American Journal of Medical Genetics 40155-158 (1991)
On the Inheritance of Primary Spontaneous Pneumothorax Igor Z. Abolnik, Izidore S. Lossos, Joel Zlotogora, and Raphael Brauer Pulmonary Unit (I.Z.A., I.S.L., R.B.) and Department of Human Genetics (J.Z.),Hadassah Medical Center and Hebrew University, Jerusalem, Israel
We report on 15 families with familial primary spontaneous pneumothorax detected through a retrospectivestudy of a large group of male patients. Genetic analysis of these families together with 14 families from the literature in which enough details were available suggested 2 possible models of inheritance. First, the familial cases are due to an autosoma1 dominant gene with incomplete penetrance, the penetrance being lower in females (21%) than in males (50%). Second, the familial cases represent a heterogeneous group of patients: some of the familial cases are due to an X-linked recessive gene and others to an autosomal dominant gene with the incomplete penetrance (35% in females and 50% in males). The second model may explain the excess of female carriers found in the families of the patients and is supported by the existence of clinical differences between the patients in each of the sub-groups. In particular the number of episodes of pneumothorax per patient was significantly higher in the subgroup with the autosomal dominant form than in the sub-groupwith the X-linked recessive form of the disease.
KEY WORDS spontaneous pneumothorax, familial, genetic analysis INTRODUCTION The incidence of primary spontaneous pneumothorax was reported to be 7.4 males and 1.2 females per 100,000 individuals [Melton et al., 19791. Most cases of spontaReceived for publication May 25,1990; revision received August 27, 1990. Igor Z. Abolnik, M.D., is now at Methodist Hospitals of Memphis, Department of Medical Education, 1 Tower, 1265 Union Avenue, Memphis, TN 38104-3499. Address reprint requests there. The opinions herein are those of the authors and not of the Israeli Defense Forces.
0 1991 Wiley-Liss, Inc.
neous pneumothorax are isolated; however, 32 families with more than one affected relative have been reported. In a Eetrospective survey of primary spontaneous pneumothorax in the Israeli Defense Forces, 15 families including 33 affected members were identified. Since the knowledge on the inheritance of the disorder is limited, we decided to review all the familial cases from the literature and to analyze them together with our cases.
MATERIALS AND METHODS In a retrospective survey of pneumothorax in males who have served in the Israeli Defense Forces, 286 patients with primary spontaneous pneumothorax were detected and interviewed. Information regarding clinical details, recurrences, height, weight, country of origin, and family history was collected. In 33 patients a family history of spontaneous pneumothorax was obtained. In one case we were unable t o obtain the full family history, in another 6 cases the relative affected was very distant from the propositus and the exact relationship was not obtained. The remaining 26 propositi originated from 15 families in which there were 7 additional patients with spontaneous pneumothorax (Fig. 1).In all 33 patients the diagnosis was confirmed in the hospital files. None of the patients had another lung or any systemic disease. In the survey of the literature we found 87 cases of spontaneous pneumothorax originating from 32 families [Atwood, 1926; Bachmann, 1940; Brock, 1948; Berlin, 1950;Boyd, 1957;Clarke, 1964;Delaney et al., 1974; Eriksson, 1965; Farber, 1921; Gotzsche, 1933; Ginzburg and Medvedovskii, 1976; Gibson, 1977; Hinson et al., 1981; Inoue et al., 1982; Kusan, 1925; Leites and Tannenbaum, 1960; Leman and Dines, 1973; Morawitz, 1933; Muler, 1934; Pierce et al., 1980; Rottenberg and Golden, 1949; Rodriguez, 1956; Rashid et al., 1986; Sharpe et al., 1980; Sugiyama et al., 1986;Taddei, 1968; Wilson and Aysworth, 19791. In 14 of these families sufficient details were given in order to allow construction of a pedigree (Fig. 2). Therefore, the genetic analysis was done in these 14 families together with our 15 families. The genetic analysis was done only in the families in which there were affected patients in more than one generation. In those families there were 29 obligatory carriers: 9 of them were affected and had at least one affected child, the other 20 were healthy but they
Abolnik et al.
