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The immotile-cilia syndrome in a newborn infant
International Journal of Pediatric Otorhinolaryngology, @IElsevier/North-Holland Biomedical Press
THE IMMOTILE-CILIA
ORVAR FINNSTROM,
SYNDROME
LARS ijDKVIST
2 (1980)
33-31
33
IN A NEWBORN INFANT
and BJijRN A. AFZELIUS
Departments of Paediatrics and Oto-Rhino-Laryngology, University Hospital, Linkiiping and (L3.A.A) Wenner-Gren Institute, University of Stockholm (Sweden) (Received September 26th, 1979) (Revised version accepted December 12th, 1979)
SUMMARY
A newborn infant was suspected to have the immotile-cilia syndrome. He had situs inversus, atelectasis and other pulmonary changes. A biopsy from the nasal mucosa at the age of 21 months confirmed the diagnosis and showed a lack of ciliary orientation and absent dynein arms. Chymotrypsin values, sweat test and most immunoglobulins were normal. The boy is now three years old. So far he has had rather mild respiratory symptoms. The importance of early diagnosis for management and prognosis is stressed.
INTRODUCTION
In 1933 Kartagener [lo] described a triad of situs inversus, bronchiectasis and recurrent sinusitis, sometimes combined with nasal polyps. This triad has become known under the name of Kartagener’s syndrome. About 30 years later 334 cases had been presented in the literature [ 111. It has recently been shown that patients with this syndrome have un-oriented and defective cilia, which are unable to function properly [ 15,161. There is also another equally large group of patients with immotile cilia and normal viscera. It has thus been possible to define a syndrome - the immotile-cilia syndrome - in which the Kartagener’s is a subgroup [ 1,7]. Kartagener’s syndrome has earlier been reported in the newborn period [13,15], but to our knowledge this is the first report of the full entity, including the ciliary defect, in a newborn infant. CASE HISTORY
A male child was born in March 1976 after an uneventful pregnancy to a healthy woman. The birth weight was 4190 g. There was a pre- and postnatal asphyxia, with Apgar scores of 4 and 9. The day after delivery the child
34
had respiratory difficulties with tachypnea, retractions, flaring of the nostrils, and generalized cyanosis. Rales were heard over both lungs. A pulmonary X-ray showed situs inversus totalis and an atelectasis of the middle lobe. He was treated with oxygen and antibiotics. The clinical symptoms disappeared in three days. Roentgenological changes in the middle lobe were still present at the age of three weeks, but disappeared later. For a few days he also had atelectasis in the upper left lobe. The boy has since been followed at regular intervals in our outpatient department. He has been in general good health but with a more or less permanent nasal discharge and a moderate cough for long periods. He has had otitis twice, a slight pneumonia once and obstructive bronchitis once. His development has been normal. Investigations. Chymotrypsin values, sweat test and immunoglobulins were normal. IgA could not be detected in an electrophoretic run performed on his ninth day with our method (upper limit 0.05 g/liter). A biopsy from the nasal mucosa was performed at the age of three weeks and examined by electron microscopy as in some earlier studies, [7,14]. The outcome of that biopsy was uninformative because cilia were lacking in the biopsy (Fig. 1). An electron microscopic evaluation of a 21-month biopsy showed a picture
Fig. 1. Cells from the patient’s nasal mucosa taken at the age of three weeks. These cells and others in the biopsy had short microvilli but lacked cilia. It is not known whether other parts of the nasal mucosa had ciliated cells. Magnification, x 7000.
