was mild fibrosis-associated infiltration of lymphocytes in the interstitium and a small bone marrow pulmonary embolus (not shown). Lung histopathologic analyses from the male sibling showed a similar pattern but with more prominent fibrotic areas associated with a chronic inflammatory infiltrate (Fig 1D).

What is the diagnosis?

Diagnosis: Acid sphingomyelinase deficiency (Niemann-Pick disease type B)

The histologic findings raised the possibility of lysosomal storage diseases. Serum levels of β-glucosidase were normal, excluding the diagnosis of Gaucher disease. Circulating leukocytes from both patients revealed low sphingomyelinase activity, and genetic test results revealed homozygosity for the R610del mutation of the SMPD1 gene, confirming the diagnosis of acid sphingomyelinase deficiency (Niemann-Pick disease type B).

Discussion

Clinical Discussion

The etiology of ILDs can be understood as the intersection of environmental factors in genetically predisposed individuals. The traditional diagnostic categories of these diseases, codified in consensus statements, are focused on identifying environmental factors (eg, autoimmunity, inhalational exposures) and patterns of radiographic and histologic findings.^{1, 2} More recently, several lines of data have provided strong evidence regarding the role of genetic predisposition in ILDs. In this context, familial ILDs, defined as diffuse parenchymal lung diseases affecting ≥ 2 first-degree relatives, are reported in 2% to 20% of series from different centers. Because clinically evident ILDs are uncommon in unselected populations, these familial clusters represent a very high likelihood of a genetic predisposition. Studies of these clusters, as well as broader genome-wide associated studies, have identified multiple genetic variants that predispose to ILD, many of which relate to the biology of mucin and surfactant proteins, senescence of alveolar epithelial cells, and lung immune mechanisms (Table 1).^{3, 4} Importantly, a given mutation can manifest with different radiographic and histologic patterns of ILD among members of a single family; for example, as hypersensitivity pneumonitis in one member and idiopathic pulmonary fibrosis in another.⁵ Thus, phenotypic and diagnostic disparity of ILDs within a kindred should not dissuade clinicians from searching for an underlying genetic predisposition.

Table 1.

Summary of Familial ILDs

Category	Biologic Process	Genes	Transmission	Other Features
Common variants conferring small risk	Mucin	MUC5B, MUC2	Polygenic	MUC5B is the most commonly identified genetic contributor to ILD and is associated with less severe disease
	Immunity	IL1RN, IL8, TLR3, HLA-DRB1, TOLLIP, TGFB1, TMEM173, GATA2, ELMOD2, MICA	Polygenic
Rare variants conferring large risk	Telomerase	TERT, RTEL1, PARN, TERC, DKC1, TINF2, NAF1	Autosomal dominant, except DKC1 (X-linked)	Macrocytic anemia, thrombocytopenia, and other hematologic diseases; chronic liver disease; premature graying of hair
	Surfactant	SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3	Autosomal dominant, except SFTPB and ABCA3 (autosomal recessive)
	ILD as part of multisystem syndromes	HPS1 (Hermansky-Pudlak)	Autosomal recessive	Albinism, nystagmus, platelet dysfunction
		NF1 (Neurofibromatosis type 1)	Autosomal dominant	CNS and peripheral nerve tumors
		GBA (Gaucher disease)	Autosomal recessive	Lysosome storage disease
		SMPD1 (Niemann-Pick type B)	Autosomal recessive	Lysosome storage disease

The genetic variants that predispose to ILD can be considered on a spectrum: at one extreme, relatively common genetic variants confer a small risk of ILD, whereas at the other, rare variants strongly predispose to disease.^{3, 4} In this construct, ILDs that occur as part of monogenic syndromes represent the extreme: they are caused by very rare genetic events that nearly always result in an ILD. Such monogenic illnesses include dyskeratosis congenita, Hermansky-Pudlak syndrome, neurofibromatosis type 1, and lysosomal storage diseases.⁶

The lysosomal storage diseases are autosomal recessive inborn errors of metabolism that result from impaired function of individual lysosomal proteins and the accumulation of substrate, producing protean patterns of organ dysfunction. The lysosomal storage disorders that present as ILD in adults are Gaucher disease, due to deficiency of β-glucocerebrosidase, and Niemann-Pick disease type B. Symptoms and radiographic findings of lung involvement in these illnesses are not specific, and the clinical clues to the diagnosis reside in subtle evidence of disease outside the lungs.