156
had a t least one affected child in addition to another affected close relative. Since the ascertainment of the offspring of the obligatory carriers was done through at least one affected child, the segregation of the abnormal gene was calculated only among the sibs of this affected child. The results were analyzed with the chi2 test, t-test, and nonparametric statistics (Rank sum test) [Hill, 1971; Siegel, 19561.
H
0
1
@----l-o
681
rn
Fig. 1. Pedigrees of the families with familial spontaneouspneumothorax from our survey. The individuals with a black dot are obligate carriers.
i?.
or0
13
orcl
Fig. 2. Pedigrees of the families from the literature with familial spontaneouspneumothorax.The individuals with a black dot are obligate carriers of the trait. In family 8 one of the affected females may have received the gene from her father or her mother and therefore none of them were included as obligatory carrier. References of the families: 1 [Ginzburg and Medvedovskii, 19761, 2 [Berlin, 19501, 3 [Ziegler, 19611, 4 [Berlin, 19501, 5 [Berlin, 19501, 6 [Wilson and Aysworth, 1979],7 [Sharpe et al., 19801,8 [Ziegler,19611,9 [Hinson et al., 19811, 10 [Delaney et al., 19741, 11 [Delaney et al., 19741, 12 [Sugiyama et al., 19861, 13 [Eriksson, 19651, 14 [Ginzburg and Medvedovskii, 19761.
RESULTS Clinical Data on our 33 Patients Among the 15 families there were 30 affected males and 3 affected females. The deviation of the sex distribution is due a t least in part to the bias of ascertainment since all our 26 propositi were males. The clinical presentation and findings on physical examination were similar to those of our patients with nonfamilial primary pneumothorax. The mean age at onset in the males was 26.5 2 9 (standard deviation, SD)years and each patient had a mean of 2.3 5 2.6 (SD)episodes of pneumothorax. All the patients were Jewish. The parents of the propositi were not related; in 2 families they were born in Israel, in another 3 in Europe or USA. In 3 cases the parents of the propositi were Jews from Yemen, they were from Morocco in another 3 cases. In 2 families the parents were from Libya and in the last 2 families the origin of the parents was mixed. The numbers are small; however, the origin of the families of the patients is very different from the origin of Israeli population in which Jews from Europe and USA represent approximately 36%, those from Israel 21.5%, from Morocco 12.5%, while those from Yemen or Libya represent only 2%of the population each [Statistical Abstract of Israel, 19891. Genetic Analysis The analysis was done on 29 families: 15 reported here (Fig. 1) and 14 from the literature (Fig. 2);they included 52 affected males and 23 affected females. The parents of the affected individuals were not consanguineous in any family. Among the 29 obligatory carriers of the gene, 19 are females (4 affected) and 10 males (5 affected). They had 107 children (59 males and 48 females).Among the sibs, there are 67 healthy children (37 females and 30 males) and 10 affected children. Autosomal Dominant Inheritance In this type of inheritance one expects the trait to be transmitted through males as well as females;the observation of 19 females among 29 obligatory carriers is a greater than expected but this difference is not statistically significant. If one assumes that the disease is autosomal dominant, then the penetrance is incomplete: 21%for females (4 affected out of 19 females) and 50%for males (5/10).As mentioned before, among the 77 sibs of the affected children born to the 29 obligatory carriers, 10 are affected and 67 are healthy. Taking into account incomplete penetrance, 16.5 of the 37 healthy females are carriers and so are 10 of the 30 healthy males. Thus, including the 10 affected children, 36.5 of
Familial Pneumothorax the children of the obligatory carriers are also carriers of the mutant gene and, therefore, among the 77 sibs of the affected children almost half are carriers of the abnormal gene as expected in an autosomal dominant disorder. X-Linked Inheritance X-Linked inheritance is incompatible with most of the pedigrees since in many cases an affected father transmitted the disease to his son. Autosomal Recessive Inheritance In many of the families the gene is transmitted from an affected parent to his offspring and since the disorder is rare and there were no instances of consanguineous mating among the parents of the affected individuals, the inheritance does not fit the autosomal recessive model. Genetic Heterogeneity One may envision that there is more than one gene involved in the inheritance of the condition. Some of the cases may be due to X-linked recessive inheritance, and the others to a dominant gene. 1. X-linked inheritance. In 4 of the pedigrees (I,J,M,N), the affected males were born to unaffected parents and are related through healthy women. In addition, in 7 families (K,L,0,11,12,13,14)only brothers were affected while both parents were normal. All 11 pedigrees are compatible with X-Linked inheritance. 