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Follow-up of adult males with chromosome 18p deletion
European Journal of Medical Genetics 48 (2005) 189–193 www.elsevier.com/locate/ejmg
Short communication
Follow-up of adult males with chromosome 18p deletion Thomy J.L. de Ravel a,*, Paul Thiry b, Jean-Pierre Fryns a a
Center for Human Genetics, UZ Gasthuisberg, 49 Herestraat, 3000 Leuven, Belgium b Sint Oda Dienstencentrum, Overpelt, Belgium Received 15 November 2004 Available online 01 February 2005
Abstract The 18p- syndrome has been known for over 40 years, the first report being by de Grouchy et al. [Comptes Rendus Hebdomadaires Séances l’Acad Sci 256 (1963) 1028]. Mental retardation of varying severity is the most constant feature. Over 100 cases have been reported. The eldest patients have been 50 years [Hum Genet 63 (1983) 139; Clin Genet 2 (1971) 338]. Follow-up of two adult patients, then 22 and 42 years [Ann Génét 29 (1986) 107], now 42 and 62 years of age, is reported. Further case reports are required in order to better define the evolution of adult patients with the 18p- syndrome. © 2005 Elsevier SAS. All rights reserved.
1. Introduction The 18p- syndrome has been known for over 40 years, the first report being by de Grouchy et al. [1]. Mental retardation of varying severity is the most constant feature. Short stature, facial dysmorphism, skeletal and cardiac anomalies are commonly seen. Over 100 cases have been reported, these being mostly children. The eldest patients have been 50 years [2,3]. Follow-up of two adult patients, then 22 and 42 years [4], now 42 and 62 years of age, is reported.
* Corresponding author. Tel.: +32 16 345903; fax: +32 16 346051. E-mail address: [email protected] (T.J.L. de Ravel). 1769-7212/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmg.2005.01.024
190
T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193
2. Clinical report 2.1. Case 1 This 22 year old man reported by Fryns et al. [4] had feeding difficulties since his premature birth (1300 g). Psychomotor retardation was evident at 12 months of age. His verbal and performance IQs were 39 and 57, respectively. He had a broad triangular facies with a large sloping forehead, mild ptosis of the eyelids, bilateral epicanthal folds and intermittent horizontal nystagmus. The long nose had a broad tip and everted nares, and he had a full lower lip and crowded disarrayed lower jaw teeth. A low hairline was present on a short neck, and the ears were large and low-set. As a result of a de novo 13/18 translocation, his karyotype was 45,XY,– 13,der(18)t(13;18)(q?;p11). Recent FISH analysis indicated the presence in the translocated chromosome of the centromeric regions of both chromosome 13 (alpha-satellite probe D13Z1, Oncor) and 18 (probe CEP18, Vysis). His karyotype is thus 45,XY,der(13;18)(q10;q10). Now 42 years, he is in good physical shape. The short neck has become more obvious. Due to the mild ptosis, divergent strabismus of the left eye and intermittent nystagmus, he constantly extends his neck and cocks his head when looking around. He has some temporal wasting, and temporal hair loss. Dental caries is rife (Fig. 1). A mild kyphosis is present and the pectus carinatum superior to the pectus excavatum is more obvious. This patient has hypothyroidism requiring replacement therapy. He is neurologically intact, walks without difficulty, and converses with everyone. He is normally a happy, most charming collaborative person, coping with most basic daily activities. His behaviour can
Fig. 1. Case 1 at 42 years of age. The head-tilting, temporal wasting, long face, large, prominent, low-set ears and dental caries are visible.
