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Rett Syndrome in a Boy with a 47,XXY Karyotype

1999; Elsevier BV; Volume: 64; Issue: 6 Linguagem: Inglês

10.1086/302424

1537-6605

José Salomão Schwartzman, Mayana Zatz, Luciana Vasquez, Raquel Ribeiro Gomes, Célia Priszkulnik Koiffmann, Cíntia Fridman, Priscilla G. Otto,

Genomic variations and chromosomal abnormalities

To the Editor: Rett syndrome (RS [MIM 312750]) is a progressive encephalopathy characterized by severe mental retardation, autism, apraxia, seizures, stereotypical hand movements, and deceleration of head growth. Its prevalence is estimated at 1:10,000–15,000 female births (Hagberg Hagberg, 1995Hagberg B Rett syndrome: clinical peculiarities and biological mysteries.Acta Paediatr. 1995; 84: 971-976Crossref PubMed Scopus (114) Google Scholar). The majority of cases are sporadic, but rare reports of familial recurrence have been made. In addition, all but 1 of the 10 MZ twins reported in the literature are concordant, whereas all 11 DZ twins reported are discordant for the disorder (Migeon et al. Migeon et al., 1995Migeon BR Dunn MA Thomas G Schmeckpeper BJ Naidu S Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome.Am J Hum Genet. 1995; 56: 647-653PubMed Google Scholar). Laboratory investigations have not revealed any metabolic abnormalities in affected individuals. Chromosomal abnormalities and/or association with another syndrome have already been reported in patients with RS: a translocation t(X;22)(p11.22;p11) by Journel et al. (Journel et al., 1990Journel H Melki J Turleau C Munnich A Grouchy J Rett phenotype with X/autosome translocation: possible mapping to the short arm of chromosome X.Am J Med Genet. 1990; 35: 142-147Crossref PubMed Scopus (35) Google Scholar), a translocation t(X;3)(p21.3;p25.2) by Zoghbi et al. (Zoghbi et al., 1990Zoghbi HY Percy AK Schultz RJ Fill C Patterns of X chromosome inactivation in Rett syndrome.Brain Dev. 1990; 12: 131-135Abstract Full Text PDF PubMed Scopus (99) Google Scholar) and Ellison et al. (Ellison et al., 1993Ellison KA Roth EJ McCabe ERB Chinault AC Zoghbi HY Isolation of a yeast artificial chromosome contig spanning the chromosomal translocation breakpoint in a patient with Rett syndrome.Am J Med Genet. 1993; 47: 1124-1134Crossref PubMed Scopus (16) Google Scholar), a deletion del(3)(3p25.1-p25.2) by Wahlström et al. (Wahlström et al., 1996Wahlström J, Uller A, Tonnby B, Darnfors C, Martinsson T, Vujuic M (1996) Congenital Rett Syndrome phenotype-deletion short arm chromosome 3. Paper presented at the World Congress on Rett Syndrome, Gothenburg, Sweden, 30 August-1 SeptemberGoogle Scholar), and a deletion del(13)(13q12.1-q21.2) by Herder et al. (Herder et al., 1996Herder GA, Skjeldal O, Hagberg B, Tranebjærg L (1996) Congenital Rett syndrome phenotype-interstitial deletion chromosome 13 and retinoblastoma. Paper presented at the World Congress on Rett syndrome, Gothenburg, Sweden, 30 August-1 SeptemberGoogle Scholar). RS was described in association with fragile X by Alembick et al. (Alembick et al., 1995Alembick Y Dott B Stoll C Rett-like syndrome in fragile X syndrome.Genet Couns. 1995; 6: 207-210PubMed Google Scholar) and with Down syndrome by Easthaugh et al. (Easthaugh et al., 1996Easthaugh P, Smith L, Leonard H (1996) Trisomy 21 associated with Rett syndrome phenotype. Paper presented at the World Congress on Rett Syndrome, Gothenburg, Sweden, 30 August-1 SeptemberGoogle Scholar). No concordance for the chromosomal abnormalities has been found, however, since different chromosomes and/or breakpoints were involved in each case. Vorsanova et al. (Vorsanova et al., 1996Vorsanova SG Demidova IA Ulas V Yu Soloviev IV Kazantzeva LZ Yurov Yu B Cytogenetic and molecular-cytogenetic investigation of Rett syndrome: analysis of 31 cases.Neuroreport. 