Kartagener syndrome? Situs inversus? Ciliary dyskinesia?

Kartagener Syndrome? Situs inversus? Ciliary dyskinesia? Summary literature review

It is also known as primary ciliary dyskinesia, immotile cilia syndrome or Kartagener’s syndrome. It is a rare, autosomal recessive ciliopathic disease. Symptoms and signs depend on ciliary movement disorder. Cilia are mobile, hairy structures found in the mucous membranes of the lower and upper respiratory tracts, middle ears and Eustachian tube, and tubes. The cilia in the respiratory tract help to expel mucus by synchronously moving in a sweeping pattern 7-22 times per second. Although cilia are feather-like in appearance, they are completely different cellular organelles in structure. Impaired ciliary movement leads to impaired mucus outflow and impaired respiratory function. Cilia are also active in some chemical processes such as nitric oxide production. This issue is still being investigated by dozens of studies. As the structure and function of cilia are better understood, the disease process of primary ciliary dyskinesia will be better understood.
The name immotile cilia syndrome has been abandoned because the cilia are generally mobile. The real problem is the nature of the movement. Sometimes this movement is not functionally active, and sometimes the synchronization of the movement is problematic. When ciliary dyskinesia is accompanied by situs inversus, sinusitis and bronchiectasis, it is called Kartagener’s syndrome. 50% of patients with primary ciliary dyskinesia fall into the Kartagener class.
The collection of symptoms associated with PSD was first described in 1904 by AKZievert. Manes Kartagener from Zürich, who gave the disease its name, published it in 1933.
The true incidence of the disease is unknown. It is estimated between 1/15000 and 1/32000. It is classified in the category of rare diseases in the USA.
Symptoms and signs:
Some of the symptoms of ciliary dysfunction are due to the inability to remove mucus and secretions from the lungs, sinuses, and ear. Sinusitis, bronchitis, pneumonia, otitis media are among these symptoms. Although the symptoms and signs are dramatic, diagnosis at an early age is rare.
Progressive damage to the respiratory system manifests itself in the form of chronic sinusitis and bronchiectasis. Cough, shortness of breath, shortness of breath due to superinfections are common symptoms. In severe cases, lower respiratory tract problems may even require lung transplantation. In cases of early diagnosis, the progression of pulmonary findings can be successfully reduced and delayed with treatment.
In the sinuses, edematous mucosa, fully opacified sinuses, nasal polyps, hypoplastic frontal sinuses, and sometimes decreased sense of smell are observed. Early and aggressive treatment of sinus disease is thought to reduce the rate of late chronic sinusitis. However, this ratio is not well documented.
Hearing loss secondary to otitis media in patients responds variably to myringotomy, tympanostomy, and tube insertion.
In some patients, the senses of taste and smell may be severely affected. This is sometimes attributed to excessive mucus accumulation in the sinuses. In other patients, the senses of taste and smell are completely normal.
Primary ciliary dyskinesia is a genetic disease. Cilia are 5-10 micron long hairy structures extending out of the cell. There are two equal cilia in the body. Motile cilia and immotile or primary cilia. Motile cilia are oscillating nanomachines, immotile cilia mostly function in sensory organs. In this article, motil cilia is meant by the word cilia unless otherwise stated. In ciliary dyskinesia, internal and external dynein arms, central part, radial extensions, etc., are the structures that reveal motile cilia. etc. damaged or structurally deficient. Therefore, the axoneme structure in the cilia lacks the ability to move smoothly. We can summarize the functions of cilia in the individual as development of the organism, movement of extracellular fluids, cell movement and reproduction.
The ciliary structure consists of approximately 250-600 different proteins. The cilia consist of two tubules in the center connected by a protein bridge and 9 pairs of tubules around it. Axonemes are structures located in the center of cilia and flagella. There is a pair of dynein arms extending from each pair of peripheral tubules A and B to the adjacent tubule. The inner inner dynein arm inside is called the outer outer dynein arm. Nexin connects the peripheral double tubules. The radial extensions connect the double tubule structure in the center to the tubules in the periphery and add rigidity to the structure. The radial extensions consist of the head and radial extensions. The entire structure is surrounded by the plasma membrane. The root part that connects the cilia to the cell is structurally different. This part consists of 9 peripheral triplets without a central pair.
