KARTAGENER’S SYNDROME

ahmad aswar siregar , amira permatasari tarigan

Departement of Pulmonology and Respiratory Medicine
School of Medicine USU / H.Adam Malik General Hospital

ABSTRACT

Kartagener’s Syndrome is an autosomal recessive disorder primarily

manifesting as ciliary movement disorder and characterized by dextrocardia or
situs inversus , bronchiectasis and sinusitis. The frequency is 1 case per
32.000 live births and situs inversus totalis occurs randomly in half patients with
primary ciliary dyskinesia. Treatment for Kartagener’s syndrome is supportive.
We report a case of a 38-year-old woman with chronic sinusitis,
bronchiectasis and situs inversus totalis. Saccharine test showed this patient
have disorder of mucociliary clearance. This patient we diagnosed with
Kartagener’s syndrome.
Key words: Kartagener’s syndrome, Primary Ciliary Dyskinesia, Dextrocardia,
Situs inversus, Bronchiectasis, Sinusitis,.

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I. INTRODUCTION
Kartagener Syndrome’s (KS) is an autosomal recessive inheritance
characterized by bronchiectasis, sinusitis and dextrocardia or situs inversus.1,2
Situs inversus can be seen in about 50% of cases. 3 The condition was first
described by Zivert in 1904 but the detail of conditions were given by Manes
Kartagener in 1933 and it was known by his name (Kartagener’s syndrome)
ever since.4,5 It is also known as Afzelius syndrome, Kartagener’s triad, Zivert’s
syndrome, or Zivert-Kartagener triad.5 Basic problem is the defective
movement of cilia. Males are generally infertile because of immotile sperms,
however some males have completely normal spermatozoa and cases of semi-
sterility in females have been reported.1 Diagnosis can be made by tests to
prove impaired cilia function, biopsy, and genetic studies. Treatment is
supportive.3 The early diagnosis and treatment of this entity avoids the risk of
diagnosis and therapeutic errors.6 In severe cases, the prognosis can be fatal if
bilateral lung transplantation is delayed.3

II. CASE REPORT

A 38-year-old woman presented with bloody cough for about 5 months,
she also had a productive cough for about 5 months. She also had experienced
rhinorrhea and headache since childhood. Episodic fever was present for this 6
months. She also suffered from shortness of breath for about 3 months and
worsened in this 1 week. She has been admitted to private hospital in this 5
days. Her previous record showed a lot of investigations including
investigations for tuberculosis such as repeated chest x-rays and examination
of the sputum. Her record also revealed that she received several courses of
antibiotics, anticoagulants, antipyretics, mucolytics, bronchodilators, and even
anti-tuberculous drugs but the response was only partial and temporary. She
had just consumed of anti-tuberculous drugs for 2 months and then she
stopped it. Because of the repeating and worsening of clinical symptoms, she
was admitted to H. Adam Malik General Hospital for further assessment.

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 Vital signs showed alert, blood pressure 120/70 mmHg, heart rate 90
beats per minute, respiratory rate 24 times per minute, and body temperature
37,3°C.
On admission, physical examination showed apex beat was on the right
side of the chest in the right lateral of midclavicle line. Her heart sounds were
heard best on the right side of the chest. She had a symmetrical chest wall
expansion, harden impression of stem fremitus on both right and left side of
chest, percussion showed hyporesonant on the both of chest. Auscultation
revealed bronchial sound heard over both chest and accompanied by an early
inspiratory crackles all over the chest. There was no digital clubbing found.
Laboratory finding: Hb: 11,0 gr/dl, WBC: 12.89 x 103/mm3, PLT: 443 x 103/mm3,
Glucose: 78.5 mg/dl, SGOT: 14 U/L, SGPT: 14 U/L.
Liver function test: Total bilirubin 0.39 mg/dL, direct bilirubin 0.16 mg/dL, total
protein 6.9, albumin 3.0 g/dL, globulin 3.9 g/dL, Procalcitonin 0.14 ng/dL.
Renal function test : ureum 33.50 mg/dl, creatinine 0.62 mg/dl, natrium 130
mEq/L, potassium 3.8 mEq/L, chloride 106 mEq/L.
Analysis of blood gases: pH 7.387, pCO2 37.7 mmHg, pO2 112.2 mmHg,
bicarbonate ion 22.4 mmol/L, total CO2 23.3 mmol/L, base excess -2.8 mmol/L,
oxygen saturation 98.1%.
From the past medical history it was notable that there is repeated
bloody cough, chest infections and chronic sinusitis from early childhood. The
diagnosis was based on the clinical symptoms, radiological picture and
saccharine test. The patient was consulting to a pulmonologist because of her
main complaint, the bloody cough, for about 3 months.
The Chest X-Ray showed dextrocardia and honey combs appearance
(Fig.1). Computed tomography (CT) of the chest showed dextrocardia and
bronchiectasis (Fig.2). Bronchoscopy showed of bleeding in the main right
bronchi (Fig.3). Spirometry revealed both of restrictive and obstructive
ventilatory defect: FEV1, 30% pred. (2.36 L); FVC, 35% (2.75 L); FEV1/FVC,
74,1% (Fig.4) . ECG showed QS waves and inverted T waves in Lead-I along
with other features of dextrocardia. (Fig.5).The sinus paranasal x-ray (Fig.6)
and CT-Scan of sinus paranasal (Fig.7) showed mucosal thickening, opacified

