Letters to the Editor Am. J. Hum. Genet. 48:815, 1991
Concurrence of Dominant Piebald Trait and Fragile X Syndrome To the Editor:
In the July 1971 issue of the Journal, Telfer et al. (1971) described two families in which piebaldism associated with neurologic impairment was transmitted as an autosomal dominant trait. The white forelock and ventral depigmentation of piebaldism were associated with varying degrees of sensorineural hearing impairment in these families; the main neurologic manifestations included motor incoordination and mental retardation of variable severity, complications which had not previously been described in association with the pigmentary and audiologic features of piebald trait. The similar histories in these two unrelated families were striking enough to warrant a separate entry (i.e., 172800) in McKusick's catalog. We have recently had the opportunity to reevaluate one of the families ("kindred B") reported in the Telfer et al. article, through the genetics service of the residential facility where both families were first identified. The father in kindred B was originally reported to be of "superior intelligence" and had high-frequency sensorineural hearing loss as well as typical pigmentary manifestations of piebald trait; his son had striking pigmentary disturbance and mild sensorineural deafness, while being additionally affected by moderate mental retardation and an unspecified degree of motor incoordination. A detailed multigenerational pedigree of both maternal and paternal families was otherwise negative for mental retardation, with or without piebald trait. The affected son of kindred B, now a 59-year-old man, continues to reside at our facility and was seen at our genetics clinic for follow-up. While ostensibly being referred because of his history of piebald trait, it soon became obvious that, apart from his pigmentary disturbances, his physical and behavioral phenotype was quite suggestive of fragile X syndrome. Indeed, fragile X analysis using a combination of cultures deficient in folate, as well as cultures which inhibit thymidylate synthetase clearly revealed the fragile X chromosome in 16% of peripheral blood cells examined. Motor incoordination in this man is currently no more pronounced than that seen in the many other fragile X-positive clients of similar IQ and age whom we see at our facility and, in our opinion, is typical of the mild motor impairment associated with the fragile
815
X syndrome. On reevaluation we found no evidence of ataxia in this client. We conclude that the neurologic impairment described in an isolated member of kindred B most likely represents the concurrence of dominant piebald trait and fragile X syndrome in this patient. To our knowledge, since the 1971 article by Telfer et al., no additional cases of dominant piebald trait with neurologic impairment have been reported; this raises the question of whether current diagnostic techniques might not also yield an alternative explanation for the mental impairment described in kindred A. Despite our repeated efforts to involve kindred A in a follow-up assessment, the family has so far declined reevaluation. BRENDA FINUCANE, CHARLES I. SCOTT, JR., AND MICHAEL B. KURTZ Medical Department Elwyn, Incorporated Elwyn, PA Reference Telfer MA, Sugar M, Jaeger EA, Mulcahy J (1971) Dominant piebald trait (white forelock and leukoderma) with neurological impairment. Am J Hum Genet 23:383-389 © 1991 by The American Society of Human Genetics. All rights reserved. 0002-9297/91 /4&04-0023$02.00
Am. J. Hum. Genet. 48:815-816, 1991
Cystic Fibrosis Patients with Liver Disease Are Not Genetically Distinct To the Editor: About 25%-30% of the patients with cystic fibrosis
(CF) develop focal biliary cirrhosis, which eventually progresses into multilobular biliary cirrhosis with portal hypertension in 2%-5% of the cases (Roy et al. 1982). These conditions are generally associated with pancreatic insufficiency (PI), which is present in 85%90% of the CF patients. The identification of the CF gene (Riordan et al. 1989) and of AF508 as the most frequent mutation causing CF has provided support for the hypothesis that the residual pancreatic activity in patients with
816
pancreatic sufficiency (PS) should be correlated with mild mutations (Kerem et al. 1989). Accordingly, PS or PI are due to different mutant CF alleles. In particular, the frequency of AF508 is higher in PI than in PS patients, and PI has been diagnosed in 477 (>98% ) of 484 CF patients homozygous for AFS08 (European Working Group on CF Genetics 1990). In order to discriminate whether patients with liver disease constitute a genetically distinct subgroup with respect to the other CF patients with or without PI, we have analyzed a sample of 47 Italian CF patients who have hepatobiliary involvement for the presence of the AF508 mutation. The liver disease in these patients was defined by the presence of clinical hepatomegaly with persistent biochemical and echographic abnormalities. All but one patient had PI, and the remaining one most likely had PS. This patient is a 14-year-old girl with both normal growth and normal steatorrea and does not take any pancreatic-enzyme supplements. Primer sequences, PCR conditions, and PAGE for detection of AF508 were as described elsewhere (Kerem et al. 1989; Cremonesi et al. 1990). The total number of chromosomes with the AF508 mutation was 58 of 94, or 61.7%. These data do not differ either from those obtained in a sample representative of the general Italian CF population (frequency of AF508 = 371/700, or 53%; x2 = 2.19, P = 0.14) or from those concerning PI patients only (frequency of AF508 = 317/527, or 60.2%; x2 = 0.03, P = 0.87) studied by the same CF centers. The distribution of genotypes with regard to the AF508 mutation does not differ significantly among the same groups of CF patients. CF patients with PI and biliary cirrhosis cannot therefore be distinguished from PI patients without biliary cirrhosis on the basis of the presence of severe or mild mutations. If the evolution of liver disease in CF is not genetically determined, this finding is relevant for the management of patients for whom the prevention of this complication might become feasible through choleretic therapy (Colombo et al. 1990).
