Kartagener syndrome

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Kartagener syndrome

Definition

Kartagener (pronounced KART-agayner) syndrome refers to a condition that involves difficulty with clearing mucus secretions from the respiratory tract, male infertility, and situs inversus. The defining characteristic of this syndrome is the situs inversus, which is a reversal of abdominal and thoracic organs.

Description

This syndrome is named after Kartagener, a physician from Switzerland. In the 1930's, Kartagener and a colleague described a familial form of bronchiectasis with situs inversus and nasal polyps. This came to be known as Kartagener syndrome. Kartagener syndrome is also known as the Siewert syndrome, after another physician, Siewert, who described the syndrome in the early 1900's.

Individuals who have Kartagener syndrome form a subset of the disorder called primary ciliary dyskinesia. Originally, primary ciliary dyskinesia was known as immotile cilia syndrome. The name, immotile cilia syndrome, is no longer used since the discovery that the cilia are actually not immotile, but rather, abnormal in movement. Individuals who have Kartagener syndrome, basically have primary ciliary dyskinesia, plus partial or complete situs inversus. The situs inversus is what sets Kartagener syndrome apart from primary ciliary dyskinesia.

Kartagener syndrome is caused by abnormalities of the cilia that line the respiratory tract and also form the flagella of sperm. Cilia are tiny hair-like structures that contain a bundle of small parallel tubes that form a central core. This core is called the axoneme. Ciliary movement is accomplished by the bending of the axoneme. One of the most important associated structures that enable ciliary movement to occur are sets of tiny arms that project from each tubule. These tiny arms are called dynein arms.

Cilia line the cells of the lungs, nose and sinuses. Before reaching the lungs, air travels through the airway where it is moistened and filtered. The nasal passages and airway are lined with mucus membranes. The mucus covering the mucus membrane traps dirt and other foreign particles that have been breathed in. The cilia, lining the membranes, beat in a wavelike manner moving the layer of mucus and carrying away the dirt and debris that has been trapped. This mucus can then be coughed out or swallowed into the stomach.

In Kartagener syndrome, the cilia do not move, move very little, or move abnormally. Because the cilia do not function properly, the mucus is not cleared from the respiratory tract, which leads to sinus infection (sinusitis) and chronic changes of the lung (bronchiectasis), which make it difficult to exhale. Mucus clearance from the middle ear can also be affected and over time can lead to hearing loss.

The male infertility in Kartagener syndrome is also caused by abnormal cilia movement. One spermatozoon consists of a head, midpiece, and a tail or flagellum. The tail of a spermatozoon is a long flagellum consisting of a central axoneme. This axoneme enables the movement of the flagellum so that the spermatozoon can propel its way to the fallopian tube and burrow through the egg coat to fertilize the egg. In Kartagener syndrome, these cilia are either immotile, or are not able to move normally to complete the journey to the fallopian tubes, nor may they be able to burrow through the egg coat. This results in male infertility.

As stated above, situs inversus is what sets Kartagener syndrome apart from primary ciliary dyskinesia. Complete situs inversus involves reversal of both the abdominal and thoracic organs so that they form a mirror image of normal. In partial situs inversus, the thoracic organs may be reversed, while the abdominal organs are normally positioned, or vice versa. Approximately one in 10,000 adults have situs inversus. Only about 20% of individuals who have complete situs inversus are diagnosed to have Kartagener syndrome. Of those with complete situs inversus who are diagnosed to have Kartagener syndrome, there is only a small risk for associated cardiac defects. Partial situs inversus may occur in individuals who have Kartagener syndrome as well. Partial situs inversus has a higher association with other abnormalities, including polysplenia or asplenia (extra or absent spleen) and cardiac defects.

One theory behind the association of situs inversus with the underlying cause of Kartagener syndrome is that the lack of ciliary movement in the developing embryo may result in incorrect organ rotation in approximately 50% of affected individuals. In fact, 50% of patients with PCD will have situs inversus and thus be diagnosed to have Kartagener syndrome. However, this is a theory supported only by some researchers.

Genetic profile

Kartagener syndrome is an autosomal recessive condition. This means that in order to have the condition, an individual needs to inherit two copies of the gene for the condition, one from each parent. Individuals who carry only one gene for an autosomal recessive syndrome are called heterozygotes. Heterozygotes for Kartagener syndrome have normal ciliary function and do not have any clinical features of the condition. If two carriers of Kartagener syndrome have children, there is a 25% chance, with each pregnancy, for having a child with Kartagener syndrome.

The components that form the cilium contain several hundred different proteins. Each is coded for by different DNA sequences, potentially on different chromosomes . A defect in any of these codes could produce an abnormal or missing protein that is a building block for the cilium and thus could cause abnormal ciliary structure and movement, resulting in Kartagener syndrome.

When the same condition can be caused by different genetic abnormalities, this is known as genetic heterogeneity. In fact, several different defects in cilia have been seen in association with Kartagener syndrome, including; overly long cilia, overly short cilia, absent cilia and randomly oriented cilia, suggesting genetic heterogeneity. Studies have suggested that the most common defect of cilia in Kartagener syndrome is the lack of dynein arms. There have been rare cases in which individuals have Kartagener syndrome, yet have no detectable abnormality of the cilia, even though the ciliary function is abnormal. Results of one study involving a genome-wide linkage search performed on 31 families, with multiple individuals affected with either PCD or Kartagener syndrome, strongly suggested extensive heterogeneity. Potential regions involving genes responsible for PCD or Kartagener syndrome were localized on chromosomes 3, 4, 5, 7, 8, 10, 11, 13, 15, 16, 17 and 19.