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sinus cavities and other features of chronic sinusitis maxillary. Saccharine Test
for mucociliary clearance of this patient is 40 minutes 35 second (normal : < 20
minutes) 9. Ultrasound of abdomen showed normal right and left kidney (Fig.8).
and also showed spleen on the right side of the abdomen while liver on the
left., spleen on the right (situs inversus) (Fig.9). Based on microbiological
assessment of the direct smear of sputum for Acid fast bacili (AFB) : There was
no AFB found in all three times of the direct smears. Gram negative bacteria
was found and fungi was not observed in the direct smear. The most common
pathogen isolated from culture of the sputum was Acinetobacter baumannii.
From the broncho-alveolar lavage fluid , the AFB was not found, fungi was not
found, bacteria negative gram was found. From the sputum culture there was
observed bacteria Acinetobacter baumannii.
Considering the clinical picture of this patient, primary ciliary dyskinesia
(PCD), sinusitis, bronchiectasis and situs inversus, the clinical diagnosis of
Kartagener’s syndrome was made. The condition was explained to the patient
and she was treated with antibiotics, anticoagulants, antipyretics, mucolytics
and inhaled bronchodilators. The nutrition for this patient was optimized, and
the environmental pollutants (including tobacco smoke) were avoided.

Fig.1 : Chest X-Ray showed dextrocardia and honey combs appearance.

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Fig.2 : Computed tomography (CT) of the chest showed dextrocardia and
bronchiectasis.

Fig.3 : Broncoscopic showed of bleeding in the main right bronchus.

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Fig. 8: Ultrasound of abdomen showed both normal kidneys on
the right and the left side.

Fig. 9: Ultrasound of abdomen showed spleen on the right side

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 of the abdomen while liver on the left, spleen on the right
(situs inversus)

Fig.4: Spirometry revealed both of restrictive and obstructive ventilatory defect:

FEV1 30% pred. (2.36 L); FVC 35% (2.75 L); FEV1/FVC 74,1% .

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Fig.5 : ECG showed the features of dextrocardia.: Sinus Tachycardia + Right Axis
Deviation + global negativity
III. DISCUSSION

Kartagener Syndrome’s (KS) is an autosomal recessive disorder

primarily manifesting as ciliary movement disorder and characterized by
dextrocardia or situs inversus , bronchiectasis and sinusitis 2,7. Cilia may be
immotile or may show uncoordinated and inefficient movement patterns. Ciliary
movement disorders may be congenital or acquired. Congenital ciliary
disorders are labeled as primary ciliary dyskinesia (PCD). KS is a part of the
larger group of disorders referred to as PCD 1,2. KS is seen in 50% cases of

