Pulmonary Disorders: Hereditary


Hereditary lung diseases can affect the airways (asthma, COPD, cystic fibrosis and primary ciliary dyskinesia), parenchyma (pulmonary fibrosis, Birt Hogg Dube syndrome and tuberous sclerosis) and vasculature (hereditary heamorrhagic 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 pathogensis of more common sporadic disease.

  • Pulmonary manifestations can be the presenting feature of several important inherited diseases.

Keywords: fibrosing alveolitis; bronchiectasis; primary ciliary dyskinesia; hyaline membrane disease; serpinopathies; pneumothorax; Birt–Hogg–Dube 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. Figures 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. The electron micrograph was 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. (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). (The components of the figure are reproduced with permission from Lomas et al., .)

Figure 4.

Birt–Hogg–Dube 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–Dube 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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Katzenstein A‐LA and Myers JL (1998) Idiopathic pulmonary fibrosis. Clinical relevance and pathological classification. American Journal of Respiratory and Critical Care Medicine 157: 1301–1315.

Lomas DA (2002) Alpha1‐antitrypsin deficiency and the serpinopathies. In: Warrell DA, Cox TM and Firth J (eds) Oxford Textbook of Medicine, 4th edn. Oxford, UK: Oxford University Press.

Lomas DA and Mahadeva R (2002) Alpha‐1‐antitrypsin polymerisation and the serpinopathies: pathobiology and prospects for therapy. Journal of Clinical Investigation 110: 1585–1590.

Marciniak SJ and Lomas DA (2009) What can naturally occurring mutations tell us about the pathogenesis of COPD? Thorax 64: 359–364.

Seaton A, Seaton D and Leitch AG (eds) (1989) Crofton and Douglas's Respiratory Diseases, 4th edn. Oxford, UK: Blackwell Science Ltd.

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Marciniak, Stefan J, and Lomas, David A(Sep 2010) Pulmonary Disorders: Hereditary. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005517.pub2]