Hum. Genet. 43, 1--11 (1978) © by Springer-Verlag 1978
Original Investigations Kartagener's Syndrome in Sibs: Clinical and Immunologic Investigations H.-D. Rott I *, H. Warnatz 2, Ria Pasch-Hilgers 3, and A. Weikl 4 11nstitut ftir Humangenetik und Anthropologie der Universit~it Erlangen-Ntirnberg, Bismarckstrage 10, D-8520 Erlangen, Federal Republic of Germany 2Institut und Poliklinik fiir klinische Immunologie der Universitgt Erlangen-Niirnberg, Federal Republic of Germany 3HNO-firztliche Abteilung im Kreiskrankenhaus, D-8553 Ebermannstadt, Federal Republic of Germany 4Kardiologische Abteilung der Medizinischen Klinik im Waldkrankenhaus, D-8520 Erlangen, Federal Republic of Germany
Summary. In a sibship of ten children descending from a first cousin's marriage, two sibs were affected by Kartagener's syndrome with the typical symptoms of situs inversus, bronchiectasis, and polyposis nasi. Clinical investigation of the entire family revealed chronic infections of the paranasal sinus in five sibs and the mother, two of whom had bronchiectasis as well. Immunologically, a persistent cellular or humoral defect could not be detected in any of the family members. In the H L A system, only the two sibs with Kartagener's syndrome had identical H L A types; all other family members had different combinations. A linkage between the loci for the H L A system and Kartagener's syndrome is discussed.
Kartagener's syndrome is a hereditary disease with the classical symptoms of situs inversus, bronchiectasis, and polyposis nasi. The combination had already been described in case reports by Siewert (1902, 1904), Oeri (1909), and Guenther (1923) before Kartagener published detailed studies on this syndrome. In 1933 he reported four and in 1935, together with Horlacher, six more cases. He pointed out that the combination of situs inversus and bronchiectasis in these cases probably was not fortuitous. Reviews of the literature on the cases published later were presented by Kartagener and Gruber (1947, 88 Cases), Kartagener and Mtilly (1956, 216 cases), Kartagener and Stucki (1962, 334 cases), and Stauffer (1967, 493 cases). There is no doubt that the inheritance of the syndrome is autosomal recessive on account of repeated occurrences in sibs and parental consanguinity (review by Stauffer, 1967). In different generations the syndrome was only seen in the family *
To whom offprint requests should be sent
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2
H.-D. Rott et al.
described by I m p e r a t o et al. (1964) in which two sisters and a maternal uncle were affected. C h r o m o s o m a l findings were n o r m a l in all cases (Glick and Graubert, 1964; Siebner and Flach, 1964; L o g a n et al., 1965; H e u k e n k a m p et al., 1972; K a t s u h a r a et al., 1972; Lake and Sharma, 1973; Shimada et al., 1973). The frequency of situs inversus being 1 : I0,000 and the complication of these cases with bronchiectasis 25%, the incidence of Kartagener's syndrome was estimated at 1:40,000 (Egbert et al., 1977). A gene frequency of 1:200 and a heterozygote frequency o f 1 : 100 m a y be calculated f r o m these values. N o basic defect causing the s y n d r o m e is yet known, nor has it been possible to find a c o m m o n pathogenetic mechanism for the typical symptoms. According to the k n o w n family observations, sibs more frequently seem to have bronchiectasis and chronic infections o f the upper respiratory tract, but a reliable test for heterozygosity is not yet possible. W h e t h e r the various anomalies and malformations of the heart, the eyes, and the skeletal system are facultative manifestations of an extensive pleiotropic gene action or merely fortuitous ones could not yet be determined.
Case
Reports
Case 1 R. H., female, * July 9, 1953, and the first often children (Fig. 1, IV,11). The parents are first cousins. During birth, aspiration of amniotic fluid; during the first year of life, she had bronchopneumonias, ten times requiring hospitalisation. Situs inversus was diagnosed at this time. At 4 years of age, an appendectomy was performed on the left side; 19 years of age, radical operation of the maxillary sinuses (Caldwell-Luc), with transmaxillary ethmoidectomy because of recurrent chronic hyperplastic sinusitis; at 20 years of age, tonsillectomy and correction of the nasal septum. Despite these operations, no substantial improvement as yet. Physical Examination. A 22-year-old woman with insufficient nasal respiration; bilateral disturbance of sound conduction; bilateral hydromyrinx; residua on both tympanic membranes; on percussion, heart and stomach bubble on the right; on auscultation, normal heart sounds on the right; rhonchi and tales over the lungs, except over the right upper segment. The remaining internal organs were normal.
II
~--~
"i
2
3
4
2
5
3 [ 4
fi
7
8
9
10
,Jr 6,1,6 11 12 13 14
15 15
rh666
"17 18 19 20 21
Fig. 1. Pedigree of family H., with two members with Kartagener's syndrome (black)
22 23 24 25
Kartagener's Syndrome in Sibs
Case I
3
Case 2
Fig. 2. ECGs of the two patients with Kartagener's syndrome: dextrocardia without any pathologic findings
Fig. 3. X-ray of the thorax of R.H. (Case 1) with dextrocardia and stomach bubble on the right. Bronchiectasis in both lower lobes of the lungs
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H.-D. Rott et al.
Fig. 4. X-ray of the thorax of T.H. (Case 2) with dextrocardia and stomach bubble on the right. Bronchiectasis in the left middle and lower lobe of the lungs
ECG. Mirror image dextrocardia; no pathologic findings (Fig. 2). X-Rays. Dextrocardia with right-sided pulmonary and aortic arch; stomach bubble on the right; bilateral basal bronchiectasis in the lungs (Fig. 3). Chronic hyperplastic frontal and ethmoidal sinusitis. Postoperative state following radical maxillary operation. Iontophoresis r. 30reVal NaC1/I sweat (normal up to 60 mVal NaC1/1 sweat). Ophthalmologic Findings2. Medium to high myopia; cystoid areal on the right fundus at 7 o'clock. Light coagulation is planned. Case 2 T. H., male * September 23, 1960 (Fig. 1, IV,17), brother of Case 1. In the first year of life, he also had several attacks of bronchopneumonia, which required hospitalisation. There, a situs inversus was diagnosed. At 14 years of age, tonsillectomy and correction of the nasal septum were performed.
Physical Examination. A 15-year-old boy with insufficient nasal respiration; eustachian tube obstruction and disturbance of sound conduction; on percussion, h e a r t and stomach bubble on the right; on auscultation, normal heart sounds on the right; rhonchi and tales over the upper and middle right lobes and over the upper left lobe. The remaining internal organs were normal.