T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193
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fluctuate to aggression towards his caregivers and trouble-seeking with his peers. He is on neuroleptics. 2.2. Case 2 Fryns et al. [4] reported a 42 year old patient with a broad flat face, ptosis of the eyelids, exophthalmos and slight antimongoloid position of the palpebral fissures. He had a beaked nose with everted nostrils, a long philtrum, relatively small mouth and everted lower lip. He had psychomotor retardation and had failed to thrive from childhood. He had severe speech disability and had a performance IQ of 53 (WISC). Poor motor control and manual coordination were reported. His karyotype was 45,XY,der(18)t(18;22)(p11;q11),–22. Recent FISH analysis of the translocated chromosome indicated the presence of the chromosome 18 centromere (probe Ref. [5]) and not the chromosome 22 centromere (probe D22Z1, Oncor), thus confirming the karyotype. At recent re-evaluation at age 62 years, he had lost 36 kg in weight (mostly in the more recent period), has become apathetic, has developed Parkinson-type signs, and recently a mild hemiplegia of the right side of the body (Fig. 2). MRI of the brain shows signs of cortico-subcortical atrophy and a few small nonspecific white-matter lesions in the frontoparietal areas bilaterally. 3. Discussion It is of importance to notice the changing and evolving phenotype with age in patients with dysmorphic features. Most patients reported with chromosome 18p deletion have been
Fig. 2. Case 2 at the age of 62 years. Note the apathetic look and closed right hand (hemiplegia).
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T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193
Table 1 Neurological status of patients over 21 years of age Age (years) 22 22 a 26 26 27 27 36 42 a 42
Sex
Neurology
Reference
F M F M M M F M M
Cooksley et al. [8] Fryns et al. [4] Rigola et al. [9] Ries et al. [6] Tezzon et al. [10] Moedjono et al. [11] Klein et al. [7] Present report, case 1 Babovic-Vuksanovic et al. [12]
42 b 42 50 50 62 b
M F M M M
Normal except ‘pseudo-myotonic’ deep tendon reflexes Normal Normal Dystonia from 15 years Severe generalized dystonia from 26 years, hypokinesia Normal except for speech articulation Dystonia Normal Paranoid schizophrenia from 20 years; decline of cognitive abilities and short term memory Normal except fine motor incoordination Normal Normal Normal Apathetic, Parkinson-type movements, hemiplegia, cortico-subcortical atrophy
a b
Fryns et al. [4] Velagaleti et al. [13] Jacobs et al. [2] Aitken et al. [3] Present report, case 2
Case 1. Case 2.
children. Clinical recognition of this condition in adults is difficult due to paucity of reported cases and poorly described phenotype and clinical problems in adult patients. Table 1 summarizes reported patients over 21 years of age and their neurological status. Dystonia has been reported in a number of patients, both starting at a young age and presenting later [6,7]. Two loci on chromosome 18p are linked to autosomal dominant forms of dystonia, DYT15 with myoclonic type of dystonia (MIM 607488) and DYT7 with adult-onset torsion dystonia (MIM 602124). As no patients have been reported or followed-up to a late adult age, the development of Parkinson-type movements in our case 2, now 62 years of age, may be an unrelated event. However, the Parkinson disease susceptibility gene, NDUFV2 is located at chromosome 18p11.31–p11.2 (MIM 600532), and one can only speculate that loss of one copy in case 2 may have played a role in his neurological state. Due to the lack of reports on patients of advanced age with chromosome 18p deletion, and a lack of detailed breakpoint and deletion delineation in these patients, the role of various genes in this syndrome is as yet not defined. Further cases are required.
References [1]
[2] [3]
J. de Grouchy, M. Lamy, S. Thieffry, M. Arthuis, C. Salmon, Dysmorphie complexe avec oligophrénie: deletion des bras courte d’un chromosome 17–18, Comptes Rendus Hebdomadaires Séances l’Acad. Sci. 256 (1963) 1028–1029. P.A. Jacobs, M. Mayer, J. Matsuura, F. Rhoads, S.C. Yee, A cytogenetic study of a population of mentally retarded males with special reference to the marker (X) syndrome, Hum. Genet. 63 (1983) 139–148. J. Aitken, M. Brunton, P.A. Jacobs, W.H. Price, K. MacColl, Chromosome studies on male patients at a mental subnormality hospital, Clin. Genet. 2 (1971) 338–346.
