Fig. 28.4  Surgical lung biopsy in a 33-year-old woman with type-B Niemann-Pick disease. At low magni cation, alveoli are lled with pale-staining macrophages (hematoxylin-eosin, 20×). (Slide courtesy Alberto Cavazza, MD)

most severe form of FD occurs in males and manifests with neuropathic pain in the distal extremities, corneal and lenticular opacities, and cutaneous vessel ectasia, while death usually results from cardiac or cerebrovascular disease or renal failure. The diagnosis requires the demonstration of de cient GLA activity or increased levels of urinary globotriaosylceramide. Pulmonary involvement generally manifests as progressive bronchial narrowing—leading to bronchial obstruction—secondary to the accumulation of glycosphingolipids within the bronchial cells [73–75]. Pulmonary disease may also manifest as pulmonary brosis [76] or diffuse alveolar hemorrhage associated with renal failure (pulmonary-renal syndrome) [73].

Enzyme replacement therapy (ERT) with recombinant α-galactosidase A may provide clinical bene ts to several outcomes and organ systems [77]. Recently, Germain and colleagues conducted a systematic review of original articles on ERT for the treatment of FD in adult patients [78]. ERT was associated with improved glomerular ltration rate, cardiac wall thickness, left ventricular mass, and quality of life in males (166 publications including 36 clinical trials) and with improvement in cardiac parameters, quality of life, and plasma and urinary globotriaosylceramide levels in females (67 publications, including 6 clinical trials) [78]. Conversely, the ef - cacy of ERT on pulmonary involvement remains to be proven [79]. New therapies for FD are being developed, including chaperones for patients with amenable GLA mutations.

Fig. 28.5  Higher magni cation showing the nely vacuolated cytoplasm of the intra-alveolar macrophages (hematoxylin-eosin, 200×). (Slide courtesy Alberto Cavazza, MD)

de cient lysosomal α-galactosidase A activity secondary to mutations in the gene encoding α-galactosidase A (GLA). FD is characterized by lysosomal accumulation of glycosphin- golipids—mainly globotriaosylceramide and, to a lesser extent, galactosylceramide, within virtually all cell types, although vascular endothelial cells and smooth muscle cells are the main targets of the disease [71]. The disease generally manifests in childhood with a median age of survival of 55 years, although patients with the milder disease can survive to older ages and be diagnosed incidentally because of cardiac involvement causing left ventricular hypertrophy, arrhythmias, or myocardial brosis [72]. The classic and

Lysinuric Protein Intolerance

Lysinuric protein intolerance (LPI) is an autosomal recessive disorder characterized by defective transport and excessive urinary loss of proteins such as lysine, arginine, and ornithine [80]. LPI is caused by mutations in the solute carrier family 7A member 7 (SLC7A7) gene, which encodes y+ LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family [81]. LPI is found worldwide but its prevalence is higher in Finland and Japan (approximately 1/60,000 newborns) [82]. Affected individuals manifest failure to thrive, growth retardation, hepatosplenomegaly, hypertonicity, and osteoporosis. The diagnosis, which requires plasma and urinary amino acid assays demonstrating low plasma concentration and increased urinary excretion of lysine, arginine, and ornithine, is con rmed by the identi cation of pathogenic variants within SLC7A7. Pulmonary involvement ranges from asymptomatic interstitial abnormalities to acute and life-­threatening acute respiratory failure secondary to PAP [83]. In a recent study, lung disease was reported in 10/16 LPI patients during follow-up [84]. Notably, all ten patients had PAP and six of

them died from respiratory failure. In PAP cases, typically, chest radiograph reveals diffuse alveolar in ltrates more prominent in the perihilar regions (“butterfy” or “bat wing” appearance), whereas HRCT shows a characteristic pattern of ground glass opacity superimposed over thickened interlobular and intralobular septa forming irregular polygonal shapes (“crazy paving”). Similar to other forms of PAP, the treatment of choice is whole-lung lavage [85], although the inhaled human recombinant granulocyte-macrophage colony-­stimulating factor (GM-CSF) sargramostim might be bene cial in a subset of LPI patients with complicated PAP not responding to maximal conventional therapy [86].

Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disorder with variable penetrance, characterized by familial hypercalcemia with hypocalciuria, granulocyte dysfunction, and interstitial lung disease (ILD) [87]. FHH is caused by inactivating mutations in the calcium-­ sensing receptor (CaSR) gene leading to calcium-­ hyposensitivity, compensatory hypercalcemia—in order to obtain intracellular response despite inactive receptors—and hypocalciuria. The low urine calcium levels distinguish FHH from primary hyperparathyroidism, in which urine calcium excretion is increased. Three forms of FHH have been described: FHH1, the most frequent subtype, is caused by mutations within CaSR (3q21–24), FHH2 is caused by mutations within GNA11, which encodes the G-protein subunit α11, whereas FHH3 is caused by mutations within AP2S1, which codes for the adaptor related protein complex 2, σ1 (AP2 σ) [88]. Lung involvement consists of a granulomatous disease, characterized by foreign body giant cells and mononuclear cells in ltration of the alveolar interstitium. However, contrary to sarcoidosis, there are no well-formed granulomas and urine calcium is normal or low while the level of 1,25-dihydroxyvitamin D3 is within normal limits. In general, FHH is a benign condition that does not require treatment. As such, the main argument for establishing the diagnosis is to avoid unnecessary parathyroidectomy. However, in chronic severe cases complicated by lung brosis, life expectancy is reduced. Chondrocalcinosis and acute pancreatitis have also been reported [89, 90]. The third feature of FHH is granulocyte dysfunction due to a myeloperoxidase de ciency and reduced anti-staphylococcal killing [91].

Neurofbromatosis Type 1

Neuro bromatosis 1 (NF1), previously known as von Recklinghausen’s disease, is a frequent systemic disorder with a prevalence of approximately 1 in 3500 caused by

loss-of-function mutations within the NF1 gene (17q11.2) that encodes neuro bromin, a tumor suppressor protein [92]. Despite its autosomal dominant pattern of inheritance, approximately half of the cases are spontaneous (i.e., caused by de novo mutations within NF1). NF1 is characterized by the typical presence of multiple (>6) café-au-lait spots along with axillary and inguinal freckling, optic gliomas, bone lesions, and cutaneous neuro broma [93]. In addition, pigmented hamartomas highly speci c for NF1 (Lisch nodules) can be observed in the iris of over 90% of adult patients but only in <10% of affected children younger than 6 years of age. These lesions do not affect vision. The diagnosis of NF1 is based upon the presence of characteristic clinical features and genetic testing is generally not required. The spectrum of clinical phenotypes ranges from mild and paucisymptomatic disease to malignant tumors arising from peripheral nerves in 10–13% of cases [94]. On average, the life expectancy of NF1 patients is reduced by 10 years compared to the general population [95].

ILD, which generally manifests between 35 and 60 years of age, complicates 10–20% of cases [96]. Chest X-ray and HRCT typically demonstrate bibasilar reticular in ltrate, ground glass opacities, and upper lobe and peripheral predominant cystic bullous changes [97–99]. Thin-walled bullae are present in almost all patients with ILD, although they may be seen in isolation. Mediastinal masses may also be seen [99]. Histologically, alveolar septal brosis represents the major abnormality, whereas an alveolitic process consisting of mononuclear cell in ltration may be observed in earlier phases of the disease [100]. Functionally, NF1-associated ILD is characterized by a mixed obstructive and restrictive ventilatory defect. NF1-associated ILD is often progressive and may lead to pulmonary hypertension (PH) and right heart failure [101, 102]. NF1-associated PH is classi ed as Group 5 PH (i.e., “PH with unclear and/or multifactorial mechanisms”) and is characterized by female predominance, advanced age at diagnosis, association with ILD in the majority of cases, and poor long-term prognosis [102]. Additional pulmonary complications of NF1 include large-­airway obstruction, bronchial or intraparenchymal neuro bromas (leading to diaphragmatic paralysis), scar carcinoma complicating brotic lung disease, and primary lung cancer developing in the walls of emphysematous cysts, and pneumothorax [103–105]. No speci c medical treatment for NF1 exists.