ECG. Mirror image dextrocardia; no pathologic findings (Fig. 2). 2
Dr. U. G6ring Priv.-Doz. Dr. F.-H. Meythaler
Kartagener's Syndrome in Sibs
5
X-Rays (Fig. 4): dextrocardia with right-sided pulmonary and aortic arch; stomach bubble on the right; some bronchiectasis in the left middle and lower lobes of the lungs. Chronic hyperplastic pansinusitis. F a m i l i a l Findings
IlL 11 H. H. (father), * January 1, 1923. He had rickets during childhood and nephrolithiasis as an adult. ECG: normal. X-rays: heart, lungs, and paranasal sinuses normal.
III, 12 L. H. (mother), * October 1, 1927. She had recurrent pneumonia during childhood. At 24 years of age, tonsillectomy was performed; one year later, radical operation of the maxillary sinus. At 39 years of age, she had a pulmonary infarct following the birth of the 9th child. ECG: normal. X-rays: heart and lungs normal. Chronic hyperplastic frontal and ethmoidal sinusitis. Maxillary sinus: postoperative stage following operation.
IV, 12 M. H. (brother), * November 30, 1954. He has been healthy except for one bout of pneumonia during childhood. ECG: normal. X-rays: heart, lungs and paranasal sinuses normal. Ophthalmologic findings3: myopia of medium size; bilateral cystoid areals in all quadrants of the fundus. Light coagulation is planned. Orthopedic findings4: Poor posture due to lordotic curve of the back with incompletely fused vertebral Th 9/10; disturbances of the lumbosacral vertebral column with bilateral spondylolysis L 5.
IV, 13 D. H. (sister), * January 18, 1956. She had recurrent attacks of pneumonia during childhood. ECG: normal. X-rays: normal heart, hilar image increased on the right. Paranasal sinuses normal.
IV, 15 E. H. (sister), * February 28, 1958. At 17years Of age, tonsillectomy was performed. She has a Dupuytren's contracture in the right hand. ECG: normal. X-rays: normal heart and lungs. Chronic hyperplastic pansinusitis on the right more severe than on the left.
IV, 16 S. H. (sister), * July 14, 1959. She had been healthy during childhood, At 16 years of age, tonsillectomy was performed. She has a weakness of M. transversus of the larynx. ECG: normal. X-rays: normal heart; bronchiectasis in the lower lobe of the lungs. Chronic hyperplastic pansinusitis.
IV, 18 Ch. H. (brother), * February 4, 1962. He frequently had attacks of pneumonia during childhood. At 12 years of age, tonsillectomy was performed. ECG: normal. X-rays: normal heart and lungs. Chronic hyperplastic pansinusitis. 4
Priv.-Doz. Dr. F.-H. Meythaler Dr. K. Liebig
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H.-D. Rott et al.
IV, 19 E. H. (sister), * September 22, 1963. She had congenital pylorospasm that was successfully treated by conservative means. ECG: normal. X-rays: normal heart and lungs. Chronic hyperplastic pansinusitis.
IV,20 U. H. (sister), * February 7, 1965. She never had a severe illness. ECG: normal. X-rays: normal heart, lungs, and paranasal sinuses.
IV,21 S. H. (sister), * August 31, 1966. After birth, hospitalization for six weeks because of aspiration of amniotic fluid. Recurrent infections of the upper respiratory tract since childhood. ECG: normal. X-rays: normal heart; bronchiectasis in the right lower lobe of the lungs. Frontal sinus not yet developed; chronic hyperplastic maxillar and ethmoidal sinusitis.
Immunologic Findings The following immunologic investigations were performed: 1.
Blood grouping. All family members had blood group 0.
2. HLA-typing (Table 1). The parents have the following haplotypes: father A1 B8/A3 BW22, mother A 2 B 7 / A 3 R . The two sibs with Kartagener's syndrome both have HLA types A1 B8/A2 B7, while all the other sibs have different types. As a secondary finding in sib IV,18, a paternal crossing over had occurred. 3. Quantitative analysis of immunoglobulins (Table 2). The levels of immunoglobulins were within the standard range of normal except the IgA fraction of IV,18 and IV,21 with values below 100 mg% (normal value 280+70 rag%). 4. Test for delayed type of hypersensitivity. Immunization against DNCB was performed in both members with Kartagener's syndrome and three of their sibs (IV,11, 15, 16, 17, and 18). Three weeks later these persons had a positive cutaneous reaction to the antigen. Table 1, HLA typing of family H. with Kartagener's syndrome Proband (pedigree No.)
HLA haplotypes Paternal
Remarks Maternal
Parents Father III/11 Mother III/12
A1 B8 / A3 BW22 A2 B7 / A3 R
Children IV/11 IV/12 IV/13 IV/15 IV/16 IV/17 IV/18 IV/19 IV/20 IV/21
A1B8 A1B8
A2B7 A3 BW22 A3 BW22
A1B8 A1B8 A1
Case 1 A3R
BW22 A3 BW22 A3 BW22 A3 BW22
A2B7 A3 R A3R A2B7 A2B7
Case 2 Pat. crossing over A3 R A3 R A3 R
Kartagener's Syndrome in Sibs
7
Table 2. Immunologic findings in family H. with Kartagener's syndrome Proband
III,11 Father III,12 Mother IV,11 Case 1 IV,12 Sib IV,13 Sib IV,15 Sib IV,16 Sib IV,17 Case 2 IV,18 Sib IV,19 Sib IV,20 Sib IV,21 Sib
Ig. quant. (mg%)
Stimulation index"
Isoaggl. titer A B
ASL I.E.)
C3 b
A" 177 M: 114 G: 1501
PHA:
4.3
1 : 16
1: 4
Below 200
72
PWM:
1.2
A: 151 M: 202 G: 1162
PHA: 20.7
1 : 16
1: 4
Below 200
83
1 : 16
1: 4
Below 200
57
1:16
1:8
400
57
1:16
1:2
Below 200
59
1:16
1:16
300
59
1:8
1:8
250
72
1:16
1:4
Below 200
61
1:16
1:16
400
74
1 : 16
1: 8
Below 200
72
1 : 16
1: 4
Below 200
69
1:16
1:4
Below 200
59
PWM:
1.3
A: 220 M: 156 G: 1684
PHA:
9.0
A: 177 M: 156 G: 1162
PHA:
A: 184 M: 252 G: 1203
PHA: 19.0
A: 151 M: 114 G: 1285
PHA: 11.6
A: 145 M: 128 G: 1731
(mg%)
PWM: 2.2 0.3
PWM: 0.7
PWM: 5.9
PWM:
3.9
PHA: 15.0 PWM: 5.6
A: 205 M: 156 G: 1083
PHA:
3.7
A: 82 M: 121 G: 1006
PHA: 13.0
A: 191 M: 128 G: 1244
PHA: 13.0
A: 109 M: 101 G: 1501
PHA: 19.0
A: 82 M: 114 G: 1162
PHA:
1.1
PWM:
1.7
PWM: 3.0
PWM: 2.8
PWM: 4.7
PWM: 3.6
Stimulation index calculated as the quotient of 3H-thymidine incorporation (in cpm) in lymphocyte cultures incubated with PHA or PWM and of the 3H-thymidine incorporation of nonstimulated culture b Measured by immunoprecipitation technique
8
H.-D. Rott et al.