T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193 [4] [5]
[6] [7] [8] [9] [10] [11] [12]
[13]
193
J.P. Fryns, A. Kleczkowska, L. Vinken, J. Geutjens, E. Smeets, H. Van Den Berghe, Acrocentric/18p translocation in two mentally retarded males, Ann. Genet. 29 (2) (1986) 107–111. P. Devilee, T. Cremer, P. Slagboom, E. Bakker, H.P. Scholl, H.D. Hager, et al., Two subsets of human alphoid repetitive DNA show distinct preferential localization in the pericentric regions of chromosomes 13, 18, and 21, Cytgenet Cell Genet 41 (4) (1986) 193–201. F. Ries, S. Beyenburg, K. Zerres, P. Buchler, R. Deugler, Generalized muscular dystonia linked to an autosomal chromosome deletion (18p-), Mov. Disord. 7 (Suppl 1) (1992) 26 [abstract]. C. Klein, C.E. Page, P. LeWitt, M.F. Gordon, D. de Leon, Y. Awaad, et al., Genetic analysis of three patients with an 18p- syndrome and dystonia, Neurology 52 (3) (1999) 649–651. W.G.E. Cooksley, A. Firouz-Abadi, D.C. Wallace, Monosomy of a “G” autosome in a 22-year-old female, Med. J. Austr. 2 (1973) 178–180. M.A. Rigola, A. Plaja, C. Mediano, R. Miró, J. Egozcue, C. Fuster, Characterization of a heritable partial monosomy 18p by molecular and cytogenetic analysis, Am. J. Med. Genet. 104 (2001) 37–41. F. Tezzon, T. Zanoni, M.G. Passarin, G. Ferrari, Dystonia in a patient with deletion of 18p, Ital. J. Neurol. Sci. 19 (1998) 90–93. S.J. Moedjono, S.J. Funderburk, R.S. Sparkes, 18p- syndrome resulting from translocation (13q;18q) in a mildly affected adult male, J. Med. Genet. 16 (1979) 399–402. D. Babovic-Vuksanovic, S.C. Jenkins, R. Ensenauer, D.C. Newman, S.M. Jalal, Subtelomeric deletion of 18p in an adult with paranoid schizophrenia and mental retardation, Am J Med Genet 124A (2004) 318–322. G.V.N. Velagaleti, S. Harris, N.J. Carpenter, J. Coldwell, B. Say, Familial deletion of chromosome 18(p11.2), Ann. Genet. 39 (4) (1996) 201–204.
Short communication
Follow-up of adult males with chromosome 18p deletion Thomy J.L. de Ravel a,*, Paul Thiry b, Jean-Pierre Fryns a a
Center for Human Genetics, UZ Gasthuisberg, 49 Herestraat, 3000 Leuven, Belgium b Sint Oda Dienstencentrum, Overpelt, Belgium Received 15 November 2004 Available online 01 February 2005
Abstract The 18p- syndrome has been known for over 40 years, the first report being by de Grouchy et al. [Comptes Rendus Hebdomadaires Séances l’Acad Sci 256 (1963) 1028]. Mental retardation of varying severity is the most constant feature. Over 100 cases have been reported. The eldest patients have been 50 years [Hum Genet 63 (1983) 139; Clin Genet 2 (1971) 338]. Follow-up of two adult patients, then 22 and 42 years [Ann Génét 29 (1986) 107], now 42 and 62 years of age, is reported. Further case reports are required in order to better define the evolution of adult patients with the 18p- syndrome. © 2005 Elsevier SAS. All rights reserved.
1. Introduction The 18p- syndrome has been known for over 40 years, the first report being by de Grouchy et al. [1]. Mental retardation of varying severity is the most constant feature. Short stature, facial dysmorphism, skeletal and cardiac anomalies are commonly seen. Over 100 cases have been reported, these being mostly children. The eldest patients have been 50 years [2,3]. Follow-up of two adult patients, then 22 and 42 years [4], now 42 and 62 years of age, is reported.