Fig. 2. Transversally sectioned cilia from the nasal mucosa of a biopsy taken from the same patient at the age of 21 months. Two features of the cilia are diagnostic for the immotilecilia syndrome: (i) there is a lack of orientation in the central pair of microtubes. The same lack of orientation could be seen in the orientation of the basal feet of the ciliary basal bodies, a feature not illustrated here; (ii) the dynein arms are completely lacking. An additional feature, which is common in many pathological disorders of ciliated tissues, is the presence of accessory microtubules. Thus the cilium at the lower left and that in the middle right has a few extra microtubules outside the circle of nine microtubular doublets. Magnification, ~100,000.
consistent with the diagnosis of immotile-cilia syndrome (Fig. 2). Dynein arms of the cilia were completely lacking and the cilia had no fixed orientation as they must have for coordinated activity. Our patient was the second child in the family. The first child, a boy, was stillborn with microcephaly and a congenital heart defect. No microscopic examinations were performed. A female cousin has allergic asthma and the maternal grandfather has chronic sinusitis. As far as the parents know, there are no cases of typical Kartagener’s syndrome, situs inversus, or male infertility in the family. DISCUSSION
Kartagener’s syndrome, and thus the immotile-cilia syndrome, was suspected when the patient was newborn, because of the situs inversus and the
36
long-standing pulmonary atelectasis. The syndrome is usually related to a lack of the dynein arms of the cilia [2,7,14]. It is a congenital disease, probably recessively inherited [ 21. Although the first biopsy specimen in our young patient was inconclusive, a later specimen showed the lack of ciliary orientation and the absence of dynein arms characteristic of the syndrome. To our knowledge, the complete syndrome has not been diagnosed at this early age before. The immotile-cilia syndrome is rare (about l/20,000) [2], but the combination of situs inversus and pulmonary changes from an early age should lead to a suspicion of this syndrome. In cases which have no situs inversus, the diagnosis at an early age is much more difficult. A late development of the IgA system is sometimes claimed to be a further characteristic of the Kartagener’s syndrome [ 61. This addition is probably, according to Holmes [9], due to a transient immunological deficiency and particularly a low IgA level. Our patient had no detectable IgA neonatally but otherwise a normal immunological status. Other newborn or young children with Kartagener’s syndrome have been examined in this respect [12, 13,171 and cases with perfectly normal values as well as cases with subnormal IgA values have been found. Thus, although Kartagener’s syndrome in some cases may be combined with a low level of some or all of the immunoglobulins, the combination is not universal. An early diagnosis may have future implications. As the treatment would be much the same as in cases of the more serious disease cystic fibrosis, a confusion with this disease would not be disadvantageous. It is well known that patients with the Kartagener’s syndrome can live a long life [4], but the condition predisposes to the development of an obstructive lung disease [ 141 including life-threatening bronchiectasies and pulmonary emphysema. Since the mucociliary transport is very low, or maybe absent [ 51, it is especially important for these patients not to start smoking. They shall have pulmonary physiotherapy including tapetement, breathing exercises and positional drainage. The absence of cilia in the middle ear and the paranasal sinuses predisposes for acute and chronic complications [ 81. Transmyringeal ventilatory tubes may be required, and later on sinus operations of the Caldwell-Luc type may be necessary. The diagnosis also has importance for the future choice of occupation. Girls with the syndrome may become mothers [ 31, whereas boys run the risk of being infertile. REFERENCES 1 Afzelius, B.A., A human syndrome caused by immotile cilia, Science, 193 (1976) 317-319. 2 Afzelius, B.A., The immotile-cilia syndrome and other ciliary diseases, Int. Rev. exp. Pathol., 19 (1978) l-43. 3 Afzelius, B.A., Camner, P. and Mossberg, B., On the function of cilia in the female reproductive tract, Fertil. Steril., 29 (1978) 72-74.