5. Stimulation of lymphocytes with phytohemagglutin (PAH) and pokeweed mitogen (PWM; Table 2). All family members were within the normal range except IV,21 with a definite reduction. This sib had an exceptional tendency to recurrent bronchial infections. 6. Analysis of natural antibodies (anti-A and anti-B agglutinins; Table 2). In all cases, values for anti-A between 1 : 8 and 1 : 16 and values between 1 : 4 and 1 : 16 for anti-B were found. 7. Analysis of antibodies against streptolysin and autoantibodies (antinuclear and antimitochondrial antibodies and rheumatoid factor; Table 2). Antibodies against streptolysin were found in four family members (IV,12, 15, 16, and 18), while autoantibodies were present in none of the persons tested.
Dermatoglyphie Findings R. H. (Case 1) Fingertips. Right: W W U W U ; left: U W U U U T.R.C. 148. Palms. Right: 9 . 7 . 5 . 1 ..... Arl 0 . 0 . 0 . L ; left: 9 . 7 . 5 . 1 ..... A r . 0 . 0 . 0 . L . Soles. Right: L d . O. Ld . Ld . ~ ; left: At . 0 . 0 . 0 . 0 . T. H. (Case 2) Fingertips. Right: U R U W W ; left: U W U W U T.R.C. 142. Palms. Right: 7.5". 5.1 -t"- Af . 0 . 0 . 0 . L; left: 7.5". 5.4-t- 0 . 0 , 0 . 0 . L. Soles. Right: W. I~ , Ld . O. Lt; left: W. Lp . 0.0.0. Interpretation. The dermatoglyphic findings do not differ substantially from the familial findings. A reversal of the known right to left asymmetry can neither be stated nor disproven on account of these two cases. Suspicious, in this context, is the ending of the right A line of Case 2 in the position 1. This ending type is seen in the general population mainly on the left (right : left = 1 : 5.3; Cummins and Midlo, 1961).
Discussion In the above-described family, two o u t of ten children descending from a marriage between first cousins were affected by K a r t a g e n e r ' s syndrome. This o b s e r v a t i o n confirms the a u t o s o m a l recessive inheritance as is generally assumed. Clinically, b o t h patients h a d the typical triad of total situs inversus with dextrocardia a n d w i t h o u t a n y other heart m a l f o r m a t i o n , polyposis nasi, a n d bronchiectasis. Cystic fibrosis was excluded by the n o r m a l iontophoresis in Case 1. Some of the other sibs h a d recurrent infections of the u p p e r respiratory tract and, of these, several had bronchiectasis as described repeatedly in the literature. The father, however, certainly b e i n g heterozygous, has never been seriously ill. Besides the a b o v e - r e p o r t e d typical symptoms, Case 1 h a d cystoid areals o n the f u n d u s of the right eye as a secondary finding. The same changes were present in her eldest b r o t h e r (IV,12). O n l y four authors report eye anomalies in K a r t a g e n e r ' s s y n d r o m e . Schettler a n d K l i n k (l 949) reported a case with unilateral vascular a n o m a l i e s o n the f u n d u s . Collier (1961) observed two sisters with p i g m e n t a t i o n in the region of the corneal limbus, h y p e r t r o p h y of the plica lunaris, c o l o b o m a of the iris, a n d h y p e r t e n s i o n of the central retinal artery. Segal et al. (1963) f o u n d a p i g m e n t a r y d e g e n e r a t i o n of the retina a n d a congenital cataract in a case of K a r t a g e n e r ' s s y n d r o m e as well as in a sib a n d the mother. A c o n n e c t i o n
Kartagener's Syndrome in Sibs
9
between these different eye anomalies and Kartagener's syndrome must be doubted, since other family members without Kartagener's syndrome were affected both in the family studied by Segal et al. and in the one under our observation. Our o w n immunologic findings as well as the earlier findings in the literature (Holmes et al., 1968; H a r t l i n e and Zelkowitz, 1971; Heyne and Beckert, 1971; Lichtenstein, 1972; Sharma, 1972; Tendler and Schaarschmidt, 1972; Lake and Sharma, 1973; Cervino et al., 1974; Egbert et al., 1977) gave neither a hint of a persistent cellular or humoral defect, nor an abnormal allergic reactivity against any environmental agent. Remarkable, however, are the findings in the H L A system (Table 1), which had not been investigated in Kartagener patients until now. Only the two affected sibs show the same H L A type whereas all other sibs have different combinations. Disregarding the rare possibility of crossing over between the two investigated H L A loci, the four different possibilities of H L A types resulting from the parental haplotypes are: A1 B8/A2B7, A1 B 8 / A 3 R , A3 BW22/A2 BT, and A3 BW22/A3 R, which all have the same probability. The probability of a random identity of two sibs is therefore 0.25, the probability for difference being 0.75. Drawing the whole sibship into consideration, there results a probability of 0.25 x (0.75) 8 = 0.025 for a random combination of the described H L A patterns. It may be assumed that these findings are caused by a linkage of the loci for the Kartagener gene and the H L A genes, In case future family findings should confirm the assumed linkage, affected families could be given more exact genetic advice. An association with certain H L A haplotypes as found for different diseases (Bertrams, 1976; Dausset and Svejgaard, 1977) must be denied, since in this group of diseases neither monogenic inheritance nor malformations are to be found and, on the other hand, the Kartagener's syndrome is sufficiently explained by autosomal recessive inheritance. The problem of heterozygote detection within the families concerned is still unsolved. The immunologic findings did not allow an exact differentiation. Three (IV,12, 13, and 20) out of the eight sibs' of the carriers were clinically normal; the other five as well as their mother had chronic infections of the upper respiratory tract and some had to undergo tonsillectomy. These sibs are suspected of being possible heterozygote carriers with an increased risk for bronchopulmonar infections. On the other hand, the father, being heterozygous, never ~had any of the above-mentioned symptoms; therefore, the genetic interpretation of such clinical findings must be performed with utmost caution and should not be the basis for risk calculations in genetic counseling. Note Added in Proof Meanwhile Eliasson et al. (1977) proved that in Kartagener's syndrome there exists a ciliary immotility of the bronchial mucosa, caused by the lack of dynein arms at the outer microtubular doublets of cilia. Thus it can be stated that the causes for the symptoms of the respiratory tract are morphologic and not immunologic ones. Eliasson, R., Mossberg, B., Camner, P., Afzelius, A.: The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. New Engl. J. Med. 297, 1--6 (1977)
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H.-D. Rott et al.