Surfactant Dysfunction Disorders

Genetic surfactant dysfunction disorders (SDDs) are caused by mutations within genes encoding proteins needed for the production and normal function of surfactant, a mixture of phospholipids and proteins synthesized, packaged, and secreted by alveolar type II cells that lower

surface tension at the air-liquid interface and prevent atelectasis at end-­expiration. SDDs may manifest as familial or sporadic lung disease and are associated with a wide spectrum of clinical presentations ranging from neonatal respiratory failure to adult-onset ILD. Surfactant proteins (SPs) A, B, C, and D are highly expressed in the lung. Additional proteins important for the production of the surfactant include ABCA3 and TTF-1.

Surfactant Protein B (SFTPB) Defciency  Surfactant protein B (SFTPB) de ciency is a rare autosomal recessive disease with an estimated incidence of <1 in 1,000,000 live births [106] that manifests in infants and is characterized by rapidly progressive respiratory failure [107]. Over 40 loss- of-­function mutations within SFTPB gene have been identi-ed so far; they result in partial to complete absence of SP-B protein. The most common mutation—a GAA substitution for C at genomic position 1549 in codon 121 (formerly referred to as “121ins2” mutation)—accounts for approximately 70% of cases and results in the absence of proand mature SFTPB protein [108]. The absence of SFTPB, in turn, leads to abnormal surfactant composition, decreased surfactant function, and structural disruption of lamellar bodies (the organelles in which surfactant is stored). Accordingly, SFTPB de ciency is characterized histologically by the accumulation of granular, eosinophilic, periodic acid-Schiff (PAS)-positive, lipoproteinaceous material in the alveolar spaces, which often contains desquamated alveolar type II cells and foamy alveolar macrophages.

Most infants with SFTPB de ciency present within hours of birth with respiratory failure requiring mechanical ventilation. Chest radiograph and HRCT appearance mimic that of hyaline membrane disease in premature infants with diffuse haziness and air bronchograms. However, infants with SFTPB de ciency are only transiently or minimally responsive to surfactant replacement therapy and, with rare exceptions, patients succumb within days of birth to 3–6 months without lung transplantation [109]. Children with mutations that allow for the partial expression of the SFTPB protein appear to survive longer and go on to develop a chronic ILD [110].

Surfactant Protein C (SFTPC) Defciency  Surfactant protein C (SFTPC) de ciency is a rare disorder originally described in an infant with NSIP whose mother had desquamative interstitial pneumonia (DIP). Both the infant and her mother carried heterozygous guanine to adenine substitution, leading to the skipping of exon 4 and deletion of 37 amino acids, in keeping with the autosomal dominant pattern of inheritance [2]. Subsequently, Thomas and colleagues described a ve-generation kindred with 14 affected members, including four adults with biopsy-proven UIP and three children with NSIP, all carrying a rare heterozygous missense mutation substituting a polar residue (glutamine) for a

neutral one (leucine) and predicted to hinder the processing of SP-C precursor protein [1]. Over 35 dominantly expressed mutations within SFTPC have been identi ed so far, half of which arise de novo, thus causing sporadic disease, whereas the remaining are inherited. The most common mutation, a T to C transition at genomic position 1295, results in a threonine substitution for isoleucine in codon 73 (I73T), and accounts for approximately one-third to one-half of all reported cases [111, 112].

The pathophysiology of lung disease due to SFTPC mutations is only partially understood. One hypothesis is that misfolded proSP-C may induce the unfolded protein response, resulting in infammation and apoptosis of alveolar type II cells [113]. The severity of disease and age of onset is highly variable, ranging from fatal respiratory distress in infants to subclinical pulmonary brosis in older adults [114]. A recent study from the Netherlands found that SFTPC mutations account for as many as 25% of familial pulmonarybrosis cases [115]. Conversely, SFTPC mutations are rarely associated with sporadic pulmonary brosis [116]. Respiratory involvement is highly variable and may change over time; in a study of ve children from a single family with long-term follow-up, HRCT showed initially ground glass opacities and subsequently the development of cysts, which was associated with a reduced extension of ground glass and clinical improvement [117].

Whether the nature and location of SFTPC mutations affect the severity of lung disease is unknown. However, affected family members harboring the same SFTPC mutation display considerable variability in the onset and severity of lung disease [1]. Such variability precludes accurate assessment of prognosis and complicates interpretation of treatment response in individual patients.