Despite the robustness of the structure, there may be biochemical and ultrastructural processes that adversely affect cilia movement. Some proteins eg. dynein arms, radial extensions, central tubules may be missing or defective. Structural defects may be found in the cilia. eg. centrioles with giant roots, complete absence of one of the internal structures in the cilia, cilia different from the normal length (eg 2 times longer). We can summarize the dysfunction in cilia as hypo- and hyper-motility, irregular alignment, oscillation in irregular rhythm and oscillation in irregular directions.
The task of the cilia is to move mucus and liquid on their surface. Chronologically, the first disorders can show their effects from early embryonic life. At the center of the disorder in the embryonic period are specialized monociliary structures. These structures lack the central double tubule found in normal cilia, so they rotate instead of sweep. In the primitive node (Henson’s node), located at the anterior end of the primitive cleft, which creates bilateral symmetry, the angle of the cilia is posteriorly. Movement of these cilia causes leftward movement of Sonic Hedgehog (Shh) protein on the embryonal disc surface. This leads to the asymmetric development of the right and left in the organism. Apart from the Hedghog pathway, cilia have effects on the Wnt pathway in embiogenesis.
In some individuals, a mutation in the genes encoding the left-right dynein protein leads to the formation of non-rotating monociliary structures. When there is no movement in the Henson node, the Shh protein is randomly distributed. Half of these individuals develop situs inversus. Situs inversus can develop without dextrocardia. These individuals also develop Kartagener syndrome. In some (6%) primary ciliary dyskinesias, heterotaxy (unstable situs or) situs ambiguus develops. These are hybrid states that fall between situs inversus and situs solitus. In situs ambiguus, splenic anomalies such as polysplenia and asplenia are found. Congenital heart anomalies are common. The stomach, liver, and (adjacent) adrenals can be found in the midline.
The relationship between nodal monocilia, PSD and situs states is the subject of current research. There are many hypotheses out there. These hypotheses change frequently.
Relationship with other diseases
Advances in genetics reveal that many syndromes and diseases that are known to be phenotypically unrelated are actually based on similar genotypic origins. Primary ciliary dyskinesia is a ciliary disease. Other known ciliopathies include Bardet-Biedl syndrome, polycystic kidney and liver diseases, nephronophthysis, Alstrom syndrome, Meckel-Gruber syndrome and some types of retinal degeneration, some of early fetal death.
Mutations in different genes such as 9, 5 and 7 have been identified in patients with primary ciliary dyskinesia. Cilia are composed of about 250 proteins, genes affecting some of them can cause primary ciliary dyskinesia. In this respect, it is not a single disease but a heterogeneous group of diseases. However, 38% of these defects occur in the DNAI1 and DNAH5 genes, which encode the outer dynein arm. An international group is trying to classify these defects.

Medicine OMIM Gene locus
CILD1 244400 DNAI1 9p21-p13
CILD2 606763 ? 19q13.3-qter
CILD3 608644 DNAH5 5p
CILD4 608646 ? 15q13
CILD5 608647 ? 16p12
CILD6 610852 TXNDC3 7p14-p13
CILD7 611884 DNAH11 7p21
CILD8 612274 ? 15q24-q25
CILD9 612444 DNAI2 17q25
CILD10 612518 KTU 14q21.3
CILD11 612649 RSPH4A 6q22
CILD12 612650 RSPH9 6p21
CILD13 613190 LRRC50 16q24.1

Chest physiotherapy has been shown to reduce the rate of infection and slow the progression of bronchiectasis. Measures to increase mucus clearance and early treatment of superinfections reduce the progression of pulmonary symptoms. Treatment is often symptomatic.

  1. Zivert AK (1904). “Über einen Fall von Bronchiectasie bei einem Patienten mit situs inversus viscerum”. Berliner klinische Wochenschrift. 41:139–141.
  2. Kartagener M (1933). “Zur Pathogenese der Bronchiektasien: Bronchiektasien bei Situs viscerum inversus”. Beiträge zur Klinik der Tuberkulose. 83: 489–501.

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