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PCD 4. This patient has PCD with situs inversus, bronchiectasis and sinusitis
that are known as KS.
The frequency is 1 case per 32.000 live births and situs inversus totalis
occurs randomly in half patients with primary ciliary disorder. However primary
ciliary dyskinesia is responsible for 5 to 10% of cases of bronchiectasis.8
The workup of patients with PCD should evaluate their respiratory cilia
with functional analysis and with ultrastructural examination by electron
microscopy. Common tests for mucociliary function measure the clearance of a
tracer from upper airway. The saccharin test is simple and cost- effective for
screening for PCD. Saccharin is placed in the anterior portion of the inferior
turbinate. As ciliary beating moves secretions into the oropharynx, the patient
will note a sweet taste. Normal saccharin transit time is 20 minutes. In other
conditions, such as CF or bronchiectasis, in which thickened mucus can delay
mucus clearance, the average transit time is about 30 min. Other tracers have
also been used to measure mucociliary clearance, such as 99m Tc-albumin
colloid droplets or radioaerosol mucociliary clearance in the lower airways.
More recently, a reduction in nasal nitric oxide has been shown to have both
sensitivity and specificity of approximately 90% for proven PCD. However, a
decrease on nNO can also be seen in some cases of CF and in severe
rhinosinusitis of either infectious or allergic nature.9

Table 1. Clinical manifestations of PCD 10

Organ Clinical manifestation
Lung Respiratory distress in term neonates
Bronchitis/recurrent infections
Bronchiectasis
Ears Otitis media
Hearing loss
Cholesteatoma (after tympanostomy)

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Nares/sinus Chronic sinusitis
Polyposis
Genitourinary tract Male and/or Female= infertility
Organ laterality Situs inversus totalis
Situs ambiguus (heterotaxy), including
(a) Polysplenia or asplenia
(b) Vascular anomalies
(c) Complex congenital heart disease
Central nervous system Hydrocephalus (rare)

Ciliated columnar epithelial move mucus and other substances via cilia,
and are found in the upper respiratory tract, the Fallopian tubes, the uterus, and
the central part of the spinal cord. Mucociliary clearance is an important primary
innate defense mechanism that protects the lungs from deleterious effects of
inhaled pollutants, allergens, and pathogens. Ciliated columnar epithelium lines
the lumen of the uterine tube, where currents generated by the cilia propel the
egg cell, toward the uterus. Cilia are also involved in maintaing left –right axis
during embryogenesis. Situs inversus can be defined as the random
distribution of internal organs during embryogenesis, probably due to the
absence of the ciliary activity that is responsible for normal organ distribution.11

Normal ultrastructure of motile cilia

Cilia and flagella are evolutionarily ancient organelles whose structure
and function have been rigidly conserved across the phylogenetic spectrum.
Historically recognized for their role in cell motility and transport of fluids over
mucosal surfaces. Fig. 10 shows the lower airway and respiratory epithelium
with cilla. The core, or axoneme, of the cilia and flagella consists of a “9+2”
microtubule structure with a ring of nine microtubule doublets surrounding a
central pair of single microtubules. The nine microtubule doublets are studded

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with dynein arms that contain adenosine triphosphatases and act as molecular
motors to effect the sliding of the peripheral microtubular pairs relative to one
another. The outer dynein arms (ODA) are positioned proximal to the ciliary
membrane and the inner dynein arms (IDA) proximal to the central apparatus of
the A microtubule. The dynein arms are large protein complexes each
comprised several heavy, light, and intermediate chains. Cilia were classified
as motile and non-motile. The classification is depicted in Figure 11. 12

Fig. 10. Diagrammatic view of the lower airway and respiratory epithelium with cilia.12

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Fig. 11. Diversity of cilia. Cross section of motile cilia (9+2 and 9+0 arrangement) and
non-motile (9+0 arrangement) is shown. This diagram is modified from the review. 12

There are three basic groups of cilia (see Fig. 11); motile 9+2 cilia with
attendant dynein arm structures (e.g., airway), nonmotile 9+0 primary cilia
lacking dynein arms. In contrast to the 9+2 pattern of motile cilia with dynein
motors, there are structural variants without dynein motors that have a 9+0
microtubular (e.g., kidney tubules), and motile 9+0 primary cilia possessing
dynein arms (e.g., embryonic node). Unlike the numerous motile cilia present
on airway epithelial cells, these primary cilia are borne as solitary appendages.
Historically thought to be nonfunctional or vestigial, they have been
rediscovered in recent years as structures central to organ positioning during
embryologic development and to the detection of mechanical and chemical
gradients. Thus, primary cilia are now recognized as structures modulating
detection, orientation, and positioning.12

