Martin-Bell syndrome in Greece, with report of another 47,XXY fragile X patient

Download Martin-Bell syndrome in Greece, with report of another 47,XXY fragile X patient

Post on 06-Jun-2016

213 views

Category:

Documents

1 download

TRANSCRIPT

  • American Journal of Medical Genetics 31:735-739 (1988)

    Martin-Bell Syndrome in Greece, With Report of Another 47,XXY Fragile X Patient

    Ariadni Mavrou, Maria Syrrou, Christine Tsenghi, Manthos Agelakis, Sotiris Youroukos, and Catherine Metaxotou

    Genetic Unit, 1st Department of Pediatrics, Athens University, (A.M., M.S., C. T., C. M.) and 7st Department of Pediatrics, Athens University, Aghia Sophia Children 's Hospital (S. Y , M. A.), Athens, Greece

    A cytogenetic investigation was carred out among 200 mentally retarded boys in Greece for the detection of the fragile X [fra(X)] syndrome. Thirteen patients were found to carry fra(X) (6.5%). Of those, six boys had a history of familial X- linked mental retardation, two had the phenotype of the Martin-Be11 syndrome, four had only mental retardation of unknown etiology, and one was a mentally retarded patient with Klinefelter syndrome. The remaining 187 boys were fra(X) negative. Our findings emphasize the importance of early identification of this syndrome in the diagnosis and prevention, through proper genetic counselling, of mental retardation.

    Key words: X-linked mental retardation, autism, fra(X) syndrome in chiidhood

    INTRODUCTION

    The prevalance of fragile X [fra(X)] syndrome is estimated to be one in 2,000- 2,500 individuals, from data on its frequency in mentally retarded populations in Europe, North America, Australia, and Japan [Sutherland and Hecht, 1985; Arinami et al., 19861.

    Affected males, except for a moderate-to-severe retardation, have dysmorphic features, a long face with large everted ears, and macro-orchidism, in about 80% of the cases [Opitz and Sutherland, 19841. This phenotype, however, is not always apparent in young boys. Children with fra(X) tend to look normal to clinicians not familiar with the syndrome, and most prepubertal fra(X) boys do not have macro- orchidism. Early diagnosis is very important for the proper handling of the patient and the genetic counselling of the family.

    Received for publication September 14, 1987: revision received August 8, 1988.

    Address repnnt requests to Anadni Mavrou, Genetic Unit, 1st Department of Pediatrics, Aghia Sophia Children's Hospital, Goudi, Athens, Greece.

    O 1988 Aian R. Liss, Inc.

  • 736 Mavrou et al.

    Fig. 1.

    Fig. 2 .

    Two brothers, aged 7 and 10, fra(X)-positive.

    Facial appearance of a profoundly retarded 19-year-old patient with fra(X).

    This study is aimed at ascertaining the frequency of fra(X) syndrome among mentally retarded boys in Greece.

    MATERIALS AND METHODS Patients

    The study included 200 mentally retarded boys referred for cytogenetic investi- gation at the Genetic Unit of the 1st Department of Pediatrics of Athens University. Their ages ranged from 10 months to 19 years. The patients were divided into three groups according to their family history and phenotypic appearance (Table 1).

    Group 1 included 20 boys from families with a history of X-linked mental retardation. They al1 had either a mentally retarded brother(s) or maternal uncle. Group 2 included 36 boys with phenotypic features compatible with the Martin-Be11

    TABLE 1. Classification of Patients Screened for fra(X)

    Group Identifying feature No. Total no. No. fra(X)

    1 Family history of X-linked - 20 6 mental retardation

    Be11 syndrome

    Be11 syndrome plus eniarged testes

    unknown eitology

    2 Phenotype of the Martin- 25 36 2

    Phenotype of the Martin- 11

    3 Mental retardation of 114 114 5

    Autism 30 Total 200 13

  • Martin-Be11 Syndrome in Greece 737

    TABLE 11. Distribution of Group 3 Patients by Level of Retardation

    Level 10 No.

    Profound < 20 19 Severe 20-35 60 Moderate 35-50 41 M i ld > 50 24 Total 144

    syndrome. Twenty of these boys were adolescents, 15-19 years old, lived in an institution for mentally handicapped, and had severe mental retardation. Eleven also had enlarged testes. Group 3 included 144 boys with nonspecific mental retardation and no characteristic facial features. Thirty of them had a diagnosis of autism. The degree of mental retardation varied, most of them being moderately to severely retarded (Table 11).

    Al1 patients had a detailed neurological examination to exclude any other reason for their retardation.

    Methods Blood samples were cultured under conditions designed to demonstrate the

    fra(X) [Sutherland, 19771, and a minimum of 50 unbanded metaphases from each patient were examined. When a fra(X) was detected, an additional 50 metaphases were screened, and the preparation was G-banded. A patient was classified as fra(X)- positive if the marker were present in over 4 % of the metaphases examined.

    G-banded conventional analysis was also carried out for the identification of other chromosomal rearrangements.

    RESULTS

    Among the 200 boys examined, 13 were fra(X)-positive (6.5%) (Table 1). Of those, 12 had a 46,XY karyotype, and 1 was 47,XXY. Fra(X)-positive boys were found in al1 three groups. Their age, leve1 of retardation, and number of cells showing the fra(X) varied (Table 111).

