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Congenital, Developmental, and Inherited Disorders


Congenital and developmental disorders of the lung manifest almost exclusively in pediatric and neonatal patients and include a wide array of disorders resulting from abnormalities of lung architecture, cellular function, and metabolism. All of these disorders are uncommon, and most are rarely encountered in clinical practice; however, together, they account for significant morbidity and mortality in the pediatric population and can often be a diagnostic challenge for the pathologist.

Diffuse Developmental Disorders

Clinical Features

Diffuse developmental disorders of lung architecture are rare entities that typically present in the neonate. Babies with acinar dysgenesis (also called acinar dysplasia ) have an early arrest of lung development resulting in respiratory distress and death in the first few hours of life ( Figs. 4.1 and 4.2 ). Most reported cases have occurred in otherwise normal female infants (9:1 female:male ratio) at or near term. Although the pathogenesis is not known, an abnormality of epithelial-mesenchymal interaction during development has been proposed. Congenital alveolar dysplasia refers to a poorly characterized disorder with arrest in lung development at a later stage and thus with a somewhat less severe presentation ( Fig. 4.3 ). Similar to acinar dysplasia, affected infants have respiratory difficulty at birth but may be sustained for some time with ventilatory support. Alveolar capillary dysplasia (ACD) with misalignment of pulmonary veins typically causes respiratory symptoms and persistent pulmonary hypertension in term or near-term infants in the first days of life. Initially identified only at autopsy, increasing clinical suspicion has resulted in diagnostic lung biopsies to exclude the diagnosis in neonates and infants ( Fig. 4.4 ). Although there are exceptions, most affected infants die in the first month of life despite intensive supportive measures. ACD is associated with other malformations, particularly involving the cardiac, gastrointestinal, and genitourinary systems. Hypoplastic left heart syndrome is the most frequently associated cardiac malformation. Sibling pairs have been reported. In 2009 FOXF1 gene mutations and deletions were described as the cause of ACD.

Diffuse Developmental Disorders—Fact Sheet

Definition

  • ▪

    A group of developmental disorders with abnormal parenchymal development and sometimes abnormal vasculature

Incidence

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    Rare

  • ▪

    ACD most common

Morbidity and Mortality

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    Uniformly lethal

Gender, Race, and Age Distribution

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    Term or near-term neonates

  • ▪

    Marked female predominance in acinar dysgenesis

Clinical Features

  • ▪

    Acinar dysgenesis—immediate respiratory distress; cannot be supported

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    Congenital alveolar dysplasia—early respiratory distress; can be supported

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    ACD—respiratory symptoms and persistent pulmonary hypertension in a term infant in the first days to weeks of life; may be associated with other malformations

Radiologic Features

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    Acinar dysgenesis—small hazy lungs; often air leak with resuscitation

  • ▪

    Congenital alveolar dysplasia and ACD—diffusely hazy lungs

Prognosis and Treatment

  • ▪

    Fatal despite maximal supportive measures

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    Survival is limited to hours in acinar dysgenesis and weeks in congenital alveolar dysplasia

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    Death usually in the first month in ACD, although longer survivals are reported

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    Lung transplantation may be an option for some

Diffuse Developmental Disorders—Pathologic Features

Gross Findings

Acinar Dysgenesis

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    Small lungs with small lobules and thickened white interlobular septa

Congenital Alveolar Dysplasia

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    Normal to increased lung weight

ACD

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    Deeply congested

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    Normal to increased lung weight

Microscopic Findings

Acinar Dysgenesis

  • ▪

    Developmental arrest in pseudoglandular phase, with normal cytodifferentiation but nearly absent acinar development

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    Sometimes prominent airway smooth muscle and ectopic cartilage

Congenital Alveolar Dysplasia

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    Developmental arrest in late canalicular/early saccular phase

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    Reduced alveolar wall capillaries in some cases

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    May have arterial hypertensive changes

ACD

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    Malpositioned dilated veins accompany arterioles in the lobules and small pulmonary arteries adjacent to bronchioles

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    Striking muscularization of small pulmonary arteries and arterioles

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    Dilated and congested veins and venules

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    Dilated central channels in alveolar walls, but deficient alveolar capillaries

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    Normal position of larger veins adjacent to bronchi

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    Lobular architectural simplification (variable)

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    Lymphangiectasia (one-third of cases)

FIG. 4.1, Acinar dysgenesis. The lungs are small and show accentuated lobules with thickened interlobular septa.

FIG. 4.2, Acinar dysgenesis. Microscopically, the lobules contain dilated branching airways and large airspaces resembling growth arrest after the pseudoglandular phase of development. No saccular structures or alveoli are present.