References Bertrams, J.: HLA-Antigene und Krankheitsempf~inglichkeit. Dtsch. Med. Wochenschr. 101, 178--184 (1976) Cervino, O. A.0 Chieri, P. de, Delbue, C.: Sindrome de Kartagener. Prensa Med. Argent. 60, 547--549 (1974) Collier, M. M.: Constatations ophthalmologiques dans le syndrome de Kartagener. Bull. Mem. Soc. Fr. Ophtalmol. 74, 429--447 (1961) Cummins, H., Midlo, C.: Finger prints, palms and soles. An introduction to dermatoglyphics. New York: Dover 1961 Dausset, J., Svejgaard, A.: HLA and disease. Copenhagen: Munksgaard 1977 Egbert, B. M., Schwartz, E., Kempson, R. L.: Kartagener syndrome. Report of a case with mesangiocapillary glomerulonephritis. Arch. Pathol. Lab. Med. 101, 95--99 (1977) Glick, J. D., Graubert, D. M.: Kartagener's syndrome and schizophrenia: A report of a case with chromosomal studies. Am. J. Psychiatry 121,603--605 (1964) Guenther, H.: Die biologische Bedeutung der Inversionen. Biol. Zentralbl. 43, 175--213 (1923) Hartline, J. V., Zelkowitz, P. S.: Kartagener's syndrome in childhood. Am. J. Dis. Child. 121, 349--352 (1971) Heukenkamp, P.-U., Marshall, M., Meier, J., Parrisius, G., Z611ner, N.: Das KartagenerSyndrom. Mitteilung yon vier F/illen und kritische Wtirdigung des sinubronchialen Syndroms. Dtsch. Med. Wochenschr. 97, 1458--1461 (1972) Heyne, K., Beckert, R.: Beitrag zum famili/iren Kartagener-Syndrom. Z. Erkr. Atmungsorgane 134, 141--148 (1971) Holmes, L. B., Blennerhassett, J. B., Austen, K. F.: A reappraisal of Kartagener's syndrome. Am. J. Med. Sci. 255, 13--28 (1968) Imperato, P. J., Palanca, L. M., Fernandez, J. P.: Successful treatment with the mucolytic agent acetylcysteine. Am. Rev. Respir. Dis. 90, 111--115 (1964) Kartagener, M.: Zur Pathogenese der Bronchiektasien. I. Mitteilung: Bronchiektasien bei Situs viscerum inversus. Beitr. Klin. Tuberk. 83, 489--501 (1933) Kartagener, M.: Bronchiektasien bei Situs viscerum inversus. Praxis 57, 622--623 (1968) Kartagener, M., Gruber, M.: Bronchiektasien und Dilatationen anderer glandul~irer und kavitfirer Organe. Schweiz. Z. Pathol. Bakt. [Suppl.] 10, 36 (1947) Kartagener, M., Horlacher, A.: Bronchiektasien bei Situs viscerum inversus. Schweiz. Med. Wochenschr. 16, 782--784 (1935) Kartagener, M., MiJlly, K.: Bronchiektasien bei Situs viscerum inversus. Schweiz. Z. Tuberk. 13, 166--191 (1956) Kartagener, M., Stucki, P.: Bronchiectasis with situs inversus. Arch. Pediatr. 79, 193--207 (1962) Katsuhara, K., Kawamoto, S., Wakabayashi, T., Belsky, J. L.: Situs inversus totalis and Kartagener's syndrome in a Japanese population. Chest 61, 56--61 (1972) Lake, K., Sharma, O. P.: Kartagener's syndrome and deaf-mutism: An unusual association. Chest 64, 661--663 (1973) Lichtenstein, J. R.: Kartagener syndrome in sibs. Birth Defects: Orig. Art. Ser. VIII/5,223--225 (1972) Logan, W. D., Jr., Abbott, O. A., Hatcher, Ch. R., Jr.: Kartagener's triad. Dis. Chest 48, 613--616 (1965) Oeri, R.: Zur Kasuistik des Situs,viscerum inversus totalis. Frankf. Z. Pathol. 3, 393--397 (1909) Schettler, G-, Klink, O.: Situs viscerum inversus totalis, mit Bronchiektasen, Polyposis nasi und GefgBmi3bildungen am Augenhintergrund. Arztl. Wochenschr. 4, 215--216 (1949) Segal, P., Kikiela, M., Mrzyglod, S., Zeromska-Zbierska, I.: Kartagener's syndrome with familial eye changes. Am. J. Ophthalmol. 55, 1043--1049 (1963) Sharma, O.: Kartagener's syndrome. Immunological studies. N.Y. State J. Med. 72, 1057 (1972) Shimada, K., Nakajiama, A., Shimokawahara, H., et al.: The pancreatic function in Kartagener's syndrome: A case report. Acta Med. (Univ. Kagoshima) 15, 163--178 (1973) Siebner, H., Flach, A.: Chromosomenbefunde bei der Kartagenerschen Trias. Mschr. Kinderheilk. 112, 465--466 (1964)
Kartagener's Syndrome in Sibs
11
Siewert, A. K.: Russkij Wratsch 1361 (1902) (cited by Kartagener, 1968) Siewert, A. K.: Uber einen Fall yon Bronchiectasie bei einem Patienten mit Situs inversus viscerurn. Berl. Klin. Wochenschr. 41, 139--141 (1904) Stauffer, U. G.: Ein Fall yon Bronchiektasen bei Situs viscerum inversus (Kartagenersches Syndrom). Beitr. Klin. Tuberk. 135, 15--26 (1967) Tendler, H., Schaarschmidt, G.: Kongenitale Bronchiektasie bei Situs inversus. Z. Erkr. Atmungsorgane 137, 161--166 (1972)
Received October 21, 1977 / February 7, 1978
Original Investigations Kartagener's Syndrome in Sibs: Clinical and Immunologic Investigations H.-D. Rott I *, H. Warnatz 2, Ria Pasch-Hilgers 3, and A. Weikl 4 11nstitut ftir Humangenetik und Anthropologie der Universit~it Erlangen-Ntirnberg, Bismarckstrage 10, D-8520 Erlangen, Federal Republic of Germany 2Institut und Poliklinik fiir klinische Immunologie der Universitgt Erlangen-Niirnberg, Federal Republic of Germany 3HNO-firztliche Abteilung im Kreiskrankenhaus, D-8553 Ebermannstadt, Federal Republic of Germany 4Kardiologische Abteilung der Medizinischen Klinik im Waldkrankenhaus, D-8520 Erlangen, Federal Republic of Germany
Summary. In a sibship of ten children descending from a first cousin's marriage, two sibs were affected by Kartagener's syndrome with the typical symptoms of situs inversus, bronchiectasis, and polyposis nasi. Clinical investigation of the entire family revealed chronic infections of the paranasal sinus in five sibs and the mother, two of whom had bronchiectasis as well. Immunologically, a persistent cellular or humoral defect could not be detected in any of the family members. In the H L A system, only the two sibs with Kartagener's syndrome had identical H L A types; all other family members had different combinations. A linkage between the loci for the H L A system and Kartagener's syndrome is discussed.
