Diagnosis of primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a genetic disorder of ciliary structure or function. It results in mucus accumulation and bacterial colonization of the respiratory tract which leads to chronic upper and lower airway infections, organ laterality defects, and fertility problems. We review the respiratory signs and symptoms of PCD, as well as the screening tests for and diagnostic investigation of the disease, together with details related to ciliary function, ciliary ultrastructure, and genetic studies. In addition, we describe the difficulties in diagnosing PCD by means of transmission electron microscopy, as well as describing patient follow-up procedures.

Figure 1.. Schematic illustration and electron micrograph of a normal airway cilium. In A, schematic illustration of an axial section of a normal cilium in a ciliated airway epithelial cell, in which the peripheral microtubular doublets (comprising the A and B tubules) are numbered from 1 to 9; the central microtubules are designated C1 and C2. The A tubule contains the outer and inner dynein arms, which interact dynamically with the B tubule of the adjacent microtubule and produce the sliding of the peripheral microtubular doublets relative to one another. The illustration also shows nexin links, which connect the microtubular doublets (thus preventing structural disarray during their sliding motion), and radial spokes, which extend from the periphery to the center of the ciliary axis. In B, electron micrograph (original magnification, ×50,000) showing the ultrastructural appearance of an axial section of a normal airway cilium. Source: Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil, 2010.

Chart 1.. Ciliary ultrastructural defects, genetic mutations, and ciliary beat pattern in patients with primary ciliary dyskinesia.

Chart 2.. Quantitative assessment of dynein arms.

Figure 2.. Electron micrographs of ciliary ultrastructural defects. In A, absence of outer dynein arms (magnification, ×65,000); in B, microtubular disorganization (magnification: ×30,000); in C, absence of the central pair of microtubules (9+0 arrangement), which is usually associated with the 8+2 transposition defect (magnification: ×65,000); in D, 8+2 transposition defect (magnification: ×65,000). Source: Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil, 2010.

Chart 3.. Screening for primary ciliary dyskinesia

Figure 3.. Axial HRCT scan of the chest of a 30-year-old patient with primary ciliary dyskinesia (absence of outer and inner dynein arms) and advanced lung disease. Note significant involvement of the lung bases, with bronchial wall thickening, the signet ring sign, areas of consolidation, and attenuation differences. Source: Department of Clinical Pulmonology, Heart Institute, University of São Paulo School of Medicine - Hospital das Clínicas, São Paulo, Brazil, 2014.

Figura 1.. Ilustração esquemática e micrografia eletrônica de cílio de via aérea normal. Em A, ilustração esquemática de corte axial de um cílio normal de célula ciliada epitelial das vias aéreas, em que os microtúbulos duplos periféricos aparecem numerados de 1 a 9 (cada qual com sua subfibra A e B); os microtúbulos centrais aparecem designados C1 e C2. Nas subfibras A encontram-se os braços externos e internos de dineína, cuja interação dinâmica com a subfibra B do microtúbulo adjacente promove o deslizamento dos microtúbulos duplos, um sobre o outro. Estão representadas também as pontes de nexina, que unem os microtúbulos duplos, impedindo o desarranjo estrutural durante o deslizamento, e as espículas radiais, dispostas da periferia para o centro do eixo ciliar. Em B, micrografia eletrônica (aumento original: 50.000×) mostrando o aspecto ultraestrutural de um corte axial de cílio normal de via aérea. Fonte: Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo (SP) Brasil, 2010.

Quadro 1.. Defeitos na ultraestrutura ciliar, mutações genéticas e padrão de batimento ciliar na discinesia ciliar primária.

Quadro 2.. Avaliação quantitativa dos braços de dineína.

Figura 2.. Micrografias eletrônicas de cílios com defeitos ultraestruturais. Em A, ausência de braços externos de dineína (aumento: 65.000×); em B, desarranjo dos microtúbulos (aumento: 30.000×); em C, ausência do par central, com a apresentação 9+0, que costuma se associar com o defeito de transposição 8+2 (aumento: 65.000×); em D, defeito de transposição 8+2 (aumento: 65.000×). Fonte: Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo (SP) Brasil, 2010.

Quadro 3.. Investigação de discinesia ciliar primária.

Figura 3.. Corte axial de TCAR de tórax de paciente de 30 anos de idade com discinesia ciliar primária (ausência de braços externos e internos de dineína) e doença pulmonar avançada. Nota-se importante comprometimento das bases pulmonares, com imagens de espessamento brônquico, sinal do anel de sinete, áreas de consolidação e diferenças de atenuação. Fonte: Divisão de Pneumologia Clínica do Instituto do Coração, Hospital das Clínicas. Faculdade de Medicina da Universidade de São Paulo (SP), Brasil, 2014.