37 4 Amjad, H., Richburg, F.D. and Adler, E., Kartagener syndrome. Case report in an elderly man, J. Amer. med. Assoc., 227 (1974) 1420-1422. 5 Camner, P., Mossberg, B. and Afzelius, B.A., Evidence for congenitally nonfunctioning cilia in the trachea-bronchial tract in two subjects, Amer. Rev. resp. Dis., 112 (1975) 807-809. 6 Chipps, B.E., Talamo, R.C. and Winkelstein, J.A., IgA deficiency, recurrent pneumonias, and bronchiectasis, Chest., 73 (1978) 519-526. 7 Eliasson, R., Mossberg, B.. Camner, P. and Afzelius, B.A., The immotile-cilia syndrome. A congenital ciliary abnormality as an etiological factor in chronic airway infections and male sterility, New Engl. J. Med., 297 (1976) l-6. 8 Fischer, T.J., McAdams, J.A., Entis, G.N., Cotton, R., Chory, J.E. and Ausdenmoore, W., Middle ear ciliary defect in Kartagener’s syndrome, Pediatrics, 62 (1978) 443445. 9 Holmes, L.B., Blennerhasset, J.B. and Austen, K.F., A reappraisal of Kartagener’s syndrome, Amer. J. med. Sci., 255 (1968) 13-28. 10 Kartagener, M., Zur Pathogenese der Bronchiectasien: Bronchiectasien bei Situs Viscerum inversus, Beitr. klin. Tuberk., 83 (1933) 489-501. 11 Kartagener, M. and Stucki, P., Bronchiectasias with situs inversus, Arch. Ped., 79 (1962) 193-203. 12 Lupin, A.J. and Misko, G.J., Kartagener’s syndrome with abnormalities of cilia, J. Otolaryng., 7 (1978) 95-102. 13 Monnet, P., Situs inversus et bronchopneumopathies au long tours, des periode neonatale, Arch. Franc. Ped., 35 (1978) 607-619. 14 Mossberg, B., Afzelius, B.A., Eliasson, R. and Camner, P., On the pathogenesis of obstructive lung disease: a study in the immotile-cilia syndrome, Stand. J. resp. Dis., 59 (1978) 55-65. 15 Nichamin, S.J., Kartagener’s syndrome in a newborn infant, J. Amer. med. Assoc., 161 (1956) 966-968. 16 Pedersen, H. and Mygind, N., Absence of axonemal arms in nasal mucosa cilia in Kartagener’s syndrome, Nature (Lond.), 262 (1976) 494-495. 17 Rott, H.-D., Warnatz, H., Pasch-Hilgers, R. and Weikl, A., Kartagener’s syndrome in sibs: clinical and immunologic investigations, Human Genet., 43 (1978) l-11.
THE IMMOTILE-CILIA
ORVAR FINNSTROM,
SYNDROME
LARS ijDKVIST
2 (1980)
33-31
33
IN A NEWBORN INFANT
and BJijRN A. AFZELIUS
Departments of Paediatrics and Oto-Rhino-Laryngology, University Hospital, Linkiiping and (L3.A.A) Wenner-Gren Institute, University of Stockholm (Sweden) (Received September 26th, 1979) (Revised version accepted December 12th, 1979)
SUMMARY
A newborn infant was suspected to have the immotile-cilia syndrome. He had situs inversus, atelectasis and other pulmonary changes. A biopsy from the nasal mucosa at the age of 21 months confirmed the diagnosis and showed a lack of ciliary orientation and absent dynein arms. Chymotrypsin values, sweat test and most immunoglobulins were normal. The boy is now three years old. So far he has had rather mild respiratory symptoms. The importance of early diagnosis for management and prognosis is stressed.