2. Autosomal dominant inheritance with incomplete penetrance. This group includes 14 pedigrees with affected individuals in more than one generation with transmission of the trait through a male and 4 families in which only sibs, including females, were affected. In the 14 pedigrees with affected individuals in more than one generation we recalculated the penetrance and the segregation of the condition among the sibs of affected children. Among the 22 obligatory carriers there are 12 females (4 affected) and 10 males (5 affected) and then the penetrance is 35% (4112) for females and 50% (5/10) for males. Among the 55 sibs of affected children of the obligatory carriers, 10 are also affected and 45 are normals (25 females and 20 males). Taking into account the incomplete penetrance, 10 of the healthy females are carriers and 7 of the healthy males. Thus, including the 10 affected sibs, there are 27 carriers of the abnormal gene among the 55 sibs of the propositi, which is very close to the expected number in an autosomal dominant disease. We compared our clinical data on affected males in the 2 possible sub-groups to look for any clinical differences between them. The age of onset was 29.2 years 11.2 (SD) in the autosomal dominant group and 23.3 ? 3.7 (SD) in the X-linked recessive group, the difference between the 2 groups was not significant. As for the number of episodes of pneumothorax per patient it was 3.3 3.3 (SD) episodes in the autosomal dominant group and 1.3 ? 0.6 (SD) in the X-linked recessive; the difference was found significant with the Rank sum test (P< 0.031). There were no differences between the different sub-groups in other parameters like height, weight, or length of follow-up.
*
*
157
DISCUSSION Spontaneous pneumothorax has been reported in patients with connective tissue disorders, for instance, in 2 families more than one member affected with Marfan syndrome were described [Chevrot et al., 1970; Hall et al., 19841. It was also reported in cases with alphalantitrypsin deficiency;however, among 19 patients with familial spontaneous pneumothorax in whom alphalantitrypsin was checked, only one had significant deficiency (Eriksson, 1965). Among the “primary” spontaneous pneumothorax the first description of familial cases was reported by Farber L19211; since then 87 cases from 32 families have been described in which the sex ratio of males to females was 1.66:l.Among the familial cases from the literature in whom data were available the mean age-of-onsetin male patients was 27.7 17.9 (SD) years and each individual had a mean of 2 1 (SD) episodes, these clinical data are very similar to those in our group of familial cases. The genetic analysis of the familial cases from our survey, together with those from the literature, suggested 2 possible explanations. The first one is that there is one autosomal dominant gene with incomplete penetrance. The second possibility is that we are dealing with more than one gene and that some of the familial cases are inherited as an X-linked recessive disorder and the others as an autosomal dominant trait with incomplete penetrance, the penetrance being higher in males (50%)than in females (35%).We favor the second possibility since it explains the excess of carrier females found in the case of a single dominant gene. In addition, supporting the model of heterogeneity are the clinical differences observed between the 2 groups of patients. The age-of-onset was somewhat earlier in the group of patients with the apparent X-linked disorder, and there was a significantly increased number of episodes of pneumothorax per patient among those with the dominant form of the disorder as compared to those with the X-linked disorder. The assumption of genetic heterogeneity is also compatible with the disorder itself, since spontaneous pneumothorax appears more to be a symptom than a definite disorder with a single pathogenesis. An unresolved question remains whether all cases of primary spontaneous pneumothorax may be explained by a monogenic defect or whether the syndrome is even more heterogeneous.