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Fig. 12. Cilia electron microscopy.
Normal ultrastructure is shown (magnification_39,000 bar).13

Ciliary abnormalities
In KS, 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.14

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Fig.13 Components of the mucociliary system: the cilia (hair type projections of the
epithelia cells), the periciliary fluid layer and the mucus. The mucus is secreted from
the goblet cells and the submucosal glands. Mucociliary clearance is the primary
mechanism of clearance of mucus. Under normal conditions, the cilia beat in a
coordinated fashion in the periciliary fluid layer propelling the mucus towards the
mouth. When mucociliary clearance fails, cough (high expiratory airflow) becomes the
secondary mechanism for clearance of mucus.14

Ciliary abnormalities are classified into two categories; specific

congenital defects of ciliary structure incident to the "primary ciliary dyskinesia"
and acquired nonspecific anomalies of the ciliary apparatus. Acquired
nonspecific ciliary abnormalities. Acquired nonspecific ciliary abnormalities
include swollen cilia, compound cilia, intracellular ciliated vacuoles,
intracytoplasmic axoneme, cilia within periciliary sheaths or intracellular cilia,

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abnormalities in the number and arrangement of axonemal microtubules, and
others. The formation of nonspecific abnormal cilia is reversible and such cilia
are almost absent in new ciliated cells that are formed by in vitro ciliogenesis.
The peripheral microtubule alterations and the presence of swollen and
compound cilia are characteristic of ciliary dyskinesia secondary to chronic
infection of the epithelium. The absence of dynein arms was the first ciliary
defect associated with KS . This deficiency can involve the inner or outer
dynein arms or both. The ultrastructural defects of the ciliary axoneme
observed in this study are the absence of inner dynein arms, which were often
observed in PCD. Ciliary ultrastructural analysis in most patients (>80%)
reveals defective dynein arms, although defects in other axonemal components
have also been observed. The axonemal dynein arms are composed of heavy,
intermediate, and light dynein chains. A defect in any one of these proteins
could lead to an abnormal dynein arm and/or defective beating activity of the
axoneme. The complete absence of dynein arms is associated with immotile
cilia. Other ciliary defects are associated with abnormal and inefficient ciliary
beat patterns. Immotile cilia and cilia that have an inefficient beat produce the
stasis of respiratory secretions.12

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Fig.14 Cilia electron microscopy. Patients’ cilia defects, which are marked with
arrows,are as follows A: absence of dynein arms (magnification_65,000, bar
200 nm); B: shortened outer dynein arm (magnification _65,000, bar 200 nm);
C: transposition defects (magnification_65,000, bar 200 nm); and D: radial
spoke with inner dynein arms defects (magnification_30,000, bar 500 nm).13

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Genetics
PCD is inherited as an autosomal recessive disease. Over 250 proteins
are involved in the formation of cilia and the disease-causing genes are
commonly very large, making genetic diagnosis of PCD a challenge . To date,
mutations have been identified in 10 genes, mainly leading to dynein arm or
radial spoke defects . The commonest of these mutations, DNAH5 mutation
and dynein axonemal intermediate chain (DNAI)1, have a combined
prevalence of 17–35% in patients with PCD . Other knownmutations are rare.
Therefore, the sensitivity of genetic testing is currently low but should increase
with the identification of new genes. With concurrent simplification of genetic
analyses, genetic testing is likely to become more widespread.15