1996; 8: 187-189Crossref PubMed Scopus (41) Google Scholar) reported a boy with RS and karyotype 46,XY/47,XXY (the 47,XXY cell line was observed in 6%–12% of the studied lymphocytes). Here, we describe a patient with RS and a 47,XXY karyotype. The propositus, a male patient born in January 1995, was referred for genetic studies at age 28 mo. His parents are healthy, were aged 30 years (father) and 29 years (mother) at the time of the birth, and are not consanguineous. The child was born at term, after an uneventful pregnancy. His birth weight was 3.330 g (25th–50th percentile), his Apgar indices were 6 (1st minute) and 7 (5th minute), and his birth occipitofrontal head circumference was 32 cm (2.5 percentile). The perinatal period was uneventful. The propositus is the fourth child, and his older sibs—two boys aged 16 and 9 years and one girl aged 13 years—are normal. There is no history of neuropsychiatric diseases in the families of the mother or the father. The propositus showed normal development until age 8 mo. At that time, he sat without support, played normally, and was able to grasp objects and to put food into his mouth. He had also started to say some words comprehensibly. The family noticed that, at age 11 mo, he had lost purposeful hand movements and language skills. He also began to show regression in social contact. At age 1 year, he began to show stereotypical hand movements, bruxism, and constipation. At age 28 mo, he presented severe global retardation and slightly diffuse hypotonia. He was socially isolated and made few spontaneous movements (other than the stereotypical hand movements). He did not grasp or otherwise show interest in any object or toy. He could vocalize but did not form any words. He reacted to luminous and sonorous stimuli. When standing up with support, he presented axial ataxia. Bruxism and short episodes of apnea were observed during consultation. No focal neurological signs or alteration in cranial nerves were observed. His occipitofrontal head circumference was 45 cm (2.5 percentile), his weight was 12.220 g (35th percentile), and his height was 87 cm (25th percentile). When the patient was last seen, at age 37 mo, the loss of purposeful hand movements, the manual apraxia, and the slight global hypotonia were persistent. The stereotypy of his hand movements was midline, was constant in vigil, and showed a slightly athetoid component. When walking with support, he presented ataxia/apraxia. He reacted to luminous and sonorous stimuli. The episodes of apnea were more frequent and more sustained. His occipitofrontal head circumference was 46 cm (2.5 percentile), his weight was 15.200 g (35th percentile), and his height was 94 cm (25th percentile). Results of electroretinogram, magnetic resonance imaging of the brain, and electroencephalogram were normal. The results for rubella, syphilis, HIV I and HIV II, cytomegalovirus, herpes, cerebrospinal fluid, and serum amino acid testing were all normal. Toxoplasmosis testing showed that the patient's IgG level was slightly increased. However, acquired neurological disorders resulting from congenital toxoplasmosis infection were ruled out, since the boy was normal from birth until age ∼8 mo. Chromosomal analysis, including GTG banding, was performed on peripheral blood leukocytes as described by Seabright (Seabright, 1971Seabright M A rapid banding technique for human chromosomes.Lancet. 