Abstract
This chapter characterizes selected disorders with a primary respiratory component as well as respiratory manifestations of systemic diseases. Respiratory disorders of the lymphatic system may present at any age and include pulmonary lymphangiectasia, lymphangioma, and lymphangiomatosis. Lymphangioleiomyomatosis is a distinct disease that presents with dyspnea, pneumothorax, and pulmonary cysts. It is most typically diagnosed in adult females. Pulmonary alveolar microlithiasis is often asymptomatic in the pediatric population despite impressive radiologic findings with chest imaging. Pulmonary manifestations of ataxia telangiectasia, Gaucher disease, Niemann-Pick disease, and dyskeratosis congenita can lead to severe respiratory disease. Lung disease due to neurofibromatosis or Hermansky-Pudlak syndrome typically occurs in adults but can be severe. Although alpha-1 antitrypsin deficiency rarely, if ever, causes pulmonary disease in pediatric patients, knowledge of the disorder holds value for pediatric respiratory practitioners related to implications for genetic screening and patient/provider education.
Keywords
rare childhood lung disorders, interstitial lung disease, pulmonary lymphangiectasia, lymphangiomatosis, Gorham-Stout disease, lymphangioleiomyomatosis, pulmonary alveolar microlithiasis, ataxia telangiectasia, Gaucher disease, Niemann-Pick disease, neurofibromatosis dyskeratosis congenital, Hermansky-Pudlak syndrome, alpha-1 antitrypsin deficiency
Introduction
Although some respiratory diseases occur rarely in the pediatric population, knowledge of these disorders is valuable from a number of perspectives. Timely diagnosis and treatment of rare disorders can be made only if the practitioner is familiar with the entity in question. Furthermore, elucidation of the pathophysiology underlying rare disorders can be applied to understanding both normal respiratory physiology and related but more prevalent disorders. Many rare lung disorders are covered in other chapters. This chapter characterizes both selected disorders with a primary respiratory component and respiratory disease occurring secondary to systemic disorders, with emphasis on interstitial lung disease. The diseases covered may present predominantly during childhood, such as respiratory disorders of the lymphatic system, or primarily during adulthood but with implications for pediatric patients, such as pulmonary alveolar microlithiasis (PAM) and alpha-1 antitrypsin (AAT) deficiency. Foundations provide invaluable information, support, and advocacy to families and patients affected by rare diseases and also function as important resources for practitioners. This chapter therefore directs the reader to selected disease-specific groups.
Respiratory Disorders of the Lymphatic System
A number of rare disorders related to dysregulation of lymphatic development occur in pediatric patients from infancy to adolescence. The normal pulmonary lymphatic system is composed of two interconnected pathways: one drains the subpleural space and outer surface of the lung, while the other follows bronchovascular bundles to drain the deeper portions of the lung (see Chapters 6 and 36 ). In humans, the pulmonary lymphatic system begins to form approximately 6 weeks into embryonic growth with sprouting of distinct endothelial cells directly from the developing venous system. A number of growth factors that direct development of the lymphatic vasculature have been identified, and the pathophysiology leading to lymphatic dysfunction varies among the disorders described in this section. For example, disordered embryonic development has been hypothesized to play a role in pulmonary lymphangiectasia (PL), a disorder that often presents in the neonatal period. In disorders that present outside of the neonatal period, such as lymphangiomatosis, disease is associated with abnormalities of lymphatic growth. Furthermore, a significant number of children with pulmonary lymphatic disorders also manifest lymphatic involvement of other organ systems, congenital cardiac disease, and chromosomal disorders. This section describes disorders associated with lymphatic dysfunction affecting the respiratory system. The reader is referred to Chapter 69 regarding congenital chylothorax.
Pulmonary Lymphangiectasia
Epidemiology
PL is characterized by dilatation of pulmonary lymphatic vessels and disordered drainage, leading to the accumulation of lymph within the lungs and a spectrum of respiratory disease. Although its exact incidence is not known, it has been estimated that 0.5%–1% of neonates who die in the neonatal period have PL. The majority of reported cases occur sporadically, and most present in the neonatal period or during infancy. However, cases of PL have also been described to occur during childhood and into adulthood.
Etiology and Pathogenesis
One commonly used classification system for PL distinguishes between disease caused by a primary developmental defect and that occurring secondary to an obstructive process impeding normal lymph drainage. It has been hypothesized that primary PL occurs secondary to failure of normal regression of the large lymphatic vessels, observed in the embryo at 9–16 weeks of gestation. A recently described murine model of PL was generated by expressing vascular endothelial growth factor (VEGF)-C on a lung-specific promoter. Lymphatic growth is regulated in part by the lymphangiogenic receptor VEGFR3, and mice lacking this gene die shortly after birth from failure of lung inflation. Some infants with primary PL present with disease that seems confined to the respiratory system, while others display more generalized symptoms characterized by lymphedema and extrathoracic involvement. Recent studies in families with inherited isolated forms of lymphedema have identified eight genes causing lymphedema (i.e., FLT4 [encoding VEGFR3] [MIM 153100 ], FOXC2 [MIM 153400 ], SOX18 [MIM 607823 ], HGF [MIM 142409 ], MET [MIM 164860 ], CCBE1 [MIM 235510 ], PTPN14 [MIM 603155 ], and GJC2 [MIM 608803 ]). Secondary causes of PL usually involve congenital cardiac diseases associated with obstructed pulmonary venous flow. Thus hypoplastic left heart syndrome, congenital mitral stenosis, and pulmonary vein atresia have all been associated with PL. In addition to cardiac disease, thoracic duct agenesis and infection may also block lymphatic drainage and cause PL.