*
*
REFERENCES Atwood AW (1926): Spontaneous pneumothorax.Boston Med Surg J 195:1237-1241. Bachmann H (1940): Familial spontaneous pneumothorax and other spontaneous pneumothorax. Dis Chest 677. Brock RC (1948): Recurrent and chronic spontaneous pneumothorax. Thorax 3:88-111. Berlin R (1950): Familial occurrence of pneumothorax simplex. Acta Med Scand 137:268-275. Boyd DHA (1957): Familial spontaneous pneumothorax. Scott Med J 2:220, 221. Clarke CA (ed) (1964): “Genetics for the Clinician,” 2nd ed. Philadelphia: FA Davis Co., 148-149. Chevrot A, Chevrot-VinentA, Gathier N, Faure C (1970):Les pneumothorax familiaux et hereditaires. J Radio1 51313-715.
158
Abolnik et al.
Delaney JC, Gale A, Walker BA (1974):Familial spontaneous pneumothorax. Postgrad Med J 50:648-649. Eriksson S (1965):Studies in alpha,-antitrypsin deficiency. Acta Med Scand [Suppll432:1-85. Farber EE (1921):Spontaneous pneumothorax in two siblings. Hospitalstid 64573, 574. Gibson GJ (1977):Familial pneumothoraces and bullae. Thorax 32:8890. Ginzburg MA, Medvedovskii BI (1976):Familial spontaneous pneumothorax. Grudn Khir 254-57. Gotzsche C (1933): Some cases of spontaneous pneumothorax in the same family. Ugeskr Laeger 95765. Hall JG, Pyeritz RE, Dudgeon DL, Haller JA (1984):Pneumothorax in the Marfan syndrome. Prevalence and therapy. Ann Thorac Surg 37:500-504. Hill AB (1971):“Principles of Medical Statistics,” 9th ed. London: The Lancet Limited. Hinson JM, Brigham KL, Daniel1 J (1981):Catamenial pneumothorax in sisters. Chest 80:634, 635. Inoue N, Kitano I, Murakami T (1982):Surgical treatment of spontaneous pneumothorax occurring in monovular twins: &port of two cases. Kyobu Geka 35447-450. Kjaergaard H (1932): Spontaneous pneumothorax in the apparently healthy. Acta Med Scand [Suppll 43:l-159. Kusan V (1925): The aetiology of spontaneous pneumothorax. Lijec Vjesn 47:759. Leites V, Tannenbaum E (1960):Familial spontaneous pneumothorax. Am Rev Respir Dis 82:240, 241. Leman CB, Dines DE (1973):Treatment of recurrent spontaneous familial pneumothorax. JAMA 225:1256. Morawitz P (1933): Gutardigen familiaren spontanpneumothorax. Munch Med Wschr 80:1861.
