Inherited Pulmonary Disorders

Abstract

Hereditary lung diseases can affect the airways (asthma, COPD, cystic fibrosis and primary ciliary dyskinesia), parenchyma (pulmonary fibrosis, Birt–Hogg–Dubé syndrome and, tuberous sclerosis) and vasculature (hereditary haemorrhagic telangiectasia) of the lung. Such conditions include simple monogenic disorders such as Kartagener syndrome and α1‐antitrypsin, wherein mutations of critical genes are sufficient to induce well‐defined disease phenotypes. However, many are complex genetic traits in which inheritance subtly affects pathogenesis, for example asthma and idiopathic pulmonary fibrosis. A greater understanding of the genetic basis of pulmonary conditions has provided new insights into their underlying pathophysiology and helped in some cases to shed light on more common sporadic forms. Importantly, the identification of causative genes has also enabled prenatal diagnosis and genetic counselling to be introduced for many diseases.

Key Concepts

  • Common diseases frequently have a genetic component which with the advent of genome‐wide association studies can now be elucidated.
  • The study of rare monogenic disorders can provide important mechanistic clues to the pathogenesis of more common sporadic disease.
  • Pulmonary manifestations can be the presenting feature of several important inherited diseases.
  • Making a definitive genetic diagnosis permits the practicing of personised medicine.
  • Molecular testing using gene panels and whole genome sequencing is revolutionising respiratory medicine.

Keywords: idiopathic pulmonary fibrosis; fibrosing alveolitis; bronchiectasis; primary ciliary dyskinesia; hyaline membrane disease; serpinopathies; pneumothorax; Birt–Hogg–Dubé syndrome; tuberous sclerosis; hereditary haemorrhagic telangiectasia; Marfan syndrome

Figure 1. Histological appearance of normal alveoli (a) and alveoli affected by disease. (b) Lung biopsy from a baby with neonatal respiratory distress syndrome from insufficient surfactant. The formation of hyaline membranes grossly distorts the delicate alveolar architecture. (c) The airway from an individual with bronchiectasis. The airway wall is grossly thickened with fibrosis and there is inflammatory exudate within the lumen. (d) A patient with the usual interstitial pneumonitis variant of cryptogenic fibrosing alveolitis. The alveolar walls are thickened with collagen which impairs gaseous exchange. Kindly provided by Dr Martin Goddard, Papworth NHS Trust, Cambridge.
Figure 2. Diagram (a) and electron micrograph (b) of the cross section of normal cilia. The central part of the spermatozoan flagellum has an identical ultrastructure. Nine microtubular doublets surround two central microtubules. The dynein arms are responsible for causing the nine microtubules to slide relative to each other. The nexin links restrict the sliding with the result that the cilium bends. Kindly provided by Dr Jeremy Skepper, Multi‐imaging centre, Department of Anatomy, University of Cambridge, UK.
Figure 3. Members of the serine proteinase inhibitor or serpin superfamily, such as α1‐antitrypsin, may be considered to act as mousetraps. Following docking (a, left) the target proteinase (grey) is inactivated by movement from the upper to the lower pole of the protein (a, right). This is associated with insertion of the reactive loop (red) as an extra strand into β‐sheet A (green). The mousetrap mechanism may be triggered spontaneously by point mutations in association with disease. The Z mutation (Glu342 Lys) of α1‐antitrypsin is at the head of a strand of β ‐sheet A (green) and the base of the reactive loop. Mutations in this region can destabilise β‐sheet A to allow the insertion of a reactive loop of a second molecule (b, middle). This dimer then extends to form long chains of polymers (b, right). In this illustration, each molecule of α1‐antitrypsin in the polymer is illustrated by a different colour. It is these polymers which then tangle in the endoplasmic reticulum to cause inclusions that result in liver disease. (a,b) Reproduced from Lomas et al. 1992 © Nature Publishing Group. (c) An inclusion body (arrow) from the liver of a patient with α1‐antitrypsin deficiency (left). The inclusions are composed of chains of molecules of α1‐antitrypsin (right). Reproduced from Lomas et al. 1993 © The American Society for Biochemistry and Molecular Biology.
Figure 4. Birt–Hogg–Dubé syndrome is an autosomal dominant condition of lung cysts, benign skin tumours and renal cell carcinoma. Cysts can rupture to cause pneumothorax. Causative mutations are found in the Folliculin gene. Some Folliculin gene mutations appear to cause only the cystic lung disease without other features of Birt–Hogg–Dubé syndrome, as in the case illustrated. Note the irregular thin‐walled cysts (arrow heads). These are frequently found in a medial basal distribution.
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Further Reading

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Marinicak, Stefan J, and Lomas, David A(Aug 2017) Inherited Pulmonary Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005517.pub3]