FIG. 4.3, Congenital alveolar dysplasia. The lung development appears arrested at a later stage in development than acinar dysgenesis, in this case resembling early saccular development in a term neonate.

FIG. 4.4, Alveolar capillary dysplasia with misalignment of pulmonary veins. Abnormal veins are markedly congested and malpositioned, accompanying the pulmonary artery branches and airways (A). Within the lobules, the dilated venules accompany the lobular arterioles and the alveolar capillary bed is deficient (B) (Movat pentachrome stain).

Differential Diagnosis

Acinar dysplasia should be distinguished from other, less severe forms of pulmonary hypoplasia. Congenital alveolar dysplasia may be difficult to separate from the changes seen in the lungs of infants with respiratory failure who have been intensively supported for long periods. The typical history of respiratory failure in a term infant and the uniformity of the histologic changes are key observations in this situation. Congenital alveolar dysplasia shows normal venous anatomy, whereas ACD is characterized by deficiency of capillaries within the alveolar walls, abnormal dilated veins within the bronchovascular bundles, and accompanying muscularized pulmonary arterioles within the lobules. These dilated veins are thought to represent dilated bronchial veins secondary to shunting due to high pulmonary arterial pressures.

Prognosis and Therapy

These diffuse developmental disorders are universally fatal. Lung transplantation may be an option for babies with ACD if recognized early.

Surfactant Dysfunction Disorders

As a group, genetic mutations affecting surfactant metabolism are an important cause of respiratory distress in otherwise healthy term or near-term infants, as well as an emerging cause of chronic lung disease in older children and adults. Mutations or deletions in six different genes are now recognized to cause surfactant dysfunction disorders. Surfactant protein B (SFTPB gene) mutations were first recognized in 1993, followed by mutations in surfactant protein C (SFTPC gene). Since 2004, mutations in the gene encoding the adenosine triphosphate (ATP)–binding cassette transporter subfamily A3 (ABCA3) have emerged as the most common cause of genetic surfactant disorders presenting in infancy. Abnormalities in the NKX2-1 gene encoding thyroid transcription factor (TTF1) may cause impaired surfactant regulation. Mutations in the genes encoding the granulocyte macrophage colony-stimulating factor (GM-CSF) receptor (CSF2RA, CSF2RB) are another genetic cause of pulmonary alveolar proteinosis.

Surfactant Dysfunction Disorders—Fact Sheet

Definition

  • ▪

    Heterogenous group of inherited disorders of surfactant metabolism

Incidence

  • ▪

    Rare

Morbidity and Mortality

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    Death in infancy (SFTPB, SFTPC, ABCA3, NKX2-1)

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    Chronic disease in infants and older children (ABCA3, SFTPC, NKX2-1)

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    Chronic lung disease and fibrosis in adults (SFTPC)

Gender, Race, and Age Distribution

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    Infancy—SFTPB

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    Infancy and older children—NKX2-1

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    Infants, older children, and adults—SFTPC, ABCA3, CSF2RA, CSF2RB

Clinical Features

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    Term infants with respiratory difficulty in first weeks and months of life (SFTPB, SFTPC, ABCA3)

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    Chronic lung disease in older children (SFTPC, ABCA3)

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    SFTPB, ABCA3—autosomal recessive

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    SFTPC, NKX2-1—autosomal-dominant loss of function

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    May have family history; parents and grandparents sometimes affected with SFTPC

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    Clinical manifestations typically milder for SFTPC than for SFTPB

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    Recurrent pulmonary alveolar proteinosis (CSF2RA, CSF2RB)

Radiologic Features

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    “Crazy paving” pattern on chest computed tomogram (SFTPB)

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    Diffuse ground-glass opacity similar to hyaline membrane disease

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    Chronic interstitial disease (SFTPC)

Prognosis and Treatment

  • ▪

    Variable prognosis

  • ▪

    Treatment with supportive measures, steroids, and hydroxychloroquine may delay the need for lung transplantation in SFTPC disease

  • ▪

    Whole-lung lavage for CSF2RA, CSF2RB

Surfactant Dysfunction Disorders—Pathologic Features

Gross Findings

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    In infancy, heavily consolidated-appearing lungs. Some with pulmonary alveolar proteinosis pattern may have yellow material visibly distending airspaces.