Niemann-Pick disease types A and B are caused by mutations in the SMPD1 gene, encoding the enzyme acid sphingomyelinase. Although the nomenclature implies a binary phenotype, the type A and B diseases should be considered as points along a spectrum of phenotypic severity resulting from the deficiency of the enzyme. Type A disease, the most severe manifestation, presents in infancy as a severe and progressive neurologic disease associated with hepatosplenomegaly and ILD, causing death in early childhood. In contrast, type B disease, in which acid sphingomyelinase retains some of its enzymatic activity, results in a milder phenotype without neuropathic manifestations that presents in adolescence or adulthood. Niemann-Pick disease type C shares the disease eponym but is biologically distinct from types A and B; it is due to mutations in NPC1 or NPC2 genes and results in impaired intracellular lipid homeostasis rather than sphingomyelin accumulation. It can present at any age with progressive neuropsychiatric disease associated with liver disease, splenomegaly, and ILD.

Therapeutic options of acid sphingomyelinase-deficient Niemann-Pick disease are currently limited to supportive care. IV replacement of recombinant acid sphingomyelinase, analogous to the established therapy of Gaucher disease, has been effective in the mouse model of acid sphingomyelinase deficiency and is currently in Phase II to III trials⁷; this therapy has the potential to transform the management of acid sphingomyelinase-deficient Niemann-Pick disease.

Radiologic Discussion

Both the severity and pattern of ILD in Niemann-Pick disease type B are highly variable, even within families. Lower lobe-predominant reticulation, honeycombing, and ground-glass opacities are most common. Other described radiographic presentations include interlobular septal thickening and emphysema in the absence of smoking, as seen in the study patients, as well as centrilobular nodules and parenchymal cysts.⁸ Extrapulmonary manifestations most commonly include hepatomegaly, splenomegaly, and hematologic derangements, but can include bone fractures, GI disorders, and fatigue. Adrenal disease, a feature in both of the study patients, is infrequently described in the literature.

Pathologic Discussion

The histologic hallmark of types A and B disease are the accumulation of engorged lipid-laden histiocytes, the so-called Niemann-Pick cells, in affected tissues, including lung, liver, spleen, and lymphatics (Figs 1C-1D insets).⁹ Lung lipid-laden macrophages can be encountered in chronic aspiration and lipoid pneumonia, fat embolism to the lungs, recurrent pneumonia, cystic fibrosis, and in the context of amiodarone therapy.^{10, 11} Apart from Niemann-Pick disease, the differential diagnosis of multisystem accumulation of lipid-laden macrophages includes Gaucher disease and Erdheim-Chester disease. Gaucher disease has a clinical presentation similar to Niemann-Pick disease type B, but the histiocyte cytoplasm stains with a pattern of fine, irregular eosinophilic lines described as “crumpled tissue paper” that were not observed in the study patients. Erdheim-Chester disease is an aggressive illness characterized by multisystem infiltration of lipid-laden histiocytes associated with granulomatous inflammation and fibrosis, features absent in the study patients. Definitive diagnosis of Niemann-Pick disease type B requires the detection of low sphingomyelinase activity levels in skin fibroblasts or blood leukocytes, followed by sequencing the SMPD1 gene in the index case, to identify the responsible mutation.¹² The most common mutation, R610del, was the cause of disease in the study patients and results in impaired proteolytic maturation of acid sphingomyelinase, which nevertheless retains residual activity.¹³

Conclusions

Niemann-Pick disease type B is an uncommon genetic illness that presents as an ILD in adulthood. The clues to the diagnosis are subtle evidence of extrapulmonary disease and extensive accumulation of lipid-laden macrophages at biopsy.