Letters to the Editor MAURIzIo FERRARI,* CARLA COLOMBO,1 GIANFRANCO SEBASTIO,4 ORNELLA CASTIGLIONE,$ SERENA QUATTRUCCI,§ BRUNO DALLAPICCOLAII GIAMBATTISTA LEONI, MAURIZIO ZANDA, * * LUCA ROMANOtt AND MARCELLA DEVOTO$$ *Istituto Scientifico H. S. Raffaele, Central Laboratory and tHI Pediatric Clinic, University of Milan, Milan; *Department of Pediatrics, II Faculty of Medicine, Naples; §Cystic Fibrosis Center, I Pediatric Clinic, and llDepartment of Public Health and Cellular Biology, HI University of Rome, Rome; #Istituto di Clinica e Biologia dell'Eta' Evolutiva and * Division of Pediatrics, Ospedale Brotzu, Cagliari, Italy; and tt I Pediatric Clinic and 14 Molecular Genetics Laboratory, G. Gaslini Institute, Genoa References Colombo C, Setchell KDR, Podda M, Crosignani A, Roda A, Curcio L, Ronchi M, et al (1990) Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis. J Pediatr 117:482-489 Cremonesi L, Ruocco L, Seia M, Russo S, Giunta A, Ronchetto P, Fenu L, et al (1990) Frequency of the AF508 mutation in a sample of 175 Italian cystic fibrosis patients. Hum Genet 85:400-402 European Working Group on CF Genetics (1990) Gradient of distribution in Europe of the major CF mutation and of its associated haplotype. Hum Genet 85:436-446 Kerem B-S, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, et al (1989) Identification ofthe cystic fibrosis gene: genetic analysis. Science 245:1073-1080 Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary cDNA. Science 245:1066-1072 Roy CC, Weber AM, Morin CL, Lepage G, Brisson G, Yousef I, Lasalle R (1982) Hepatobiliary disease in cystic fibrosis: a survey of current issues and concepts. J Pediatr Gastroenterol Nutr 1:469-478 o 1991 by The American Society of Human Genetics. All rights reserved. 0002-9297/91/4804-0024$02.00
Concurrence of Dominant Piebald Trait and Fragile X Syndrome To the Editor:
In the July 1971 issue of the Journal, Telfer et al. (1971) described two families in which piebaldism associated with neurologic impairment was transmitted as an autosomal dominant trait. The white forelock and ventral depigmentation of piebaldism were associated with varying degrees of sensorineural hearing impairment in these families; the main neurologic manifestations included motor incoordination and mental retardation of variable severity, complications which had not previously been described in association with the pigmentary and audiologic features of piebald trait. The similar histories in these two unrelated families were striking enough to warrant a separate entry (i.e., 172800) in McKusick's catalog. We have recently had the opportunity to reevaluate one of the families ("kindred B") reported in the Telfer et al. article, through the genetics service of the residential facility where both families were first identified. The father in kindred B was originally reported to be of "superior intelligence" and had high-frequency sensorineural hearing loss as well as typical pigmentary manifestations of piebald trait; his son had striking pigmentary disturbance and mild sensorineural deafness, while being additionally affected by moderate mental retardation and an unspecified degree of motor incoordination. A detailed multigenerational pedigree of both maternal and paternal families was otherwise negative for mental retardation, with or without piebald trait. The affected son of kindred B, now a 59-year-old man, continues to reside at our facility and was seen at our genetics clinic for follow-up. While ostensibly being referred because of his history of piebald trait, it soon became obvious that, apart from his pigmentary disturbances, his physical and behavioral phenotype was quite suggestive of fragile X syndrome. Indeed, fragile X analysis using a combination of cultures deficient in folate, as well as cultures which inhibit thymidylate synthetase clearly revealed the fragile X chromosome in 16% of peripheral blood cells examined. Motor incoordination in this man is currently no more pronounced than that seen in the many other fragile X-positive clients of similar IQ and age whom we see at our facility and, in our opinion, is typical of the mild motor impairment associated with the fragile
815
X syndrome. On reevaluation we found no evidence of ataxia in this client. We conclude that the neurologic impairment described in an isolated member of kindred B most likely represents the concurrence of dominant piebald trait and fragile X syndrome in this patient. To our knowledge, since the 1971 article by Telfer et al., no additional cases of dominant piebald trait with neurologic impairment have been reported; this raises the question of whether current diagnostic techniques might not also yield an alternative explanation for the mental impairment described in kindred A. Despite our repeated efforts to involve kindred A in a follow-up assessment, the family has so far declined reevaluation. BRENDA FINUCANE, CHARLES I. SCOTT, JR., AND MICHAEL B. KURTZ Medical Department Elwyn, Incorporated Elwyn, PA Reference Telfer MA, Sugar M, Jaeger EA, Mulcahy J (1971) Dominant piebald trait (white forelock and leukoderma) with neurological impairment. Am J Hum Genet 23:383-389 © 1991 by The American Society of Human Genetics. All rights reserved. 0002-9297/91 /4&04-0023$02.00