Situs Inversus in Kartageners Syndrome

It is assumed that during early embryonic life ciliary beats in the growing
embryo determine the type of laterality. When ciliary movements are absent
laterality may develop fortuitously, thus affecting a situs inversus in about half
the affected cases. The numerical evaluation of pedigrees from the literature
supports this assumption. 11
Development of asymmetry along the left-right axis is a critical step in
the formation of the vertebrate body plan. Disruptions of normal
left-right patterning are associated with abnormalities of multiple organ
systems, including significant congenital heart disease. Position of the viscera
(heart, lungs, liver, spleen and bowels) is defined very early in embryogenesis.
Normally, an asymmetry exists between the left and the right side of the human
body, as the liver is on the right and the spleen on the left side. However,
defects in asymmetry may occur during embryogenesis and there is a spectrum
of malformations ranging from reverse asymmetry (situs inversus) to a
complete lack of physiologic asymmetry (situs ambiguous) Amazingly, interplay
between motile and sensory cilia is required for determination of left–right axis
in early vertebrate development. Several recent breakthroughs indicate that
cilia direct left–right asymmetry by signaling within the embryonic node soon
after anterior–posterior and proximal–distal axes are established. The node is a

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transiently appearing, bowl-like structure within the midline notochord
containing an elegant cilia-powered apparatus. In the center of this bowl are
cells with a single motile cilium (moving in an unusual vertical motion) that
generate vectoral flow to transmit a signal received by primary cilia on the
periphery. These sensory cilia bend in response to flow and generate a
calcium-dependent response. This response triggers a program resulting in a
left-sided, asymmetric heart and asymmetric patterning of visceral organs.
Thus, left–right axis formation depends on proper node cell differentiation and
cilia function. Accordingly, failure in node cilia function can result in
randomization of left– right axis (half have situs inversus). 11
The recognition of situs inversus is important for preventing surgical
mishaps that result from the failure to recognize reversed anatomy or an
atypical history. For example, in a patient with situs inversus, cholecystitis
typically causes left upper quadrant pain, and appendicitis causes left lower
quadrant pain. A trauma patient with evidence of external trauma over the ninth
to eleventh ribs on the right side is at risk for splenic injury. If surgery is planned
on the basis of radiographic findings in a patient with situs inversus, the
surgeon should pay careful attention to image labeling to avoid errors such as a
right thoracotomy for a left lung nodule.11

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Fig. 15. Human laterality disorders and current models for establishing left–
right asymmetry. a | Schematic illustration of normal left–right body asymmetry
(situs solitus) and five laterality defects that affect the lungs, heart, liver, stomach and
spleen. By their vigorous circular movements, motile monocilia at the embryonic node
generate a leftward flow of extra-embryonic fluid (nodal flow). b | The nodal vesicular
parcel (NVP) model predicts that vesicles filled with morphogens (such as sonic
hedgehog and retinoic acid) are secreted from the right side of the embryonic node
and transported to the left side by nodal flow, where they are smashed open by force.
The released contents probably bind to specific transmembrane receptors in the
axonemal membrane of cilia on the left side. The consequent initiation of left-sided
intracellular Ca2+ release induces downstream signalling events that break bilaterality.
In this model, the flow of extra-embryonic fluid is not detected by cilia-based
mechanosensation. c | In the two-cilia model, non-sensing motile cilia in the centre of
the node create a leftward nodal flow that is mechanically sensed through passive
bending of non-motile sensory cilia at the periphery of the node. Bending of the cilia on
the left side leads to a left-sided release of Ca2+ that initiates the establishment of
body asymmetry.16,17

Fig.16. Defining situs anomalies in PCD with chest x-ray. Posterior-anterior chest
radiographs of 47-year-old monozygotic twins with PCD demonstrate situs solitus (A)
and situs inversus totalis (B). C, Posterior-anterior chest radiograph of a 30-year-old
female with PCD demonstrates abdominal situs inversus. Genotyping identified 1
DNAH5 and no DNAI1 mutation. D, Posterior-anterior chest radiograph of a 4-year-old
male with PCD demonstrates isolated dextrocardia. H indicates heart apex; L, liver; S,
stomach. 17,18

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Treatment and management
Treatment of Kartagener syndrome includes daily chest physiotherapy,
antibiotics with good pseudomonal coverage, and supportive pulmonary care.
The effectiveness of DNase and other mucolytic agents such as hypertonic
saline and acetylcysteine has not been fully assessed in these patients, but
may be tried, particularly in patients with recurrent infections or ongoing
respiratory symptoms. Surgical intervention for bronchiectasis is rarely
recommended, but can be beneficial when the disease is localized.9

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 but in severe cases prognosis can
be fatal if bilateral lung transplantation is delayed.3

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