1971; 2: 971-972Abstract PubMed Scopus (3910) Google Scholar). Karyotype analyses from all 300 banded metaphase preparations showed 47 chromosomes with an extra X chromosome (47,XXY). To establish the origin of the nondisjunction, we analyzed DNA from the mother and the propositus with eight microsatellite markers from the dystrophin gene—5′DYSI; 5′DYSII; 3′DYSMS; STR 44; STR 45; STR 49; STR 50; and 3′-19n8. DNA from the father was not available. DNA analysis showed that the propositus had an allele that was not present in his mother, indicating, therefore, that the additional sex chromosome was paternal in origin—that is, it resulted from nondisjunction at the paternal first meiotic division. For X-inactivation analyses, DNA was extracted from peripheral blood from the mother and the propositus, and 1 μg of digested (with AluI and CfoI) and nondigested DNA samples were used as templates for amplification of the androgen receptor (AR) highly polymorphic (CAG)n repeat, as reported (Allen et al. Allen et al., 1992Allen RC Zoghbi HY Moseley AB Rosenblatt HM Belmont JW Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation.Am J Hum Genet. 1992; 51: 1229-1239PubMed Google Scholar; Edwards et al. Edwards et al., 1992Edwards AL Hammond HÁ Jin L Cakey CT Chakraborty R Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups.Genomics. 1992; 12: 241-253Crossref PubMed Scopus (1155) Google Scholar). All samples were run in duplicate in a 5% polyacrylamide gel (19:1 acrylamide:bis-acrylamide). A densitometer (Shimadzu CS-9000) was used to determine the ratio of X inactivation in each sample, and the mean of two readings was considered for each case. Since one allele may amplify more than the other, a correction factor was applied to compensate for unequal amplification of alleles. We did this for the mother and for the son, calculating, first, the ratio between the two alleles of the undigested DNA and correcting the final values for preferential PCR amplification (Pegoraro et al. Pegoraro et al., 1994Pegoraro E Schimke RN Arahata K Hayashi Y Stern H Marks H Glasberg MR et al.Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.Am J Hum Genet. 1994; 54: 989-1003PubMed Google Scholar). We calculated the degree of X inactivation on the digested DNA by normalizing the sum of allele A plus allele B to 100%, as reported in Sumita et al. (Sumita et al., 1998Sumita DR Vainzof M Campiotto S Cerqueira AM Cánovas M Otto PA Passos-Bueno MR et al.Absence of correlation between skewed X inactivation in blood and serum creatine-kinase (CK) levels in Duchenne/Becker female carriers.Am J Med Genet. 1998; 80: 356-361Crossref PubMed Scopus (27) Google Scholar). The analysis of the X-chromosome–inactivation pattern in blood DNA showed X-inactivation ratios of 73:27 in the mother and 41XP:59XM in the affected son. To rule out a possible diagnosis of Angelman syndrome (AS), the methylation status of the locus SNRPN mapped within the PWS/AS region was assessed by Southern blotting. The probe used was a 0.6-kb EcoRI-Notl fragment that contains exon 1 of SNRPN (Glenn et al. Glenn et al., 1996Glenn CC Saitoh S Jong MTC Filbrandt MM Surti U Driscoll DJ Nicholls RD Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene.Am J Hum Genet. 1996; 58: 335-346PubMed Google Scholar). Methylation assay for AS was analyzed at the SNRPN CpG island and a normal result was obtained, with the presence of the 0.9-kb band from the unmethylated paternal allele and a 4.2-kb band from the methylated maternal allele. This method confirms the diagnosis in ∼80% of cases, since in the remaining 20% AS may be due to UBE3A mutations or other unknown mechanisms (Kishino et al. Kishino et al., 1997Kishino T Lalande M Wagstaff J UBE3A/E6AP mutations cause Angelman syndrome.Nat Genet. 1997; 15: 70-73Crossref PubMed Scopus (942) Google Scholar; Matsuura et al. Matsuura et al., 1997Matsuura T Sutcliffe JS Fang P Galjaard R-J Jiang Y Benton CS Rommens JM et al.De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.Nat Genet. 1997; 15: 74-173Crossref PubMed Scopus (637) Google Scholar) The parental origin of additional sex chromosomes was studied by Lorda-Sanchez et al. (Lorda-Sanchez et al., 1992Lorda-Sanchez I Binkert F Maechler M Robinson WP Schinzel A Reduced recombination and paternal age effect in Klinefelter syndrome.Hum Genet. 