Clinical Features
A number of chromosomal disorders are associated with PL, including Noonan syndrome, Hennekam syndrome, yellow nail syndrome, and Down syndrome. Children with PL associated with chromosomal disorders are more likely to present with generalized lymphangiectasia. These patients may display a less severe pulmonary component and may have a better prognosis when compared with those who present with primarily pulmonary disease during the neonatal period.
At birth, infants with PL often present with respiratory distress that progresses rapidly to respiratory failure. Chylous pleural effusions may be prominent, but a significant number of children with PL do not present with effusions. Individuals who first develop symptoms later in infancy or during childhood usually display less severe disease when compared with those with neonatal onset. In later-presenting forms, initial symptoms include chronic tachypnea, recurrent cough, and wheezing. PL in these individuals has been associated with chylothorax, chylopericardium, and chylous ascites. These patients have frequent respiratory exacerbations, possibly related to lower respiratory tract infection that leads to transient worsening of lymphatic drainage.
Imaging
The diagnostic workup of the child with suspected PL includes plain chest radiography, high-resolution tomography of the chest (HRCT), and lung biopsy. Chest radiography often reveals interstitial infiltrates and hyperinflation, with or without pleural effusion. HRCT shows thickening of peribronchovascular septa and septa surrounding lobules ( Fig. 55.1 ). Lung biopsy, the “gold standard” for diagnosing PL, is characterized by the appearance of dilated lymphatic vessels located in the interlobular septa, near bronchovascular bundles and/or within the pleura. Dilated lymphatic vessels may occasionally appear cystic. In addition to lymphatic findings, lung biopsy may also show thickening and widening of interlobular septa. The risk of worsened lymphatic leak should be considered in the decision to proceed with lung biopsy. Because lymphangiectasia may be part of a systemic dysplasia, consideration should also be given to careful evaluation for extrapulmonary disease manifestations, such as gastrointestinal involvement, bone disease, or skin lesions from draining lymphatics.
Management
There is no known cure for PL, and treatment is primarily supportive. Respiratory failure in a significant number of neonates with PL is refractory to conventional positive-pressure ventilation and high-frequency oscillation. In these cases, inhaled nitric oxide and extracorporeal membranous oxygenation (ECMO) have been used with variable success. Therapy for older children with PL includes supplemental oxygen, judicious use of antibiotics for bacterial respiratory infection and treatment for recurrent wheezing or cough. A number of medications have been reported to be effective for the management of PL and chylothorax in case reports and small series, but none have been tested in randomized clinical trials.
Prognosis
Although the natural course of PL is variable among individuals, the disease has historically carried a high mortality rate when diagnosed in the neonatal period. One report suggests improved survival with aggressive interventions and modern neonatal intensive care. Subsequently, however, Mettauer et al. have reported survival in only one of seven children referred to their tertiary center. The authors concluded that although the prognosis for PL is poor, the condition is survivable with aggressive intervention. Furthermore, those who survive the neonatal period seem to eventually experience improvement of their disease. Clearly a spectrum of severity exists. With further delineation of the molecular mechanisms controlling development of the lymphatic system, it is likely that new methods of classifying and ultimately treating PL will become available.
Lymphangioma, Lymphangiomatosis, and Gorham-Stout Disease
Abnormal proliferation of lymphatic vessels distinguishes lymphangioma, lymphangiomatosis, and Gorham-Stout disease from other lymphatic disorders of the lung. Whereas lymphangioma refers to a solitary malformation, lymphangiomatosis refers to the presence of multiple lymphangiomas and is less common than the occurrence of a single lymphangioma. Gorham-Stout disease is a related syndrome characterized by chylothorax and bone cysts, with lymphangioma seen on biopsy.
Lymphangiomatosis is a severe disease characterized by the occurrence of numerous lymphangiomas, often affecting multiple organs. Involvement of the liver, soft tissue, spleen, bones, mediastinum, and lungs may occur. The disease is reported more frequently in children than adults, and a significant percentage of these cases present during infancy. Lymphangiomatosis involving the thorax can manifest in the mediastinum, pleural space, chest wall, lungs, or pericardium. Individuals with thoracic involvement may present with cough, chest pain, dyspnea, or wheezing. Chylous effusions are often a prominent component of the clinical disease pattern of lymphangiomatosis. Chest radiography reveals interstitial infiltrates, chest masses, effusions, or bone lesions. In addition to multiple lymphangiomas, HRCT of the chest may exhibit smooth thickening of interlobular septa and bronchovascular bundles, ground-glass attenuation, or effusions. Biopsies of lymphatic lesions are characterized by increased numbers of dilated lymphatic channels lined by endothelium.