* Corresponding author. Tel.: +32 16 345903; fax: +32 16 346051. E-mail address: [email protected] (T.J.L. de Ravel). 1769-7212/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmg.2005.01.024
190
T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193
2. Clinical report 2.1. Case 1 This 22 year old man reported by Fryns et al. [4] had feeding difficulties since his premature birth (1300 g). Psychomotor retardation was evident at 12 months of age. His verbal and performance IQs were 39 and 57, respectively. He had a broad triangular facies with a large sloping forehead, mild ptosis of the eyelids, bilateral epicanthal folds and intermittent horizontal nystagmus. The long nose had a broad tip and everted nares, and he had a full lower lip and crowded disarrayed lower jaw teeth. A low hairline was present on a short neck, and the ears were large and low-set. As a result of a de novo 13/18 translocation, his karyotype was 45,XY,– 13,der(18)t(13;18)(q?;p11). Recent FISH analysis indicated the presence in the translocated chromosome of the centromeric regions of both chromosome 13 (alpha-satellite probe D13Z1, Oncor) and 18 (probe CEP18, Vysis). His karyotype is thus 45,XY,der(13;18)(q10;q10). Now 42 years, he is in good physical shape. The short neck has become more obvious. Due to the mild ptosis, divergent strabismus of the left eye and intermittent nystagmus, he constantly extends his neck and cocks his head when looking around. He has some temporal wasting, and temporal hair loss. Dental caries is rife (Fig. 1). A mild kyphosis is present and the pectus carinatum superior to the pectus excavatum is more obvious. This patient has hypothyroidism requiring replacement therapy. He is neurologically intact, walks without difficulty, and converses with everyone. He is normally a happy, most charming collaborative person, coping with most basic daily activities. His behaviour can
Fig. 1. Case 1 at 42 years of age. The head-tilting, temporal wasting, long face, large, prominent, low-set ears and dental caries are visible.
T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193
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fluctuate to aggression towards his caregivers and trouble-seeking with his peers. He is on neuroleptics. 2.2. Case 2 Fryns et al. [4] reported a 42 year old patient with a broad flat face, ptosis of the eyelids, exophthalmos and slight antimongoloid position of the palpebral fissures. He had a beaked nose with everted nostrils, a long philtrum, relatively small mouth and everted lower lip. He had psychomotor retardation and had failed to thrive from childhood. He had severe speech disability and had a performance IQ of 53 (WISC). Poor motor control and manual coordination were reported. His karyotype was 45,XY,der(18)t(18;22)(p11;q11),–22. Recent FISH analysis of the translocated chromosome indicated the presence of the chromosome 18 centromere (probe Ref. [5]) and not the chromosome 22 centromere (probe D22Z1, Oncor), thus confirming the karyotype. At recent re-evaluation at age 62 years, he had lost 36 kg in weight (mostly in the more recent period), has become apathetic, has developed Parkinson-type signs, and recently a mild hemiplegia of the right side of the body (Fig. 2). MRI of the brain shows signs of cortico-subcortical atrophy and a few small nonspecific white-matter lesions in the frontoparietal areas bilaterally. 3. Discussion It is of importance to notice the changing and evolving phenotype with age in patients with dysmorphic features. Most patients reported with chromosome 18p deletion have been
Fig. 2. Case 2 at the age of 62 years. Note the apathetic look and closed right hand (hemiplegia).
192
T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193
Table 1 Neurological status of patients over 21 years of age Age (years) 22 22 a 26 26 27 27 36 42 a 42
Sex
Neurology
Reference
F M F M M M F M M
Cooksley et al. [8] Fryns et al. [4] Rigola et al. [9] Ries et al. [6] Tezzon et al. [10] Moedjono et al. [11] Klein et al. [7] Present report, case 1 Babovic-Vuksanovic et al. [12]
42 b 42 50 50 62 b
M F M M M
Normal except ‘pseudo-myotonic’ deep tendon reflexes Normal Normal Dystonia from 15 years Severe generalized dystonia from 26 years, hypokinesia Normal except for speech articulation Dystonia Normal Paranoid schizophrenia from 20 years; decline of cognitive abilities and short term memory Normal except fine motor incoordination Normal Normal Normal Apathetic, Parkinson-type movements, hemiplegia, cortico-subcortical atrophy
a b
Fryns et al. [4] Velagaleti et al. [13] Jacobs et al. [2] Aitken et al. [3] Present report, case 2
Case 1. Case 2.