Kartagener's syndrome is a hereditary disease with the classical symptoms of situs inversus, bronchiectasis, and polyposis nasi. The combination had already been described in case reports by Siewert (1902, 1904), Oeri (1909), and Guenther (1923) before Kartagener published detailed studies on this syndrome. In 1933 he reported four and in 1935, together with Horlacher, six more cases. He pointed out that the combination of situs inversus and bronchiectasis in these cases probably was not fortuitous. Reviews of the literature on the cases published later were presented by Kartagener and Gruber (1947, 88 Cases), Kartagener and Mtilly (1956, 216 cases), Kartagener and Stucki (1962, 334 cases), and Stauffer (1967, 493 cases). There is no doubt that the inheritance of the syndrome is autosomal recessive on account of repeated occurrences in sibs and parental consanguinity (review by Stauffer, 1967). In different generations the syndrome was only seen in the family *
To whom offprint requests should be sent
0340-6717/78/0043/0001/$02.20
2
H.-D. Rott et al.
described by I m p e r a t o et al. (1964) in which two sisters and a maternal uncle were affected. C h r o m o s o m a l findings were n o r m a l in all cases (Glick and Graubert, 1964; Siebner and Flach, 1964; L o g a n et al., 1965; H e u k e n k a m p et al., 1972; K a t s u h a r a et al., 1972; Lake and Sharma, 1973; Shimada et al., 1973). The frequency of situs inversus being 1 : I0,000 and the complication of these cases with bronchiectasis 25%, the incidence of Kartagener's syndrome was estimated at 1:40,000 (Egbert et al., 1977). A gene frequency of 1:200 and a heterozygote frequency o f 1 : 100 m a y be calculated f r o m these values. N o basic defect causing the s y n d r o m e is yet known, nor has it been possible to find a c o m m o n pathogenetic mechanism for the typical symptoms. According to the k n o w n family observations, sibs more frequently seem to have bronchiectasis and chronic infections o f the upper respiratory tract, but a reliable test for heterozygosity is not yet possible. W h e t h e r the various anomalies and malformations of the heart, the eyes, and the skeletal system are facultative manifestations of an extensive pleiotropic gene action or merely fortuitous ones could not yet be determined.
Case
Reports
Case 1 R. H., female, * July 9, 1953, and the first often children (Fig. 1, IV,11). The parents are first cousins. During birth, aspiration of amniotic fluid; during the first year of life, she had bronchopneumonias, ten times requiring hospitalisation. Situs inversus was diagnosed at this time. At 4 years of age, an appendectomy was performed on the left side; 19 years of age, radical operation of the maxillary sinuses (Caldwell-Luc), with transmaxillary ethmoidectomy because of recurrent chronic hyperplastic sinusitis; at 20 years of age, tonsillectomy and correction of the nasal septum. Despite these operations, no substantial improvement as yet. Physical Examination. A 22-year-old woman with insufficient nasal respiration; bilateral disturbance of sound conduction; bilateral hydromyrinx; residua on both tympanic membranes; on percussion, heart and stomach bubble on the right; on auscultation, normal heart sounds on the right; rhonchi and tales over the lungs, except over the right upper segment. The remaining internal organs were normal.
II
~--~
"i
2
3
4
2
5
3 [ 4
fi
7
8
9
10
,Jr 6,1,6 11 12 13 14
15 15
rh666
"17 18 19 20 21
Fig. 1. Pedigree of family H., with two members with Kartagener's syndrome (black)
22 23 24 25
Kartagener's Syndrome in Sibs
Case I
3
Case 2
Fig. 2. ECGs of the two patients with Kartagener's syndrome: dextrocardia without any pathologic findings
Fig. 3. X-ray of the thorax of R.H. (Case 1) with dextrocardia and stomach bubble on the right. Bronchiectasis in both lower lobes of the lungs
4
H.-D. Rott et al.
Fig. 4. X-ray of the thorax of T.H. (Case 2) with dextrocardia and stomach bubble on the right. Bronchiectasis in the left middle and lower lobe of the lungs
ECG. Mirror image dextrocardia; no pathologic findings (Fig. 2). X-Rays. Dextrocardia with right-sided pulmonary and aortic arch; stomach bubble on the right; bilateral basal bronchiectasis in the lungs (Fig. 3). Chronic hyperplastic frontal and ethmoidal sinusitis. Postoperative state following radical maxillary operation. Iontophoresis r. 30reVal NaC1/I sweat (normal up to 60 mVal NaC1/1 sweat). Ophthalmologic Findings2. Medium to high myopia; cystoid areal on the right fundus at 7 o'clock. Light coagulation is planned. Case 2 T. H., male * September 23, 1960 (Fig. 1, IV,17), brother of Case 1. In the first year of life, he also had several attacks of bronchopneumonia, which required hospitalisation. There, a situs inversus was diagnosed. At 14 years of age, tonsillectomy and correction of the nasal septum were performed.
Physical Examination. A 15-year-old boy with insufficient nasal respiration; eustachian tube obstruction and disturbance of sound conduction; on percussion, h e a r t and stomach bubble on the right; on auscultation, normal heart sounds on the right; rhonchi and tales over the upper and middle right lobes and over the upper left lobe. The remaining internal organs were normal.