1992; 89: 524-530Crossref PubMed Scopus (93) Google Scholar) in 47 patients with a 47,XXY chromosome constitution. In 23 (49%) cases, the error occurred during the first paternal meiotic division, as observed in the present case. No significant clinical differences were found among patients of distinct parental origin. To date, RS has been convincingly described only in females. Some cases described as RS syndrome in males have been reported (Coleman Coleman, 1990Coleman M Is classical Rett syndrome ever present in males?.Brain Dev. 1990; 12: 31-32Abstract Full Text PDF PubMed Scopus (18) Google Scholar; Eeg-Olofsson et al. Eeg-Olofsson et al., 1990Eeg-Olofsson O Al-Zuhair AGH Teebi AS Zaki M Daoud AS A boy with Rett syndrome?.Brain Dev. 1990; 12: 529-532Abstract Full Text PDF PubMed Scopus (15) Google Scholar; Philippart Philippart, 1990Philippart M The Rett syndrome in males.Brain Dev. 1990; 12: 33-36Abstract Full Text PDF PubMed Scopus (21) Google Scholar; Topçu et al. Topçu et al., 1991Topçu M Topaglu H Renda Y Berket M Turani G The Rett syndrome in males.Brain Dev. 1991; 13: 62Abstract Full Text PDF PubMed Scopus (10) Google Scholar; Christen and Hanefeld Christen and Hanefeld, 1995Christen HJ Hanefeld F Male Rett variant.Neuropediatrics. 1995; 26: 81-82Crossref PubMed Scopus (17) Google Scholar; Vorsanova et al. Vorsanova et al., 1996Vorsanova SG Demidova IA Ulas V Yu Soloviev IV Kazantzeva LZ Yurov Yu B Cytogenetic and molecular-cytogenetic investigation of Rett syndrome: analysis of 31 cases.Neuroreport. 1996; 8: 187-189Crossref PubMed Scopus (41) Google Scholar). The clinical signs and symptoms, however, were but suggestive, atypical, and/or partial. In the present report, the clinical and laboratory findings do not overlap with any described for Klinefelter syndrome. AS was excluded with 80% certainty, and extensive testing did not disclose any other alternative etiology, such as infantile neuronal ceroid-lipofuscinosis. The clinical findings met the criteria of inclusion and exclusion for the diagnosis of RS (Trevathan and Naidu Trevathan and Naidu, 1988Trevathan E Naidu S The clinical recognition and differential diagnosis of Rett syndrome.J Child Neurol. 1988; 3: S6-S16Crossref PubMed Scopus (19) Google Scholar). Several authors (Zoghbi et al. Zoghbi et al., 1990Zoghbi HY Percy AK Schultz RJ Fill C Patterns of X chromosome inactivation in Rett syndrome.Brain Dev. 1990; 12: 131-135Abstract Full Text PDF PubMed Scopus (99) Google Scholar; Webb et al. Webb et al., 1993Webb T Watkiss E Woods CG Neither uniparental disomy nor skewed X-inactivation explains Rett syndrome.Clin Genet. 1993; 44: 236-240Crossref PubMed Scopus (17) Google Scholar; Camus et al. Camus et al., 1996Camus P Abbadi N Perrier M-C Chéry M Gilgenkrantz S X chromosome inactivation in 30 girls with Rett syndrome: analysis using the probe.Hum Genet. 1996; 97: 247-250Crossref PubMed Scopus (25) Google Scholar; Webb and Watkiss Webb and Watkiss, 1996Webb T Watkiss E A comparative study of X inactivation in Rett syndrome probands and control subjects.Clin Genet. 1996; 49: 189-195Crossref PubMed Scopus (21) Google Scholar; Krepischi et al. Krepischi et al., 1998Krepischi ACV Kok F Otto PG X chromosome inactivation patterns in patients with Rett syndrome.Hum Genet. 1998; 102: 319-321Crossref PubMed Scopus (22) Google Scholar) reported that, as a group, RS patients tended to present a higher frequency of moderate skewing (20%–35% or 65%–80%) of X inactivation in lymphocytes, when compared with their mothers and normal controls, and that this skewing, when present, favors, in most cases, preferential inactivation of the paternally inherited X chromosome. On the other hand, it has been suggested that extreme skewed X inactivation could prevent manifestation of the RS phenotype in mutant-gene female carriers, which would be consistent with RS being a male-lethal trait (Schanen and Franke Schanen and Francke, 1998Schanen C Francke U A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map.Am J Hum Genet. 