Melton U,Hepper NGG, Offered KP (1979):Incidence of spontaneous pneumothorax in Olmsted County, Minnesota: 1950 to 1974. Am Rev Respir Dis 120:1379-1382. Muler P (1934): Uber Gutartigen familiaren spontanpneumothorax. Klin Wochenschr 13:137, 138. Nakamura H, Konishiike J, Sugamura A, Takeno Y (1986):Epidemiology of spontaneous pneumothorax in women. Chest 89:378-382. Pierce JA, Suarez B, Reich T (1980): More on familial spontaneous pneumothorax. Chest 78:263. Rashid A, Sendi A, Al-Kadhimi A, Donelly RJ (1986): Concurrent spontaneous pneumothorax in identical twins. Thorax 41:971. Rodriguez FB (1956): Un caso de pnemoneumothorax, con cuadro abdominal agudo, y otro de pneumothorax espontaneo en dos hermanos. Rev Esp Tuberc 25:553. Rottenberg LA, Golden R (1949):Spontaneous pneumothorax: A study of 105 cases. Radiology 53:157-167. Sharpe IK, Ahmad M, Braun W (1980):Familial spontaneous pneumothorax and HLA antigens. Chest 78:264-268. Siege1 S (1956): “Non-Parametric Statistics for the Behavioral Sciences.” McGraw-Hill, Kogakusha Ltd. Statistical Abstract of Israel (1989):40. Central Bureau of Statistics. Sugiyama Y, Maeda H, Yatsumoto H, Takaka F (1986):Familial spontaneous pneumothorax. Thorax 41:969, 970. Taddei M (1968): Le pneumothorax spontane familial. Schweiz Med Wochenschr 98:1396-1397. Voge WM, Anthracite R (1986):Spontaneous pneumothorax in USAF air crew population: A retrospective study. Aviat Space Environ Med 57:939-949. Wilson WG, Aysworth AS (1979):Familial spontaneous pneumothorax. Pediatrics 64:172-175. Ziegler E (1961): Familiarer idiopathischer Spontanpneumothorax. Helv Paediatr Acta 16:347-367.
On the Inheritance of Primary Spontaneous Pneumothorax Igor Z. Abolnik, Izidore S. Lossos, Joel Zlotogora, and Raphael Brauer Pulmonary Unit (I.Z.A., I.S.L., R.B.) and Department of Human Genetics (J.Z.),Hadassah Medical Center and Hebrew University, Jerusalem, Israel
We report on 15 families with familial primary spontaneous pneumothorax detected through a retrospectivestudy of a large group of male patients. Genetic analysis of these families together with 14 families from the literature in which enough details were available suggested 2 possible models of inheritance. First, the familial cases are due to an autosoma1 dominant gene with incomplete penetrance, the penetrance being lower in females (21%) than in males (50%). Second, the familial cases represent a heterogeneous group of patients: some of the familial cases are due to an X-linked recessive gene and others to an autosomal dominant gene with the incomplete penetrance (35% in females and 50% in males). The second model may explain the excess of female carriers found in the families of the patients and is supported by the existence of clinical differences between the patients in each of the sub-groups. In particular the number of episodes of pneumothorax per patient was significantly higher in the subgroup with the autosomal dominant form than in the sub-groupwith the X-linked recessive form of the disease.
KEY WORDS spontaneous pneumothorax, familial, genetic analysis INTRODUCTION The incidence of primary spontaneous pneumothorax was reported to be 7.4 males and 1.2 females per 100,000 individuals [Melton et al., 19791. Most cases of spontaReceived for publication May 25,1990; revision received August 27, 1990. Igor Z. Abolnik, M.D., is now at Methodist Hospitals of Memphis, Department of Medical Education, 1 Tower, 1265 Union Avenue, Memphis, TN 38104-3499. Address reprint requests there. The opinions herein are those of the authors and not of the Israeli Defense Forces.
0 1991 Wiley-Liss, Inc.
neous pneumothorax are isolated; however, 32 families with more than one affected relative have been reported. In a Eetrospective survey of primary spontaneous pneumothorax in the Israeli Defense Forces, 15 families including 33 affected members were identified. Since the knowledge on the inheritance of the disorder is limited, we decided to review all the familial cases from the literature and to analyze them together with our cases.