ECG. Mirror image dextrocardia; no pathologic findings (Fig. 2). 2
Dr. U. G6ring Priv.-Doz. Dr. F.-H. Meythaler
Kartagener's Syndrome in Sibs
5
X-Rays (Fig. 4): dextrocardia with right-sided pulmonary and aortic arch; stomach bubble on the right; some bronchiectasis in the left middle and lower lobes of the lungs. Chronic hyperplastic pansinusitis. F a m i l i a l Findings
IlL 11 H. H. (father), * January 1, 1923. He had rickets during childhood and nephrolithiasis as an adult. ECG: normal. X-rays: heart, lungs, and paranasal sinuses normal.
III, 12 L. H. (mother), * October 1, 1927. She had recurrent pneumonia during childhood. At 24 years of age, tonsillectomy was performed; one year later, radical operation of the maxillary sinus. At 39 years of age, she had a pulmonary infarct following the birth of the 9th child. ECG: normal. X-rays: heart and lungs normal. Chronic hyperplastic frontal and ethmoidal sinusitis. Maxillary sinus: postoperative stage following operation.
IV, 12 M. H. (brother), * November 30, 1954. He has been healthy except for one bout of pneumonia during childhood. ECG: normal. X-rays: heart, lungs and paranasal sinuses normal. Ophthalmologic findings3: myopia of medium size; bilateral cystoid areals in all quadrants of the fundus. Light coagulation is planned. Orthopedic findings4: Poor posture due to lordotic curve of the back with incompletely fused vertebral Th 9/10; disturbances of the lumbosacral vertebral column with bilateral spondylolysis L 5.
IV, 13 D. H. (sister), * January 18, 1956. She had recurrent attacks of pneumonia during childhood. ECG: normal. X-rays: normal heart, hilar image increased on the right. Paranasal sinuses normal.
IV, 15 E. H. (sister), * February 28, 1958. At 17years Of age, tonsillectomy was performed. She has a Dupuytren's contracture in the right hand. ECG: normal. X-rays: normal heart and lungs. Chronic hyperplastic pansinusitis on the right more severe than on the left.
IV, 16 S. H. (sister), * July 14, 1959. She had been healthy during childhood, At 16 years of age, tonsillectomy was performed. She has a weakness of M. transversus of the larynx. ECG: normal. X-rays: normal heart; bronchiectasis in the lower lobe of the lungs. Chronic hyperplastic pansinusitis.
IV, 18 Ch. H. (brother), * February 4, 1962. He frequently had attacks of pneumonia during childhood. At 12 years of age, tonsillectomy was performed. ECG: normal. X-rays: normal heart and lungs. Chronic hyperplastic pansinusitis. 4
Priv.-Doz. Dr. F.-H. Meythaler Dr. K. Liebig
6
H.-D. Rott et al.
IV, 19 E. H. (sister), * September 22, 1963. She had congenital pylorospasm that was successfully treated by conservative means. ECG: normal. X-rays: normal heart and lungs. Chronic hyperplastic pansinusitis.
IV,20 U. H. (sister), * February 7, 1965. She never had a severe illness. ECG: normal. X-rays: normal heart, lungs, and paranasal sinuses.
IV,21 S. H. (sister), * August 31, 1966. After birth, hospitalization for six weeks because of aspiration of amniotic fluid. Recurrent infections of the upper respiratory tract since childhood. ECG: normal. X-rays: normal heart; bronchiectasis in the right lower lobe of the lungs. Frontal sinus not yet developed; chronic hyperplastic maxillar and ethmoidal sinusitis.
Immunologic Findings The following immunologic investigations were performed: 1.
Blood grouping. All family members had blood group 0.
2. HLA-typing (Table 1). The parents have the following haplotypes: father A1 B8/A3 BW22, mother A 2 B 7 / A 3 R . The two sibs with Kartagener's syndrome both have HLA types A1 B8/A2 B7, while all the other sibs have different types. As a secondary finding in sib IV,18, a paternal crossing over had occurred. 3. Quantitative analysis of immunoglobulins (Table 2). The levels of immunoglobulins were within the standard range of normal except the IgA fraction of IV,18 and IV,21 with values below 100 mg% (normal value 280+70 rag%). 4. Test for delayed type of hypersensitivity. Immunization against DNCB was performed in both members with Kartagener's syndrome and three of their sibs (IV,11, 15, 16, 17, and 18). Three weeks later these persons had a positive cutaneous reaction to the antigen. Table 1, HLA typing of family H. with Kartagener's syndrome Proband (pedigree No.)
HLA haplotypes Paternal
Remarks Maternal
Parents Father III/11 Mother III/12
A1 B8 / A3 BW22 A2 B7 / A3 R
Children IV/11 IV/12 IV/13 IV/15 IV/16 IV/17 IV/18 IV/19 IV/20 IV/21
A1B8 A1B8
A2B7 A3 BW22 A3 BW22
A1B8 A1B8 A1
Case 1 A3R
BW22 A3 BW22 A3 BW22 A3 BW22
A2B7 A3 R A3R A2B7 A2B7
Case 2 Pat. crossing over A3 R A3 R A3 R
Kartagener's Syndrome in Sibs
7
Table 2. Immunologic findings in family H. with Kartagener's syndrome Proband
III,11 Father III,12 Mother IV,11 Case 1 IV,12 Sib IV,13 Sib IV,15 Sib IV,16 Sib IV,17 Case 2 IV,18 Sib IV,19 Sib IV,20 Sib IV,21 Sib
Ig. quant. (mg%)
Stimulation index"
Isoaggl. titer A B
ASL I.E.)
C3 b
A" 177 M: 114 G: 1501
PHA:
4.3
1 : 16
1: 4
Below 200
72
PWM:
1.2
A: 151 M: 202 G: 1162
PHA: 20.7
1 : 16
1: 4
Below 200
83
1 : 16
1: 4
Below 200
57
1:16
1:8
400
57
1:16
1:2
Below 200
59
1:16
1:16
300
59
1:8
1:8
250
72
1:16
1:4
Below 200
61
1:16
1:16
400
74
1 : 16
1: 8
Below 200
72
1 : 16
1: 4
Below 200
69
1:16
1:4
Below 200
59
PWM:
1.3
A: 220 M: 156 G: 1684
PHA:
9.0
A: 177 M: 156 G: 1162
PHA:
A: 184 M: 252 G: 1203
PHA: 19.0
A: 151 M: 114 G: 1285
PHA: 11.6
A: 145 M: 128 G: 1731
(mg%)
PWM: 2.2 0.3
PWM: 0.7
PWM: 5.9
PWM:
3.9
PHA: 15.0 PWM: 5.6
A: 205 M: 156 G: 1083
PHA:
3.7
A: 82 M: 121 G: 1006
PHA: 13.0
A: 191 M: 128 G: 1244
PHA: 13.0
A: 109 M: 101 G: 1501
PHA: 19.0
A: 82 M: 114 G: 1162
PHA:
1.1
PWM:
1.7
PWM: 3.0
PWM: 2.8
PWM: 4.7
PWM: 3.6
Stimulation index calculated as the quotient of 3H-thymidine incorporation (in cpm) in lymphocyte cultures incubated with PHA or PWM and of the 3H-thymidine incorporation of nonstimulated culture b Measured by immunoprecipitation technique
8
H.-D. Rott et al.