1998; 63: 267-269Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar; Xiang et al. Xiang et al., 1998Xiang F Zhang Z Clarke A Pereira JL Naidu S Budden S Delozier-Blanchet CD et al.Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.J Med Genet. 1998; 35: 297-300Crossref PubMed Scopus (35) Google Scholar). In the present report, analysis of X inactivation in the proband and his mother did not show extreme skewed X inactivation, suggesting that the proband might be the result of a new paternal or maternal germ line mutation event. However, as shown previously, it is not known whether the X-inactivation pattern found in DNA from blood is representative of other tissues and, furthermore, a skewed pattern of X-inactivation in blood is not rare in normal females (Naumova et al. Naumova et al., 1996Naumova AK Plenge RM Bird LM Leppert M Morgan K Willard HF Sapienza C Heritability of X chromosome-inactivation phenotype in a large family.Am J Hum Genet. 1996; 58: 1111-1119PubMed Google Scholar; Sumita et al. Sumita et al., 1998Sumita DR Vainzof M Campiotto S Cerqueira AM Cánovas M Otto PA Passos-Bueno MR et al.Absence of correlation between skewed X inactivation in blood and serum creatine-kinase (CK) levels in Duchenne/Becker female carriers.Am J Med Genet. 1998; 80: 356-361Crossref PubMed Scopus (27) Google Scholar). Therefore, although the occurrence of moderate skewing is more frequent in RS patients and extreme skewed X inactivation has been observed in obligate RS carriers (Sirianni et al. Sirianni et al., 1998Sirianni N Naidu S Pereira JL Pillotto RF Hoffman EP Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28.Am J Hum Genet. 1998; 63: 1552-1558Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar), a correlation between X-inactivation skewing and the RS phenotype must be interpreted with caution. An explanation for the exclusive occurrence of RS in females, without evidence of male lethality, was proposed by Thomas (Thomas, 1996Thomas GH High male:female ratio of germ-line mutations: an alternative explanation for postulated gestational lethality in males in X-linked dominant disorders.Am J Hum Genet. 1996; 58: 1364-1368PubMed Google Scholar) on the basis of the fact that de novo X-linked mutations occurring exclusively in male germ cells could only be passed on to, and result in, an affected daughter. Under such a hypothesis, the absence of affected males is explained by the fact that sons do not inherit their X chromosomes from their fathers. Since our patient inherited one of his two X chromosomes from his father, his RS phenotype would be consistent with Thomas's hypothesis if the mutated gene was on the paternal X chromosome. On the other hand, RS-affected half sisters with the same mothers have been described (Archidiacono et al. Archidiacono et al., 1991Archidiacono N Lerone M Rocchi M Anvret M Ozcelik T Francke U Romeo G Rett syndrome: exclusion mapping following the hypothesis of germinal mosaicism for new X-linked mutations.Hum Genet. 1991; 86: 604-606Crossref PubMed Scopus (28) Google Scholar; Sirianni et al. Sirianni et al., 1998Sirianni N Naidu S Pereira JL Pillotto RF Hoffman EP Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28.Am J Hum Genet. 1998; 63: 1552-1558Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). However, under Thomas's hypothesis, it would be expected, in rare instances, to find families with half sisters with the same father, because of germinal mosaicism. This has already been demonstrated for other disorders such as achondroplasia (Philip et al. Philip et al., 1988Philip N Auger M Mattei JF Giraud F Achondroplasia in sibs of normal parents.J Med Genet. 1988; 25: 857-859Crossref PubMed Scopus (11) Google Scholar) and Duchenne muscular dystrophy (Darras and Francke Darras and Francke, 1987Darras BT Francke U A partial deletion of the muscular dystrophy gene transmitted twice by an unaffected male.Nature. 