MATERIALS AND METHODS In a retrospective survey of pneumothorax in males who have served in the Israeli Defense Forces, 286 patients with primary spontaneous pneumothorax were detected and interviewed. Information regarding clinical details, recurrences, height, weight, country of origin, and family history was collected. In 33 patients a family history of spontaneous pneumothorax was obtained. In one case we were unable t o obtain the full family history, in another 6 cases the relative affected was very distant from the propositus and the exact relationship was not obtained. The remaining 26 propositi originated from 15 families in which there were 7 additional patients with spontaneous pneumothorax (Fig. 1).In all 33 patients the diagnosis was confirmed in the hospital files. None of the patients had another lung or any systemic disease. In the survey of the literature we found 87 cases of spontaneous pneumothorax originating from 32 families [Atwood, 1926; Bachmann, 1940; Brock, 1948; Berlin, 1950;Boyd, 1957;Clarke, 1964;Delaney et al., 1974; Eriksson, 1965; Farber, 1921; Gotzsche, 1933; Ginzburg and Medvedovskii, 1976; Gibson, 1977; Hinson et al., 1981; Inoue et al., 1982; Kusan, 1925; Leites and Tannenbaum, 1960; Leman and Dines, 1973; Morawitz, 1933; Muler, 1934; Pierce et al., 1980; Rottenberg and Golden, 1949; Rodriguez, 1956; Rashid et al., 1986; Sharpe et al., 1980; Sugiyama et al., 1986;Taddei, 1968; Wilson and Aysworth, 19791. In 14 of these families sufficient details were given in order to allow construction of a pedigree (Fig. 2). Therefore, the genetic analysis was done in these 14 families together with our 15 families. The genetic analysis was done only in the families in which there were affected patients in more than one generation. In those families there were 29 obligatory carriers: 9 of them were affected and had at least one affected child, the other 20 were healthy but they
Abolnik et al.
156
had a t least one affected child in addition to another affected close relative. Since the ascertainment of the offspring of the obligatory carriers was done through at least one affected child, the segregation of the abnormal gene was calculated only among the sibs of this affected child. The results were analyzed with the chi2 test, t-test, and nonparametric statistics (Rank sum test) [Hill, 1971; Siegel, 19561.
H
0
1
@----l-o
681
rn
Fig. 1. Pedigrees of the families with familial spontaneouspneumothorax from our survey. The individuals with a black dot are obligate carriers.
i?.
or0
13
orcl
Fig. 2. Pedigrees of the families from the literature with familial spontaneouspneumothorax.The individuals with a black dot are obligate carriers of the trait. In family 8 one of the affected females may have received the gene from her father or her mother and therefore none of them were included as obligatory carrier. References of the families: 1 [Ginzburg and Medvedovskii, 19761, 2 [Berlin, 19501, 3 [Ziegler, 19611, 4 [Berlin, 19501, 5 [Berlin, 19501, 6 [Wilson and Aysworth, 1979],7 [Sharpe et al., 19801,8 [Ziegler,19611,9 [Hinson et al., 19811, 10 [Delaney et al., 19741, 11 [Delaney et al., 19741, 12 [Sugiyama et al., 19861, 13 [Eriksson, 19651, 14 [Ginzburg and Medvedovskii, 19761.
RESULTS Clinical Data on our 33 Patients Among the 15 families there were 30 affected males and 3 affected females. The deviation of the sex distribution is due a t least in part to the bias of ascertainment since all our 26 propositi were males. The clinical presentation and findings on physical examination were similar to those of our patients with nonfamilial primary pneumothorax. The mean age at onset in the males was 26.5 2 9 (standard deviation, SD)years and each patient had a mean of 2.3 5 2.6 (SD)episodes of pneumothorax. All the patients were Jewish. The parents of the propositi were not related; in 2 families they were born in Israel, in another 3 in Europe or USA. In 3 cases the parents of the propositi were Jews from Yemen, they were from Morocco in another 3 cases. In 2 families the parents were from Libya and in the last 2 families the origin of the parents was mixed. The numbers are small; however, the origin of the families of the patients is very different from the origin of Israeli population in which Jews from Europe and USA represent approximately 36%, those from Israel 