5. Stimulation of lymphocytes with phytohemagglutin (PAH) and pokeweed mitogen (PWM; Table 2). All family members were within the normal range except IV,21 with a definite reduction. This sib had an exceptional tendency to recurrent bronchial infections. 6. Analysis of natural antibodies (anti-A and anti-B agglutinins; Table 2). In all cases, values for anti-A between 1 : 8 and 1 : 16 and values between 1 : 4 and 1 : 16 for anti-B were found. 7. Analysis of antibodies against streptolysin and autoantibodies (antinuclear and antimitochondrial antibodies and rheumatoid factor; Table 2). Antibodies against streptolysin were found in four family members (IV,12, 15, 16, and 18), while autoantibodies were present in none of the persons tested.
Dermatoglyphie Findings R. H. (Case 1) Fingertips. Right: W W U W U ; left: U W U U U T.R.C. 148. Palms. Right: 9 . 7 . 5 . 1 ..... Arl 0 . 0 . 0 . L ; left: 9 . 7 . 5 . 1 ..... A r . 0 . 0 . 0 . L . Soles. Right: L d . O. Ld . Ld . ~ ; left: At . 0 . 0 . 0 . 0 . T. H. (Case 2) Fingertips. Right: U R U W W ; left: U W U W U T.R.C. 142. Palms. Right: 7.5". 5.1 -t"- Af . 0 . 0 . 0 . L; left: 7.5". 5.4-t- 0 . 0 , 0 . 0 . L. Soles. Right: W. I~ , Ld . O. Lt; left: W. Lp . 0.0.0. Interpretation. The dermatoglyphic findings do not differ substantially from the familial findings. A reversal of the known right to left asymmetry can neither be stated nor disproven on account of these two cases. Suspicious, in this context, is the ending of the right A line of Case 2 in the position 1. This ending type is seen in the general population mainly on the left (right : left = 1 : 5.3; Cummins and Midlo, 1961).
Discussion In the above-described family, two o u t of ten children descending from a marriage between first cousins were affected by K a r t a g e n e r ' s syndrome. This o b s e r v a t i o n confirms the a u t o s o m a l recessive inheritance as is generally assumed. Clinically, b o t h patients h a d the typical triad of total situs inversus with dextrocardia a n d w i t h o u t a n y other heart m a l f o r m a t i o n , polyposis nasi, a n d bronchiectasis. Cystic fibrosis was excluded by the n o r m a l iontophoresis in Case 1. Some of the other sibs h a d recurrent infections of the u p p e r respiratory tract and, of these, several had bronchiectasis as described repeatedly in the literature. The father, however, certainly b e i n g heterozygous, has never been seriously ill. Besides the a b o v e - r e p o r t e d typical symptoms, Case 1 h a d cystoid areals o n the f u n d u s of the right eye as a secondary finding. The same changes were present in her eldest b r o t h e r (IV,12). O n l y four authors report eye anomalies in K a r t a g e n e r ' s s y n d r o m e . Schettler a n d K l i n k (l 949) reported a case with unilateral vascular a n o m a l i e s o n the f u n d u s . Collier (1961) observed two sisters with p i g m e n t a t i o n in the region of the corneal limbus, h y p e r t r o p h y of the plica lunaris, c o l o b o m a of the iris, a n d h y p e r t e n s i o n of the central retinal artery. Segal et al. (1963) f o u n d a p i g m e n t a r y d e g e n e r a t i o n of the retina a n d a congenital cataract in a case of K a r t a g e n e r ' s s y n d r o m e as well as in a sib a n d the mother. A c o n n e c t i o n
Kartagener's Syndrome in Sibs
9
between these different eye anomalies and Kartagener's syndrome must be doubted, since other family members without Kartagener's syndrome were affected both in the family studied by Segal et al. and in the one under our observation. Our o w n immunologic findings as well as the earlier findings in the literature (Holmes et al., 1968; H a r t l i n e and Zelkowitz, 1971; Heyne and Beckert, 1971; Lichtenstein, 1972; Sharma, 1972; Tendler and Schaarschmidt, 1972; Lake and Sharma, 1973; Cervino et al., 1974; Egbert et al., 1977) gave neither a hint of a persistent cellular or humoral defect, nor an abnormal allergic reactivity against any environmental agent. Remarkable, however, are the findings in the H L A system (Table 1), which had not been investigated in Kartagener patients until now. Only the two affected sibs show the same H L A type whereas all other sibs have different combinations. Disregarding the rare possibility of crossing over between the two investigated H L A loci, the four different possibilities of H L A types resulting from the parental haplotypes are: A1 B8/A2B7, A1 B 8 / A 3 R , A3 BW22/A2 BT, and A3 BW22/A3 R, which all have the same probability. The probability of a random identity of two sibs is therefore 0.25, the probability for difference being 0.75. Drawing the whole sibship into consideration, there results a probability of 0.25 x (0.75) 8 = 0.025 for a random combination of the described H L A patterns. It may be assumed that these findings are caused by a linkage of the loci for the Kartagener gene and the H L A genes, In case future family findings should confirm the assumed linkage, affected families could be given more exact genetic advice. An association with certain H L A haplotypes as found for different diseases (Bertrams, 1976; Dausset and Svejgaard, 1977) must be denied, since in this group of diseases neither monogenic inheritance nor malformations are to be found and, on the other hand, the Kartagener's syndrome is sufficiently explained by autosomal recessive inheritance. The problem of heterozygote detection within the families concerned is still unsolved. The immunologic findings did not allow an exact differentiation. Three (IV,12, 13, and 20) out of the eight sibs' of the carriers were clinically normal; the other five as well as their mother had chronic infections of the upper respiratory tract and some had to undergo tonsillectomy. These sibs are suspected of being possible heterozygote carriers with an increased risk for bronchopulmonar infections. On the other hand, the father, being heterozygous, never ~had any of the above-mentioned symptoms; therefore, the genetic interpretation of such clinical findings must be performed with utmost caution and should not be the basis for risk calculations in genetic counseling. Note Added in Proof Meanwhile Eliasson et al. (1977) proved that in Kartagener's syndrome there exists a ciliary immotility of the bronchial mucosa, caused by the lack of dynein arms at the outer microtubular doublets of cilia. Thus it can be stated that the causes for the symptoms of the respiratory tract are morphologic and not immunologic ones. Eliasson, R., Mossberg, B., Camner, P., Afzelius, A.: The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. New Engl. J. Med. 297, 1--6 (1977)
10
H.-D. Rott et al.