1987; 329: 556-558Crossref PubMed Scopus (69) Google Scholar) but apparently has not been reported for RS. In a recent report, Sirianni et al. (Sirianni et al., 1998Sirianni N Naidu S Pereira JL Pillotto RF Hoffman EP Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28.Am J Hum Genet. 1998; 63: 1552-1558Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar) postulated that the relatively high frequency for RS would be explained by a high mutation rate in either male or female germ lines. In the present case, it was not possible to determine whether the mutation was inherited through paternal or maternal gametes. With respect to the etiology of RS, several investigators have suggested the possibility of an alteration in the timing of replication of a gene (or genes) on the late X chromosome in RS patients (Riccardi Riccardi, 1986Riccardi VM The Rett syndrome: genetics and the future.Am J Med Genet Suppl. 1986; 24: 389-402Crossref Scopus (32) Google Scholar; Martinho et al. Martinho et al., 1990Martinho PS Otto PG Kok F Diament A Marques-Dias MJ Gonzalez CH In search of a genetic basis for the Rett syndrome.Hum Genet. 1990; 86: 131-134Crossref PubMed Scopus (20) Google Scholar; Kormann-Bortolotto Kormann-Bortolotto et al., 1992Kormann-Bortolotto MH Woods CG Green SH Webb T X-inactivation in girls with Rett syndrome.Clin Genet. 1992; 42: 296-301Crossref PubMed Scopus (13) Google Scholar; Webb and Watkiss Webb and Watkiss, 1996Webb T Watkiss E A comparative study of X inactivation in Rett syndrome probands and control subjects.Clin Genet. 1996; 49: 189-195Crossref PubMed Scopus (21) Google Scholar). If this alteration represents the “misbehavior” of a gene (or genes) that should be inactive on the inactivated X chromosome but, when mutated, does not respond to XIST (the product of the X-inactivation–center gene), the consequence would be transient functional disomy at one or more loci. Partial functional disomy as a cause for RS (Webb et al. Webb et al., 1993Webb T Watkiss E Woods CG Neither uniparental disomy nor skewed X-inactivation explains Rett syndrome.Clin Genet. 1993; 44: 236-240Crossref PubMed Scopus (17) Google Scholar) and other abnormal phenotypes, such as hypomelanosis of Ito or mental retardation, has already been suggested (Journel Journel et al., 1990Journel H Melki J Turleau C Munnich A Grouchy J Rett phenotype with X/autosome translocation: possible mapping to the short arm of chromosome X.Am J Med Genet. 1990; 35: 142-147Crossref PubMed Scopus (35) Google Scholar; Schmidt and Du Sart Schmidt and Du Sart, 1992Schmidt M Du Sart D Functional disomies of the X chromosome influence the cell selection and hence the X inactivation pattern in females with balanced X-autosome translocations: a review of 122 cases.Am J Med Genet. 1992; 42: 161-169Crossref PubMed Scopus (129) Google Scholar; Correa-Cerro et al. Correa-Cerro et al., 1997Correa-Cerro LS Rivera H Vasquez AI Functional Xp disomy and de novo t(X;13)(q10;q10) in a girl with hypomelanosis of Ito.J Med Genet. 1997; 34: 161-163Crossref PubMed Scopus (9) Google Scholar; Wolff et al. Wolff et al., 1998Wolff DJ Schwartz S Montgomery T Zackowski JL Random X inactivation in a girl with a balanced t(X;9) and an abnormal phenotype.Am J Med Genet. 1998; 77: 401-404Crossref PubMed Scopus (8) Google Scholar). If such a mechanism occurred in RS patients, this condition could be the result of functional disomy. The present report, confirming an RS phenotype in a 47,XXY male, is consistent with the hypothesis that two X chromosomes are required for the manifestation of Rett syndrome. The collaboration of Drs. Mariz Vainzof, Maria Rita Passos-Bueno, and Lygia V. Pereira and of Constancia Urbani is gratefully acknowledged. This research was supported with grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo, Programa de Apoio à Núcleos de Excelência, and Conselho Nacional de Desenvolvimento Científico e Tecnológico.