INTRODUCTION
In 1933 Kartagener [lo] described a triad of situs inversus, bronchiectasis and recurrent sinusitis, sometimes combined with nasal polyps. This triad has become known under the name of Kartagener’s syndrome. About 30 years later 334 cases had been presented in the literature [ 111. It has recently been shown that patients with this syndrome have un-oriented and defective cilia, which are unable to function properly [ 15,161. There is also another equally large group of patients with immotile cilia and normal viscera. It has thus been possible to define a syndrome - the immotile-cilia syndrome - in which the Kartagener’s is a subgroup [ 1,7]. Kartagener’s syndrome has earlier been reported in the newborn period [13,15], but to our knowledge this is the first report of the full entity, including the ciliary defect, in a newborn infant. CASE HISTORY
A male child was born in March 1976 after an uneventful pregnancy to a healthy woman. The birth weight was 4190 g. There was a pre- and postnatal asphyxia, with Apgar scores of 4 and 9. The day after delivery the child
34
had respiratory difficulties with tachypnea, retractions, flaring of the nostrils, and generalized cyanosis. Rales were heard over both lungs. A pulmonary X-ray showed situs inversus totalis and an atelectasis of the middle lobe. He was treated with oxygen and antibiotics. The clinical symptoms disappeared in three days. Roentgenological changes in the middle lobe were still present at the age of three weeks, but disappeared later. For a few days he also had atelectasis in the upper left lobe. The boy has since been followed at regular intervals in our outpatient department. He has been in general good health but with a more or less permanent nasal discharge and a moderate cough for long periods. He has had otitis twice, a slight pneumonia once and obstructive bronchitis once. His development has been normal. Investigations. Chymotrypsin values, sweat test and immunoglobulins were normal. IgA could not be detected in an electrophoretic run performed on his ninth day with our method (upper limit 0.05 g/liter). A biopsy from the nasal mucosa was performed at the age of three weeks and examined by electron microscopy as in some earlier studies, [7,14]. The outcome of that biopsy was uninformative because cilia were lacking in the biopsy (Fig. 1). An electron microscopic evaluation of a 21-month biopsy showed a picture
Fig. 1. Cells from the patient’s nasal mucosa taken at the age of three weeks. These cells and others in the biopsy had short microvilli but lacked cilia. It is not known whether other parts of the nasal mucosa had ciliated cells. Magnification, x 7000.
Fig. 2. Transversally sectioned cilia from the nasal mucosa of a biopsy taken from the same patient at the age of 21 months. Two features of the cilia are diagnostic for the immotilecilia syndrome: (i) there is a lack of orientation in the central pair of microtubes. The same lack of orientation could be seen in the orientation of the basal feet of the ciliary basal bodies, a feature not illustrated here; (ii) the dynein arms are completely lacking. An additional feature, which is common in many pathological disorders of ciliated tissues, is the presence of accessory microtubules. Thus the cilium at the lower left and that in the middle right has a few extra microtubules outside the circle of nine microtubular doublets. Magnification, ~100,000.
consistent with the diagnosis of immotile-cilia syndrome (Fig. 2). Dynein arms of the cilia were completely lacking and the cilia had no fixed orientation as they must have for coordinated activity. Our patient was the second child in the family. The first child, a boy, was stillborn with microcephaly and a congenital heart defect. No microscopic examinations were performed. A female cousin has allergic asthma and the maternal grandfather has chronic sinusitis. As far as the parents know, there are no cases of typical Kartagener’s syndrome, situs inversus, or male infertility in the family. DISCUSSION
Kartagener’s syndrome, and thus the immotile-cilia syndrome, was suspected when the patient was newborn, because of the situs inversus and the
36