children. Clinical recognition of this condition in adults is difficult due to paucity of reported cases and poorly described phenotype and clinical problems in adult patients. Table 1 summarizes reported patients over 21 years of age and their neurological status. Dystonia has been reported in a number of patients, both starting at a young age and presenting later [6,7]. Two loci on chromosome 18p are linked to autosomal dominant forms of dystonia, DYT15 with myoclonic type of dystonia (MIM 607488) and DYT7 with adult-onset torsion dystonia (MIM 602124). As no patients have been reported or followed-up to a late adult age, the development of Parkinson-type movements in our case 2, now 62 years of age, may be an unrelated event. However, the Parkinson disease susceptibility gene, NDUFV2 is located at chromosome 18p11.31–p11.2 (MIM 600532), and one can only speculate that loss of one copy in case 2 may have played a role in his neurological state. Due to the lack of reports on patients of advanced age with chromosome 18p deletion, and a lack of detailed breakpoint and deletion delineation in these patients, the role of various genes in this syndrome is as yet not defined. Further cases are required.
References [1]
[2] [3]
J. de Grouchy, M. Lamy, S. Thieffry, M. Arthuis, C. Salmon, Dysmorphie complexe avec oligophrénie: deletion des bras courte d’un chromosome 17–18, Comptes Rendus Hebdomadaires Séances l’Acad. Sci. 256 (1963) 1028–1029. P.A. Jacobs, M. Mayer, J. Matsuura, F. Rhoads, S.C. Yee, A cytogenetic study of a population of mentally retarded males with special reference to the marker (X) syndrome, Hum. Genet. 63 (1983) 139–148. J. Aitken, M. Brunton, P.A. Jacobs, W.H. Price, K. MacColl, Chromosome studies on male patients at a mental subnormality hospital, Clin. Genet. 2 (1971) 338–346.
T.J.L. de Ravel et al. / European Journal of Medical Genetics 48 (2005) 189–193 [4] [5]
[6] [7] [8] [9] [10] [11] [12]
[13]
193
J.P. Fryns, A. Kleczkowska, L. Vinken, J. Geutjens, E. Smeets, H. Van Den Berghe, Acrocentric/18p translocation in two mentally retarded males, Ann. Genet. 29 (2) (1986) 107–111. P. Devilee, T. Cremer, P. Slagboom, E. Bakker, H.P. Scholl, H.D. Hager, et al., Two subsets of human alphoid repetitive DNA show distinct preferential localization in the pericentric regions of chromosomes 13, 18, and 21, Cytgenet Cell Genet 41 (4) (1986) 193–201. F. Ries, S. Beyenburg, K. Zerres, P. Buchler, R. Deugler, Generalized muscular dystonia linked to an autosomal chromosome deletion (18p-), Mov. Disord. 7 (Suppl 1) (1992) 26 [abstract]. C. Klein, C.E. Page, P. LeWitt, M.F. Gordon, D. de Leon, Y. Awaad, et al., Genetic analysis of three patients with an 18p- syndrome and dystonia, Neurology 52 (3) (1999) 649–651. W.G.E. Cooksley, A. Firouz-Abadi, D.C. Wallace, Monosomy of a “G” autosome in a 22-year-old female, Med. J. Austr. 2 (1973) 178–180. M.A. Rigola, A. Plaja, C. Mediano, R. Miró, J. Egozcue, C. Fuster, Characterization of a heritable partial monosomy 18p by molecular and cytogenetic analysis, Am. J. Med. Genet. 104 (2001) 37–41. F. Tezzon, T. Zanoni, M.G. Passarin, G. Ferrari, Dystonia in a patient with deletion of 18p, Ital. J. Neurol. Sci. 19 (1998) 90–93. S.J. Moedjono, S.J. Funderburk, R.S. Sparkes, 18p- syndrome resulting from translocation (13q;18q) in a mildly affected adult male, J. Med. Genet. 16 (1979) 399–402. D. Babovic-Vuksanovic, S.C. Jenkins, R. Ensenauer, D.C. Newman, S.M. Jalal, Subtelomeric deletion of 18p in an adult with paranoid schizophrenia and mental retardation, Am J Med Genet 124A (2004) 318–322. G.V.N. Velagaleti, S. Harris, N.J. Carpenter, J. Coldwell, B. Say, Familial deletion of chromosome 18(p11.2), Ann. Genet. 39 (4) (1996) 201–204.