21.5%, from Morocco 12.5%, while those from Yemen or Libya represent only 2%of the population each [Statistical Abstract of Israel, 19891. Genetic Analysis The analysis was done on 29 families: 15 reported here (Fig. 1) and 14 from the literature (Fig. 2);they included 52 affected males and 23 affected females. The parents of the affected individuals were not consanguineous in any family. Among the 29 obligatory carriers of the gene, 19 are females (4 affected) and 10 males (5 affected). They had 107 children (59 males and 48 females).Among the sibs, there are 67 healthy children (37 females and 30 males) and 10 affected children. Autosomal Dominant Inheritance In this type of inheritance one expects the trait to be transmitted through males as well as females;the observation of 19 females among 29 obligatory carriers is a greater than expected but this difference is not statistically significant. If one assumes that the disease is autosomal dominant, then the penetrance is incomplete: 21%for females (4 affected out of 19 females) and 50%for males (5/10).As mentioned before, among the 77 sibs of the affected children born to the 29 obligatory carriers, 10 are affected and 67 are healthy. Taking into account incomplete penetrance, 16.5 of the 37 healthy females are carriers and so are 10 of the 30 healthy males. Thus, including the 10 affected children, 36.5 of
Familial Pneumothorax the children of the obligatory carriers are also carriers of the mutant gene and, therefore, among the 77 sibs of the affected children almost half are carriers of the abnormal gene as expected in an autosomal dominant disorder. X-Linked Inheritance X-Linked inheritance is incompatible with most of the pedigrees since in many cases an affected father transmitted the disease to his son. Autosomal Recessive Inheritance In many of the families the gene is transmitted from an affected parent to his offspring and since the disorder is rare and there were no instances of consanguineous mating among the parents of the affected individuals, the inheritance does not fit the autosomal recessive model. Genetic Heterogeneity One may envision that there is more than one gene involved in the inheritance of the condition. Some of the cases may be due to X-linked recessive inheritance, and the others to a dominant gene. 1. X-linked inheritance. In 4 of the pedigrees (I,J,M,N), the affected males were born to unaffected parents and are related through healthy women. In addition, in 7 families (K,L,0,11,12,13,14)only brothers were affected while both parents were normal. All 11 pedigrees are compatible with X-Linked inheritance. 2. Autosomal dominant inheritance with incomplete penetrance. This group includes 14 pedigrees with affected individuals in more than one generation with transmission of the trait through a male and 4 families in which only sibs, including females, were affected. In the 14 pedigrees with affected individuals in more than one generation we recalculated the penetrance and the segregation of the condition among the sibs of affected children. Among the 22 obligatory carriers there are 12 females (4 affected) and 10 males (5 affected) and then the penetrance is 35% (4112) for females and 50% (5/10) for males. Among the 55 sibs of affected children of the obligatory carriers, 10 are also affected and 45 are normals (25 females and 20 males). Taking into account the incomplete penetrance, 10 of the healthy females are carriers and 7 of the healthy males. Thus, including the 10 affected sibs, there are 27 carriers of the abnormal gene among the 55 sibs of the propositi, which is very close to the expected number in an autosomal dominant disease. We compared our clinical data on affected males in the 2 possible sub-groups to look for any clinical differences between them. The age of onset was 29.2 years 11.2 (SD) in the autosomal dominant group and 23.3 ? 3.7 (SD) in the X-linked recessive group, the difference between the 2 groups was not significant. As for the number of episodes of pneumothorax per patient it was 3.3 3.3 (SD) episodes in the autosomal dominant group and 1.3 ? 0.6 (SD) in the X-linked recessive; the difference was found significant with the Rank sum test (P< 0.031). There were no differences between the different sub-groups in other parameters like height, weight, or length of follow-up.