Demographics

Kartagener syndrome occurs in approximately one in 32,000 live births, which is half the incidence of primary ciliary dyskinesia (one in 16,000 live births). Kartagener syndrome is not found more commonly in any particular sex, ethnic background or geographic region. Males, however, may be diagnosed more often than females because of infertility investigation.

Signs and symptoms

Newborns who have Kartagener syndrome may present with neonatal respiratory distress. Often when individuals are diagnosed to have Kartagener syndrome in later childhood, problems such as neonatal respiratory distress may be identified in their history. Symptoms that may present in childhood include; recurrent ear infections (otitis media) that can lead to hearing loss, chronic productive cough, reactive airway disease, pneumonia, chronic bronchitis, runny nose (rhinitis) with a thin discharge, and sinus infection (sinusitis). Situs inversus usually does not present symptomatically, unless it is associated with a congenital heart defect.

The most common clinical expression of Kartagener syndrome in adults includes chronic upper and lower airway disease presenting as sinusitis and bronchiectasis. Clubbing of the digits (fingers) may occur as the result of chronic hypoxia (lack of oxygen) from bronchiectasis. In males of reproductive age, male infertility is almost universal. In females who have Kartagener syndrome, infertility is not usually a characteristic. This suggests that the egg transport down the fallopian tube is associated more with muscle contractions than with ciliary movement.

Several other conditions should be considered when the aforementioned symptoms present, including; Cystic fibrosis (CF), immune deficiencies and severe allergies. Although the causes of Kartagener syndrome and CF are completely different, the symptoms of these two diseases are very similar. Often when the symptoms present, children with Kartagener syndrome are tested for CF first because the incidence of CF is much higher (one in 2,400) than the incidence of Kartagener syndrome. CF is also associated with male infertility.

Diagnosis

Diagnosis of Kartagener syndrome is confirmed by identifying the ciliary abnormalities of structure and movement. This is accomplished by biopsy of the mucus membranes of the respiratory tract and/or by examination of sperm, looking for ciliary dyskinesia. Situs inversus can be identified by x ray or ultrasound examination. Infertility investigation may elicit the possibility of Kartagener syndrome in a patient previously undiagnosed. After a diagnosis is made, genetic counseling should be provided to discuss the inheritance pattern, to help identify other possible affected family members and to discuss reproductive options.

As Kartagener syndrome is an autosomal recessive disorder, individuals who have had a child with Kartagener syndrome have a 25% chance, with each future pregnancy, of having another child with Kartagener syndrome. Prenatal diagnosis may be possible for a couple with a previously affected child, by performing ultrasound examination to identify a fetus who has situs inversus. Although, if the fetus does not exhibit situs inversus, it is still possible for the fetus to have PCD. Also, it is important to remember that identifying a fetus who has situs inversus in a family not known to be at an increased risk for Kartagener syndrome, does not mean that the fetus has Kartagener syndrome as only 20% of individuals who have situs inversus have Kartagener syndrome. As of January 2001, DNA testing for Kartagener syndrome is not possible.

Treatment and management

Treatment for Kartagener syndrome involves treatment of the symptoms. Treatment for sinusitis includes the use of antibiotics to treat and prevent recurrent infection. Occasionally, surgery to relieve the sinusitis and remove nasal polyps that may be present is necessary. Daily chest physiotherapy to loosen mucus secretions is a common therapy as well, and if started early in life can help to prevent or delay development of bronchiectasis. Tympanoplasty in children with recurrent ear infections is often necessary.

Advances in reproductive technology allow for men who have Kartagener syndrome to have the opportunity to have children. A procedure called intracytoplasmic sperm injection or ICSI, now allow immotile or dysmotile sperm to fertilize an egg. ICSI involves injection of a single sperm into single eggs in order for fertilization to occur. This procedure first involves ovulation induction and egg retrieval to obtain eggs for attempt at fertilization by ICSI. In Vitro Fertilization (ICSI) pregnancy rates vary from center to center. Overall pregnancy rates of 10%-40% have been quoted worldwide, utilizing these procedures.

The chance for an affected male and his unaffected partner to have a child who has Kartagener syndrome is small. If the disease incidence is one in 32,000, then the chance for the unaffected woman to be a carrier of Kartagener syndrome is approximately one in 100 and the chance for having an affected child would be expected to be approximately one in 200 (0.5%). However, all children of affected males or females will be carriers for Kartagener syndrome.

Prognosis

The severity of Kartagener syndrome is variable. With the advent of antibiotic use for infection control, the life expectancy of a patient with Kartagener syndrome is close to or within the normal range, if there are no immediate problems in the newborn period.

Resources

BOOKS

Jones, Kenneth Lyons. Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B.Saunders Company, 1997.

PERIODICALS

Guichard, Cècile, et al. "Axonemal Dynein Intermediate-Chain Gene (DNAI1) Mutations Result in Situs Inversus and Primary Ciliary Dyskinesia (Kartagener Syndrome)." American Journal of Human Genetics (April 2001): 1030.

ORGANIZATIONS

American Lung Association. 1740 Broadway, New York, NY 10019-4374. (212) 315-8700 or (800) 586-4872. http;//www.lungusa.org.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.