Adenosine Triphosphate Binding Cassette Family Member 3 (ABCA3) Defciency  Mutations in the Adenosine Triphosphate Binding Cassette family member 3 (ABCA3) gene are the most common cause of genetic SDDs in humans [118, 119], with an estimated disease incidence ranging between 1 in 4400 and 1 in 20,000 [120]. ABCA3 mutations result in loss or reduced functional activity of the ABCA3 protein, which facilitates the translocation of phospholipids into lysosomally-derived organelles called lamellar bodies for the production of surfactant. Over 200 mutations have been reported to date. Glu292Val, the most common, accounts for <10% of all identi ed mutations and is associated with relatively mild disease [121, 122]. However, disease severity and presentation vary widely, mainly based on the genotype. The most severe phenotype is characterized by neonatal respiratory failure and death by 1 year of age and is associated with mutations predicted to impede ABCA3 expression on both alleles (null/null) [123, 124], consistent with an autosomal recessive manner of inheritance. However,

patients may also present later in infancy or childhood. Notably, discordant outcomes have been reported in siblings carrying the same ABCA3 mutations, suggesting that factors other than genotype contribute to disease severity [125]. The predominant histopathological patterns of ILD include PAP, DIP, and NSIP. However, a UIP pattern of pulmonary brosis has also been described in a 15-year-old boy carrying mutations in ABCA3 [126].

NK2 homeobox 1/Thyroid Transcription Factor 1 (NKX2–1/ TTF-1) Mutations  NK2 homeobox 1 (NKX2-1) encodes thyroid transcription factor 1 (TTF-1), which is a critical regulator of SP-B, SP-C and ABCA3 expression. Deletions or loss-of-function mutations on one NKX2.1 allele (haploinsuf ciency) can cause severe respiratory distress syndrome and ILD [127]. Lung disease is thought to result from decreased amounts of several gene products in combination or reduced amounts of a key protein, particularly SP-B or ABCA3, below a critical level. The incidence and prevalence of lung disease due to NKX2.1 haploinsuf ciency are unknown. The majority of reported variants have occurred de novo [128], but an autosomal dominant pattern of inheritance has also been observed [129]. Haploinsuf ciency for NKX2.1 may cause neurological symptoms (i.e., muscular hypotonia, ataxia and choreoathetosis), hypothyroidism, and lung disease, a triad of manifestations commonly referred to as “Brain-Thyroid-Lung syndrome” [130]. Affected individuals may present during the neonatal period with rapidly progressive respiratory failure, while other patients may develop a more chronic phenotype characterized by recurrent pulmonary infections [131]. In a study of 21 patients, 76% presented with neonatal lung disease and 19% with ILD [132].

Irrespective of the gene involved, lung histology ndings in SDDs are similar and include prominent hyperplasia of

alveolar type II epithelial cells, thickening of the interstitium with mesenchymal cells and foamy macrophages, and accumulation of granular, eosinophilic proteinaceous material within the air spaces [133]. To date, no speci c therapies for SDDs have been demonstrated to be effective. The mainstay of treatment remains therefore supportive care. Neonates presenting with clinical and radiographic features of respiratory distress syndrome are often treated with exogenous surfactant, which may improve transiently lung function but does not correct the underlying intracellular defects. The main features of surfactant dysfunction disorders are summarized in Table 28.1.

Concluding Remarks

The umbrella term “rare diffuse lung diseases of genetic origin” refers to a large spectrum of disorders with complex pathogenesis, diverse clinical manifestations (Table 28.2), speci c histopathologic and radiographic features (Table 28.3), and variable natural history and prognosis. In the past decade, there have been major advances in our knowledge and understanding of these entities but much work remains to be done. For instance, how multiple susceptibility alleles interact with each other and with environmental factors to determine disease risk and phenotypes is poorly understood. Ongoing basic research will also provide insights into the molecular basis of ILD pathogenesis (including genetic factors causing familial disease) and is expected to identify markers of disease, pathways of disease regulation, and novel potential targets for therapeutic intervention. To this end, the importance of international collaboration cannot be overemphasized. Hopefully, this will help reduce the considerable morbidity and mortality associated with these disorders.