Am. J. Hum. Genet. 48:815-816, 1991
Cystic Fibrosis Patients with Liver Disease Are Not Genetically Distinct To the Editor: About 25%-30% of the patients with cystic fibrosis
(CF) develop focal biliary cirrhosis, which eventually progresses into multilobular biliary cirrhosis with portal hypertension in 2%-5% of the cases (Roy et al. 1982). These conditions are generally associated with pancreatic insufficiency (PI), which is present in 85%90% of the CF patients. The identification of the CF gene (Riordan et al. 1989) and of AF508 as the most frequent mutation causing CF has provided support for the hypothesis that the residual pancreatic activity in patients with
816
pancreatic sufficiency (PS) should be correlated with mild mutations (Kerem et al. 1989). Accordingly, PS or PI are due to different mutant CF alleles. In particular, the frequency of AF508 is higher in PI than in PS patients, and PI has been diagnosed in 477 (>98% ) of 484 CF patients homozygous for AFS08 (European Working Group on CF Genetics 1990). In order to discriminate whether patients with liver disease constitute a genetically distinct subgroup with respect to the other CF patients with or without PI, we have analyzed a sample of 47 Italian CF patients who have hepatobiliary involvement for the presence of the AF508 mutation. The liver disease in these patients was defined by the presence of clinical hepatomegaly with persistent biochemical and echographic abnormalities. All but one patient had PI, and the remaining one most likely had PS. This patient is a 14-year-old girl with both normal growth and normal steatorrea and does not take any pancreatic-enzyme supplements. Primer sequences, PCR conditions, and PAGE for detection of AF508 were as described elsewhere (Kerem et al. 1989; Cremonesi et al. 1990). The total number of chromosomes with the AF508 mutation was 58 of 94, or 61.7%. These data do not differ either from those obtained in a sample representative of the general Italian CF population (frequency of AF508 = 371/700, or 53%; x2 = 2.19, P = 0.14) or from those concerning PI patients only (frequency of AF508 = 317/527, or 60.2%; x2 = 0.03, P = 0.87) studied by the same CF centers. The distribution of genotypes with regard to the AF508 mutation does not differ significantly among the same groups of CF patients. CF patients with PI and biliary cirrhosis cannot therefore be distinguished from PI patients without biliary cirrhosis on the basis of the presence of severe or mild mutations. If the evolution of liver disease in CF is not genetically determined, this finding is relevant for the management of patients for whom the prevention of this complication might become feasible through choleretic therapy (Colombo et al. 1990).
Letters to the Editor MAURIzIo FERRARI,* CARLA COLOMBO,1 GIANFRANCO SEBASTIO,4 ORNELLA CASTIGLIONE,$ SERENA QUATTRUCCI,§ BRUNO DALLAPICCOLAII GIAMBATTISTA LEONI, MAURIZIO ZANDA, * * LUCA ROMANOtt AND MARCELLA DEVOTO$$ *Istituto Scientifico H. S. Raffaele, Central Laboratory and tHI Pediatric Clinic, University of Milan, Milan; *Department of Pediatrics, II Faculty of Medicine, Naples; §Cystic Fibrosis Center, I Pediatric Clinic, and llDepartment of Public Health and Cellular Biology, HI University of Rome, Rome; #Istituto di Clinica e Biologia dell'Eta' Evolutiva and * Division of Pediatrics, Ospedale Brotzu, Cagliari, Italy; and tt I Pediatric Clinic and 14 Molecular Genetics Laboratory, G. Gaslini Institute, Genoa References Colombo C, Setchell KDR, Podda M, Crosignani A, Roda A, Curcio L, Ronchi M, et al (1990) Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis. J Pediatr 117:482-489 Cremonesi L, Ruocco L, Seia M, Russo S, Giunta A, Ronchetto P, Fenu L, et al (1990) Frequency of the AF508 mutation in a sample of 175 Italian cystic fibrosis patients. Hum Genet 85:400-402 European Working Group on CF Genetics (1990) Gradient of distribution in Europe of the major CF mutation and of its associated haplotype. Hum Genet 85:436-446 Kerem B-S, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, et al (1989) Identification ofthe cystic fibrosis gene: genetic analysis. Science 245:1073-1080 Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary cDNA. Science 245:1066-1072 Roy CC, Weber AM, Morin CL, Lepage G, Brisson G, Yousef I, Lasalle R (1982) Hepatobiliary disease in cystic fibrosis: a survey of current issues and concepts. J Pediatr Gastroenterol Nutr 1:469-478 o 1991 by The American Society of Human Genetics. All rights reserved. 0002-9297/91/4804-0024$02.00