Microscopic Findings

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    In infancy, all show diffuse prominent alveolar epithelial hyperplasia with at least focal periodic acid–Schiff–positive globular or granular proteinaceous material in alveoli

Various Histologic Patterns Can Be Seen

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    Classic pulmonary alveolar proteinosis pattern—associated most commonly with SFTPB mutations, as well as CSF2RA and CSF2RB

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    Variant pulmonary alveolar proteinosis pattern with some lobular remodeling, interstitial widening, foamy macrophages, and granular proteinosis—more commonly associated with ABCA3 mutations

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    Chronic pneumonitis of infancy pattern with lobular remodeling, interstitial widening, abundant foamy macrophages, few cholesterol clefts, mild interstitial inflammation, and sparse proteinosis—usually associated with SFTPC mutations

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    Desquamative interstitial pneumonia pattern—usually associated with SFTPC mutations

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    Nonspecific interstitial pneumonia—associated with SFTPC and ABCA3 mutations in infants and older children

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    Idiopathic pulmonary fibrosis—associated with SFTPC mutations in older children and adults

Ancillary Studies

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    Electron microscopy

    • –

      SFTPB —absence of normal lamellar bodies with hybrid lamellar/multivesicular bodies and absent tubular myelin

    • –

      ABCA3 —distinctive tiny lamellar bodylike structures with electron-dense inclusion “fried egg”; sometimes absence of lamellar bodies

    • –

      SFTPC, NKX2-1, CSF2RA, CSF2RB —nonspecific ultrastructural abnormalities

  • ▪

    Surfactant gene mutation studies on blood or frozen lung tissue

Differential Diagnosis

  • ▪

    Pulmonary alveolar proteinosis pattern—Acquired proteinosis in immunodeficient patients or those with antibodies to GM-CSF. These patients are typically older and do not have the diffuse marked alveolar epithelial hyperplasia seen in the setting of congenital alveolar proteinosis.

  • ▪

    Chronic pneumonitis of infancy—Other forms of chronic interstitial lung disease with endogenous lipoid pneumonia.

Pathologic Features

In infants, mutations of SFTPB and ABCA3 typically manifest as pulmonary alveolar proteinosis ( Fig. 4.5 ), whereas SFTPC mutations typically result in more lobular remodeling and less alveolar proteinosis, yielding a pattern of chronic pneumonitis of infancy ( Fig. 4.6 ). SFTPC mutations are also recognized as a cause of idiopathic and familial pulmonary fibrosis in older children and adults, and ABCA3 mutations have also been identified in a few older children and young adults with chronic fibrosing lung disease. NKX2-1 disorders have variable pathologic features, including impaired alveolarization, accumulation of foamy macrophages, and chronic pneumonitis of infancy pattern. GM-CSF disorders result in accumulation of abundant pulmonary alveolar proteinosis material, with little to no lobular remodeling. It should be noted that there are cases with morphology consistent with surfactant dysfunction in which no mutation has been identified in the known genes. Other genes and clinical patterns of disease will almost certainly be identified as more is learned about this complex set of metabolic disorders. Mutations in surfactant proteins and related proteins may also be genetic modifiers affecting the natural history and prognosis of various forms of acquired lung disease.

FIG. 4.5, Pulmonary alveolar proteinosis pattern (surfactant protein B, ABCA3 mutations). Mutations in the surfactant protein B gene (A) and ABCA3 gene (B) typically result in a pulmonary alveolar proteinosis pattern in infants, with slightly granular abundant eosinophilic proteinosis material in airspaces, occasional foamy histiocytes, and diffuse alveolar epithelial hyperplasia (periodic acid Schiff).

FIG. 4.6, Chronic pneumonitis of infancy pattern (surfactant protein C mutation). Mutations in surfactant protein C result in variable morphology depending in part on age at diagnosis. In infants, the lung typically has a pattern of chronic pneumonitis of infancy, characterized by lobular remodeling, diffuse prominent alveolar epithelial hyperplasia, scattered globular eosinophilic proteinosis material, and foamy histiocytes, often with occasional cholesterol cleft formation. Mutations or deletions in NKX2-1 gene encoding TTF1 may cause a similar pattern of disease.

Developmental “Cystic” Lesions

Clinical and Pathologic Features

Congenital pulmonary airway malformations (CPAMs) have been classified by Stocker according to cyst size and histomorphologic resemblance to segments of the developing bronchial tree and airspaces, from proximal (CPAM, type 0) to distal (CPAM, type 4). The two most common of these are more simply described as the large cyst type (Stocker type 1) and the small cyst type (Stocker type 2) CPAMs. The other three morphologic types are all thought to represent different pathogenetic processes: acinar dysplasia (type 0), pulmonary hyperplasia (type 3), and low-grade cystic pleuropulmonary blastoma (PPB) (type 4).

CPAM, Large Cyst Type—Fact Sheet

Definition

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    Focal developmental malformation of the lung, usually forming a single large, often multiloculated, cystic structure

Incidence and Location

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    Uncommon, but commonest of the cystic maldevelopments

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    Any lobe may be involved, lower lobe somewhat more commonly, and the left lung slightly more than the right

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