References Bertrams, J.: HLA-Antigene und Krankheitsempf~inglichkeit. Dtsch. Med. Wochenschr. 101, 178--184 (1976) Cervino, O. A.0 Chieri, P. de, Delbue, C.: Sindrome de Kartagener. Prensa Med. Argent. 60, 547--549 (1974) Collier, M. M.: Constatations ophthalmologiques dans le syndrome de Kartagener. Bull. Mem. Soc. Fr. Ophtalmol. 74, 429--447 (1961) Cummins, H., Midlo, C.: Finger prints, palms and soles. An introduction to dermatoglyphics. New York: Dover 1961 Dausset, J., Svejgaard, A.: HLA and disease. Copenhagen: Munksgaard 1977 Egbert, B. M., Schwartz, E., Kempson, R. L.: Kartagener syndrome. Report of a case with mesangiocapillary glomerulonephritis. Arch. Pathol. Lab. Med. 101, 95--99 (1977) Glick, J. D., Graubert, D. M.: Kartagener's syndrome and schizophrenia: A report of a case with chromosomal studies. Am. J. Psychiatry 121,603--605 (1964) Guenther, H.: Die biologische Bedeutung der Inversionen. Biol. Zentralbl. 43, 175--213 (1923) Hartline, J. V., Zelkowitz, P. S.: Kartagener's syndrome in childhood. Am. J. Dis. Child. 121, 349--352 (1971) Heukenkamp, P.-U., Marshall, M., Meier, J., Parrisius, G., Z611ner, N.: Das KartagenerSyndrom. Mitteilung yon vier F/illen und kritische Wtirdigung des sinubronchialen Syndroms. Dtsch. Med. Wochenschr. 97, 1458--1461 (1972) Heyne, K., Beckert, R.: Beitrag zum famili/iren Kartagener-Syndrom. Z. Erkr. Atmungsorgane 134, 141--148 (1971) Holmes, L. B., Blennerhassett, J. B., Austen, K. F.: A reappraisal of Kartagener's syndrome. Am. J. Med. Sci. 255, 13--28 (1968) Imperato, P. J., Palanca, L. M., Fernandez, J. P.: Successful treatment with the mucolytic agent acetylcysteine. Am. Rev. Respir. Dis. 90, 111--115 (1964) Kartagener, M.: Zur Pathogenese der Bronchiektasien. I. Mitteilung: Bronchiektasien bei Situs viscerum inversus. Beitr. Klin. Tuberk. 83, 489--501 (1933) Kartagener, M.: Bronchiektasien bei Situs viscerum inversus. Praxis 57, 622--623 (1968) Kartagener, M., Gruber, M.: Bronchiektasien und Dilatationen anderer glandul~irer und kavitfirer Organe. Schweiz. Z. Pathol. Bakt. [Suppl.] 10, 36 (1947) Kartagener, M., Horlacher, A.: Bronchiektasien bei Situs viscerum inversus. Schweiz. Med. Wochenschr. 16, 782--784 (1935) Kartagener, M., MiJlly, K.: Bronchiektasien bei Situs viscerum inversus. Schweiz. Z. Tuberk. 13, 166--191 (1956) Kartagener, M., Stucki, P.: Bronchiectasis with situs inversus. Arch. Pediatr. 79, 193--207 (1962) Katsuhara, K., Kawamoto, S., Wakabayashi, T., Belsky, J. L.: Situs inversus totalis and Kartagener's syndrome in a Japanese population. Chest 61, 56--61 (1972) Lake, K., Sharma, O. P.: Kartagener's syndrome and deaf-mutism: An unusual association. Chest 64, 661--663 (1973) Lichtenstein, J. R.: Kartagener syndrome in sibs. Birth Defects: Orig. Art. Ser. VIII/5,223--225 (1972) Logan, W. D., Jr., Abbott, O. A., Hatcher, Ch. R., Jr.: Kartagener's triad. Dis. Chest 48, 613--616 (1965) Oeri, R.: Zur Kasuistik des Situs,viscerum inversus totalis. Frankf. Z. Pathol. 3, 393--397 (1909) Schettler, G-, Klink, O.: Situs viscerum inversus totalis, mit Bronchiektasen, Polyposis nasi und GefgBmi3bildungen am Augenhintergrund. Arztl. Wochenschr. 4, 215--216 (1949) Segal, P., Kikiela, M., Mrzyglod, S., Zeromska-Zbierska, I.: Kartagener's syndrome with familial eye changes. Am. J. Ophthalmol. 55, 1043--1049 (1963) Sharma, O.: Kartagener's syndrome. Immunological studies. N.Y. State J. Med. 72, 1057 (1972) Shimada, K., Nakajiama, A., Shimokawahara, H., et al.: The pancreatic function in Kartagener's syndrome: A case report. Acta Med. (Univ. Kagoshima) 15, 163--178 (1973) Siebner, H., Flach, A.: Chromosomenbefunde bei der Kartagenerschen Trias. Mschr. Kinderheilk. 112, 465--466 (1964)
Kartagener's Syndrome in Sibs
11
Siewert, A. K.: Russkij Wratsch 1361 (1902) (cited by Kartagener, 1968) Siewert, A. K.: Uber einen Fall yon Bronchiectasie bei einem Patienten mit Situs inversus viscerurn. Berl. Klin. Wochenschr. 41, 139--141 (1904) Stauffer, U. G.: Ein Fall yon Bronchiektasen bei Situs viscerum inversus (Kartagenersches Syndrom). Beitr. Klin. Tuberk. 135, 15--26 (1967) Tendler, H., Schaarschmidt, G.: Kongenitale Bronchiektasie bei Situs inversus. Z. Erkr. Atmungsorgane 137, 161--166 (1972)
Received October 21, 1977 / February 7, 1978
