Primary ciliary dyskinesia


Primary ciliary dyskinesia (PCD) is a rare condition due to mutations in genes that control the transport, assembly, and functioning of cilia. The failure of these organelles, which are found in the respiratory tract and in the reproductive system, causes the accumulation of mucus in the mucous membranes, which favors the development of bacteria and consequently of infections. This condition is clinically heterogeneous and is usually characterized by respiratory symptoms such as chronic and recurrent sinopulmonary infections, male infertility, and, in approximately 50% of patients, laterality defects (situs inversus) in what is termed Kartagener syndrome. PCD is also characterized by genetic heterogeneity: to date, more than 40 genes associated with this condition are known, which in almost all cases follow an autosomal recessive transmission. Rarely autosomal dominant or X-linked inheritance have been reported.

Detailed clinical description

Primary ciliary dyskinesia is characterized by phenotypic heterogeneity and different age at onset. In severe cases, patients may present with symptoms from birth such as respiratory distress and rarely hydrocephalus. During childhood, patients manifest recurrent infections, chronic cough, chronic rhinosinusitis with nasal polyposis, and recurrent otitis, which can cause deafness. Recurrent infections can evolve into a picture of bronchiectasis.

In about 50% of cases, patients have all internal organs (heart, spleen, liver, intestines) in an inverted position from normal (situs inversus totalis). In this case, we talk about Kartagener syndrome. In a smaller percentage, about 12%, partial heterotaxia is instead present, a condition for which only some of the internal organs are incorrectly positioned. In general, situs inversus totalis does not give clinical symptoms, while partial heterotaxia is often associated with asplenia, congenital heart malformations, renal, biliary and intestinal anomalies.

PCD is also often associated with infertility. In males there are often problems with sperm motility, due to the fact that the flagella, the mobile part of the spermatozoa, can also be affected. Females, on the other hand, have a greater risk of ectopic pregnancy, due to the failure of the cilia present in the fallopian tubes.

The diagnosis of PCD is based on the identification of typical clinical signs and is confirmed through biopsy of the respiratory epithelium and genetic test. For a first step towards diagnosis, the measurement of nasal nitric oxide levels is used in children over the age of 5, to makes it possible to identify patients who should undergo a biopsy. The biopsy of the ciliary mucosa allows identifying the ciliary function (in the form of the frequency of the ciliary beat) and the ciliary structure with transmission electron microscopy. However, it should be emphasized that about 30% of patients with a strong clinical suspicion of PCD do not have ultrastructural abnormalities of the cilia.

Prevalence and/or incidence

PCD is a rare disease, but it is the second most common congenital respiratory disease after cystic fibrosis. It has an estimated incidence of about 1/16,000 – 1/20,000 live births. Kartagener syndrome, on the other hand, has an incidence of about 1/32,000 – 1/40,000.

Molecular genetics

PCD is characterized by genetic heterogeneity and more than 40 associated genes are known to date. However, in some cases the gene locus has been mapped, but the responsible gene has not been identified.

In almost all cases, PCD has an autosomal recessive inheritance; with the exception of FOXJ1 which has an autosomal dominant inheritance and OFD1 and PIH1D3 which have an X-linked inheritance.

It should be noted that in about 20% -30% of cases the molecular cause underlying the disease is not identified.

The most frequently mutated genes are DNAH5 (15% -29% of cases), DNAI1 (2% -10%), DNAH11 (6% -9%), CCDC39 (4% -9%). The ARMC4, CCDC40, CCDC103, CCDC151, SPAG1 and ZMYND10 genes have a mutation rate of 2% -4% each, while all other genes are very rarely mutated.

Differential diagnosis

Cystic fibrosis, due to mutations in CFTR. It is characterized by recurrent respiratory tract infections, bronchiectasis, but there are laterality defects.

Immunodeficiencies, such as IgG deficiency, characterized by recurrent infections of the ears, sinuses, lungs and bronchi.

Other conditions such as allergic rhinitis, gastroesophageal reflux and Wegner’s granulomatosis.

Visceral heterotaxia, a condition in which patients have abnormal positioning of internal organs, in the absence of recurrent infections and respiratory symptoms.

Genetic testing strategy

Since PCD is characterized by high genetic heterogeneity, it is recommended to proceed with the analysis of a Next Generation Sequencing panel that includes all the genes associated with this condition. Breda Genetics offers the analysis of genes for primary ciliary dyskinesia through multi-gene panels based on whole exome (EXOME 60MB) or whole genome (FULL GENOME) sequencing. Furthermore, in the event of a negative result, it is possible to proceed with the analysis of large deletions/duplications on the genes of interest starting from the sequencing data (algorithmic CNV), or through specific methods such as MLPA and qPCR.

Panel testing recommended at Breda Genetics for this condition:

Pan28 – Primary ciliary dyskinesia (ARMC4, CCDC103, CCDC114, CCDC151, CCDC39, CCDC40, CCDC65, CCNO, CENPF, CFAP221, CFAP298, CFAP300, DNAAF1, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAH1, DNAH11, DNAH5, DNAH9, DNAI1, DNAI2, DNAJB13, DNAL1, DRC1, FOXJ1, GAS2L2, GAS8, HYDIN, LRRC6, LRRC56, MCIDAS, NEK10, NME5, NME8, OFD1, PIH1D3, RSPH1, RSPH3, RSPH4A, RSPH9, SPAG1, STK36, TTC12, TTC25, ZMYND10)


OMIM phenotypic series Primary ciliary dyskinesia – PS244400

Bhatt R, Hogg C. Primary ciliary dyskinesia: a major player in a bigger game. Breathe (Sheff). 2020 Jun;16(2):200047. doi: 10.1183/20734735.0047-2020. PMID: 33304404

Horani A, Ferkol TW. Understanding Primary Ciliary Dyskinesia and Other Ciliopathies. J Pediatr. 2021 Mar;230:15-22.e1. doi: 10.1016/j.jpeds.2020.11.040. Epub 2020 Nov 23. PMID: 33242470.

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