*
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157
DISCUSSION Spontaneous pneumothorax has been reported in patients with connective tissue disorders, for instance, in 2 families more than one member affected with Marfan syndrome were described [Chevrot et al., 1970; Hall et al., 19841. It was also reported in cases with alphalantitrypsin deficiency;however, among 19 patients with familial spontaneous pneumothorax in whom alphalantitrypsin was checked, only one had significant deficiency (Eriksson, 1965). Among the “primary” spontaneous pneumothorax the first description of familial cases was reported by Farber L19211; since then 87 cases from 32 families have been described in which the sex ratio of males to females was 1.66:l.Among the familial cases from the literature in whom data were available the mean age-of-onsetin male patients was 27.7 17.9 (SD) years and each individual had a mean of 2 1 (SD) episodes, these clinical data are very similar to those in our group of familial cases. The genetic analysis of the familial cases from our survey, together with those from the literature, suggested 2 possible explanations. The first one is that there is one autosomal dominant gene with incomplete penetrance. The second possibility is that we are dealing with more than one gene and that some of the familial cases are inherited as an X-linked recessive disorder and the others as an autosomal dominant trait with incomplete penetrance, the penetrance being higher in males (50%)than in females (35%).We favor the second possibility since it explains the excess of carrier females found in the case of a single dominant gene. In addition, supporting the model of heterogeneity are the clinical differences observed between the 2 groups of patients. The age-of-onset was somewhat earlier in the group of patients with the apparent X-linked disorder, and there was a significantly increased number of episodes of pneumothorax per patient among those with the dominant form of the disorder as compared to those with the X-linked disorder. The assumption of genetic heterogeneity is also compatible with the disorder itself, since spontaneous pneumothorax appears more to be a symptom than a definite disorder with a single pathogenesis. An unresolved question remains whether all cases of primary spontaneous pneumothorax may be explained by a monogenic defect or whether the syndrome is even more heterogeneous.
*
*
REFERENCES Atwood AW (1926): Spontaneous pneumothorax.Boston Med Surg J 195:1237-1241. Bachmann H (1940): Familial spontaneous pneumothorax and other spontaneous pneumothorax. Dis Chest 677. Brock RC (1948): Recurrent and chronic spontaneous pneumothorax. Thorax 3:88-111. Berlin R (1950): Familial occurrence of pneumothorax simplex. Acta Med Scand 137:268-275. Boyd DHA (1957): Familial spontaneous pneumothorax. Scott Med J 2:220, 221. Clarke CA (ed) (1964): “Genetics for the Clinician,” 2nd ed. Philadelphia: FA Davis Co., 148-149. Chevrot A, Chevrot-VinentA, Gathier N, Faure C (1970):Les pneumothorax familiaux et hereditaires. J Radio1 51313-715.
158
Abolnik et al.
Delaney JC, Gale A, Walker BA (1974):Familial spontaneous pneumothorax. Postgrad Med J 50:648-649. Eriksson S (1965):Studies in alpha,-antitrypsin deficiency. Acta Med Scand [Suppll432:1-85. Farber EE (1921):Spontaneous pneumothorax in two siblings. Hospitalstid 64573, 574. Gibson GJ (1977):Familial pneumothoraces and bullae. Thorax 32:8890. Ginzburg MA, Medvedovskii BI (1976):Familial spontaneous pneumothorax. Grudn Khir 254-57. Gotzsche C (1933): Some cases of spontaneous pneumothorax in the same family. Ugeskr Laeger 95765. Hall JG, Pyeritz RE, Dudgeon DL, Haller JA (1984):Pneumothorax in the Marfan syndrome. Prevalence and therapy. Ann Thorac Surg 37:500-504. Hill AB (1971):“Principles of Medical Statistics,” 9th ed. London: The Lancet Limited. Hinson JM, Brigham KL, Daniel1 J (1981):Catamenial pneumothorax in sisters. Chest 80:634, 635. Inoue N, Kitano I, Murakami T (1982):Surgical treatment of spontaneous pneumothorax occurring in monovular twins: &port of two cases. Kyobu Geka 35447-450. Kjaergaard H (1932): Spontaneous pneumothorax in the apparently healthy. Acta Med Scand [Suppll 43:l-159. Kusan V (1925): The aetiology of spontaneous pneumothorax. Lijec Vjesn 47:759. Leites V, Tannenbaum E (1960):Familial spontaneous pneumothorax. Am Rev Respir Dis 82:240, 241. Leman CB, Dines DE (1973):Treatment of recurrent spontaneous familial pneumothorax. JAMA 225:1256. Morawitz P (1933): Gutardigen familiaren spontanpneumothorax. Munch Med Wschr 80:1861.
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