The natural history of lymphangiomatosis entails progressive growth of lymphangiomas, which eventually compress vital structures. Both young age and respiratory involvement predict a particularly poor outcome. However, successfully treated cases of lymphangiomatosis with thoracic involvement have been reported. Therapy for severely symptomatic pleural effusions may include thoracentesis or pleurodesis. When lymphangiomas are diffuse, complete surgical resection may not be possible. Medical therapy for lymphangiomatosis using sirolimus or interferon alpha-2b has been reported, with the aim of halting the lymphatic proliferation that is the hallmark of the disease.
Gorham-Stout disease is characterized by the proliferation of vascular structures within bones, leading to osteolytic lesions evident on radiography. Chylothorax is associated with the disease, possibly related to dysplasia of lymphatic vessels at the pleura. Children are more commonly affected than adults, and presenting symptoms may include cough, dyspnea, and pain. The presence of chylothorax is associated with worsened prognosis in this severe disease. Similar to what is reported in lymphangiomatosis, there are case reports describing approaches to medical therapy. Ongoing efforts to improve the classification and phenotyping of lymphatic dysplasias, including PL and lymphangiomatosis, may lead to improved diagnostic strategies, molecular understanding, and targeted therapeutic considerations. The Lymphangiomatosis and Gorham Disease Alliance advocates on behalf of patients and families and provides education and support ( https://www.lgdalliance.org/ ).
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle proliferation and cystic destruction in the lung. This disorder typically presents in women of childbearing age with recurrent pneumothoraces, progressive dyspnea, and/or multiple lung cysts evident on HRCT. Although lymphatic involvement is not always a prominent feature, some patients may develop chylous effusion. Despite the similar-sounding terminology, LAM is distinct from lymphangiomatosis and is differentiated based on the presence of lung cysts and distinct immunohistochemistry. LAM may occur sporadically, without a known inheritance pattern, or it may be associated with tuberous sclerosis complex (TSC), an autosomal dominant disease with variable penetrance. Rarely, cystic pulmonary disease can occur in children with TSC ( Fig. 55.2 ). Although at least 40% of adult women with TSC have lung cysts compatible with LAM, symptomatic pulmonary disease is rare in girls with TSC. One study from a single referral center reported age-dependent risk of LAM in females with TSC, with a prevalence of 26% in females with TSC below 21 years of age and 81% in those above 40 years of age. Consensus guidelines published in 2013 recommend LAM screening in females with TSC starting at age 18 years. The Tuberous Sclerosis Alliance ( www.tsalliance.org ) and LAM Foundation ( www.thelamfoundation.org ) offer information, resources, and a worldwide network to those affected.
Pulmonary Alveolar Microlithiasis
Epidemiology
PAM is an autosomal recessive disease characterized by the deposition of calcium phosphate calculi within alveoli. Although the majority of reported cases of PAM historically describe adults, increased numbers of children with the disorder have been identified more recently. A few cases report diagnosis during infancy and early childhood. Tachibana et al. report 52% of a series of 111 patients identified before the age of 15 in Japan. In Turkey and Italy, the mean age of diagnosis was 27 and 30 years, respectively.
Etiology and Pathogenesis
A gene linked to PAM has been identified, and the cause of the disease has been linked to disordered phosphate transport in the alveolar space. SLC34A2 encodes a type IIb sodium-dependent phosphate transporter and is expressed in type II alveolar cells. Mutations most often lead to a loss of function or premature termination. One of the functions of type II alveolar cells involves degradation of surfactant. Phosphate is a waste product of this degradation and will build up in cells unless properly removed. Saito et al. showed that epithelial deletion of the SLC34A2 gene product NPT2b sodium-dependent phosphate cotransporter in mice results in a PAM phenotype. Mice with this deletion develop microlith accumulation in alveoli, typical radiographic findings, and pulmonary fibrosis, strongly suggesting that dysfunction of NPT2b causes PAM.
Clinical Features
Individuals with PAM, especially in the pediatric population, are usually asymptomatic at the time of diagnosis. Remarkably, this absence of symptoms occurs despite impressive radiologic changes evident on chest imaging. Mariotta et al. reviewed the literature to describe 576 cases of the disorder and reported the presence of symptoms (including dyspnea, cough, and chest pain) in only about half of those affected.
Patients may also present with digital clubbing or, less commonly, pneumothorax. The micronodules evident on chest radiography often appear denser at the lung bases and can obscure the borders of the cardiac silhouette and diaphragm. HRCT may reveal micronodules, ground-glass opacities, subpleural interstitial thickening, and interlobular septal thickening. In pediatric patients, ground-glass opacification can predominate over the nodular calcific densities classically ascribed to the disease in adults ( Fig. 55.3 ). At diagnosis, pulmonary function testing may be normal or show slightly decreased vital capacity or diffusing capacity. Decline of pulmonary function and occurrence of respiratory insufficiency occur over decades.
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