long-standing pulmonary atelectasis. The syndrome is usually related to a lack of the dynein arms of the cilia [2,7,14]. It is a congenital disease, probably recessively inherited [ 21. Although the first biopsy specimen in our young patient was inconclusive, a later specimen showed the lack of ciliary orientation and the absence of dynein arms characteristic of the syndrome. To our knowledge, the complete syndrome has not been diagnosed at this early age before. The immotile-cilia syndrome is rare (about l/20,000) [2], but the combination of situs inversus and pulmonary changes from an early age should lead to a suspicion of this syndrome. In cases which have no situs inversus, the diagnosis at an early age is much more difficult. A late development of the IgA system is sometimes claimed to be a further characteristic of the Kartagener’s syndrome [ 61. This addition is probably, according to Holmes [9], due to a transient immunological deficiency and particularly a low IgA level. Our patient had no detectable IgA neonatally but otherwise a normal immunological status. Other newborn or young children with Kartagener’s syndrome have been examined in this respect [12, 13,171 and cases with perfectly normal values as well as cases with subnormal IgA values have been found. Thus, although Kartagener’s syndrome in some cases may be combined with a low level of some or all of the immunoglobulins, the combination is not universal. An early diagnosis may have future implications. As the treatment would be much the same as in cases of the more serious disease cystic fibrosis, a confusion with this disease would not be disadvantageous. It is well known that patients with the Kartagener’s syndrome can live a long life [4], but the condition predisposes to the development of an obstructive lung disease [ 141 including life-threatening bronchiectasies and pulmonary emphysema. Since the mucociliary transport is very low, or maybe absent [ 51, it is especially important for these patients not to start smoking. They shall have pulmonary physiotherapy including tapetement, breathing exercises and positional drainage. The absence of cilia in the middle ear and the paranasal sinuses predisposes for acute and chronic complications [ 81. Transmyringeal ventilatory tubes may be required, and later on sinus operations of the Caldwell-Luc type may be necessary. The diagnosis also has importance for the future choice of occupation. Girls with the syndrome may become mothers [ 31, whereas boys run the risk of being infertile. REFERENCES 1 Afzelius, B.A., A human syndrome caused by immotile cilia, Science, 193 (1976) 317-319. 2 Afzelius, B.A., The immotile-cilia syndrome and other ciliary diseases, Int. Rev. exp. Pathol., 19 (1978) l-43. 3 Afzelius, B.A., Camner, P. and Mossberg, B., On the function of cilia in the female reproductive tract, Fertil. Steril., 29 (1978) 72-74.
37 4 Amjad, H., Richburg, F.D. and Adler, E., Kartagener syndrome. Case report in an elderly man, J. Amer. med. Assoc., 227 (1974) 1420-1422. 5 Camner, P., Mossberg, B. and Afzelius, B.A., Evidence for congenitally nonfunctioning cilia in the trachea-bronchial tract in two subjects, Amer. Rev. resp. Dis., 112 (1975) 807-809. 6 Chipps, B.E., Talamo, R.C. and Winkelstein, J.A., IgA deficiency, recurrent pneumonias, and bronchiectasis, Chest., 73 (1978) 519-526. 7 Eliasson, R., Mossberg, B.. Camner, P. and Afzelius, B.A., The immotile-cilia syndrome. A congenital ciliary abnormality as an etiological factor in chronic airway infections and male sterility, New Engl. J. Med., 297 (1976) l-6. 8 Fischer, T.J., McAdams, J.A., Entis, G.N., Cotton, R., Chory, J.E. and Ausdenmoore, W., Middle ear ciliary defect in Kartagener’s syndrome, Pediatrics, 62 (1978) 443445. 9 Holmes, L.B., Blennerhasset, J.B. and Austen, K.F., A reappraisal of Kartagener’s syndrome, Amer. J. med. Sci., 255 (1968) 13-28. 10 Kartagener, M., Zur Pathogenese der Bronchiectasien: Bronchiectasien bei Situs Viscerum inversus, Beitr. klin. Tuberk., 83 (1933) 489-501. 11 Kartagener, M. and Stucki, P., Bronchiectasias with situs inversus, Arch. Ped., 79 (1962) 193-203. 12 Lupin, A.J. and Misko, G.J., Kartagener’s syndrome with abnormalities of cilia, J. Otolaryng., 7 (1978) 95-102. 13 Monnet, P., Situs inversus et bronchopneumopathies au long tours, des periode neonatale, Arch. Franc. Ped., 35 (1978) 607-619. 14 Mossberg, B., Afzelius, B.A., Eliasson, R. and Camner, P., On the pathogenesis of obstructive lung disease: a study in the immotile-cilia syndrome, Stand. J. resp. Dis., 59 (1978) 55-65. 15 Nichamin, S.J., Kartagener’s syndrome in a newborn infant, J. Amer. med. Assoc., 161 (1956) 966-968. 16 Pedersen, H. and Mygind, N., Absence of axonemal arms in nasal mucosa cilia in Kartagener’s syndrome, Nature (Lond.), 262 (1976) 494-495. 17 Rott, H.-D., Warnatz, H., Pasch-Hilgers, R. and Weikl, A., Kartagener’s syndrome in sibs: clinical and immunologic investigations, Human Genet., 43 (1978) l-11.