    Six boys (30%) had a family history of retardation. In two families from group 1, two other retarded brothers were also found to carry the fra(X). In one of these families, the younger boy, 7 years old and mentally retarded, was identified first. The older brother, autistic, had been examined in the past by conventional techniques and had been found normal. When he was tested again for fra(X) he, as well as the mother, were fra(X)-positive (Fig. 1).

    In group 2, two patients were fra(X)-positive (5.5%), and both had enlarged testes. One of them was 19 years old, profoundly retarded, and had been in an institution since age 4 (Fig. 2).

    Five boys from group 3 (3.5%) were fra(X)-positive. Fra(X) was found in 2 of the 30 autistic boys (6.6%). Another patient from group 3 had a 47,XXY karyotype, and a fra(X) chromosome was present in 23% of his cells. He was 18 years old and had been referred for cytogenetic investigation because of hypogonadism. He also had mild mental retardation and poorly developed secondary sex characteristics.

  • 738 Mavrou et al.

    TABLE 111. Cytogenetic and Clinical Data on the 13 Boys With fra(X)

    Age % Cells Mental Group (Years) with fra(X) retardation Remarks

    1 7 27 Severe 3 20 Moderate

    15 6 Moderate 4 % 18 Severe 3 15 Moderate

    10 (mos.) 4 Severe 2 19 25 Profound Enlarged testes

    15 20 Severe Enlarged testes

    3 7 18 Severe Autism 18 23 Mild 47,XXY, fra(X) 3 6 Mild 5% 25 Severe Autism 15 15 Moderate

    DISCUSSION

    The incidence of fra(X) in our patients was 6.5%, but this frequency was unequally distributed in the three groups. Our findings agree with those reported in the literature, and verify that there is no ethnic difference in the incidence of this syndrome [Blomquist et al., 1983; Webb et al., 1986, 1987; Froster-Iskenius et al., 1983; Arinami et al., 19861. In group 3, 5 out of the 144 boys were fra(X)-positive. According to Nielsen [ 19831, the characteristic facial appearance emerges around ages 8-12, just prior to puberty, and the most useful and constant feature in children is ear size and shape. In our patients, ear size was not measured, although many of the boys had what can be called bat ears (Fig. 1). None of the boys in this group had macro-orchidism. This is in agreement with the report [Sutherland and Hecht, 19851 that only 15% of fra(X) boys have enlarged testes.

    Five percent of the autistic boys were fra(X)-positive. The association of fra(X) and autism is often mentioned in the literature, but the reports about positive correla- tions are contradictory [Watson et al., 1984; Chudley and Hagerman, 19871.

    The concurrence of a fra(X) and XXY is reported by severa1 authors [Froster- Iskenius et al., 1982; Fryns et al., 19841. In our patient, there was mild mental retardation, but the sexual development was consistent with the Klinefelter syndrome.

    Due to the absence of a characteristic phenotype that can help the clinician identify the fra(X) syndrome in children, we now examine with the special technique for detection of the fra(X) al1 mentally retarded boys referred for cytogenetic investigation.

    Martin-Be11 syndrome should be considered in any mentally retarded child when the cause has not been determined, even in the absence of a positive family history. Early diagnosis will provide an opportunity for the patient and his family to benefit from treatment, genetic counselling, and possibly prenatal diagnosis.

    REFERENCES

    Arinami T, Kondo 1, Nakajima S (1986): Frequency of the fragile X syndrome in Japanese mentally

  • Martin-Beii Syndrome in Greece 739

    retarded males. Hum Genet 73:309-312. Blomquist HK:son, Gustavson KH, Holmgren G, Nordenson 1, Plsson-Stre U (1983): Fragile X

    syndrome in mildly retarded children in a Northern Swedish county: A prevalence study. Clin Genet 24:393-398.

    Chudley AE, Hagerman RJ (1987): Fragile X syndrome. J Pediatr 110:821-831. Froster-Iskenius U, Schwinger E, Weigert M, Fonatsch C (1982): Replication pattern in XXY cells with

    Froster-Iskenius U, Felsch G, Schirren C, Schwinger E (1983): Screening for fra(X)(q) in a population

    Fryns JP, Kleczkowska A, Wolfs 1, Van den Berghe H (1984): Klinefelter syndrorne and two fragile X

    Nielsen KB (1983): Diagnosis of the fragile X syndrome (Martin-Bell syndrorne). Clinical findings in

    Opitz JM, Sutherland GR (1984): Conference Report: International workshop on the fragile X and X-

    Sutherland GR (1977): Fragile Sites on human chromosomes: Dernonstration of their dependence on the

    Sutherland GR, Hecht F (1985): Fragile Sites on Human Chrornosomes. New York: Oxford University

    Watson MS, Leckman JF, Annex B, Breg WR, Boles D, Volkmar FR, Cohen DJ (1984): Fragile X in a

    Webb TP, Bundey SE, Thake A, Todd J (1986): The frequency of the fragile X chromosome arnong

    Webb TP, Thake AI , Bundey SE, Todd J (1987): A cytogenetic survey of a mentally retarded school-

    fragile X. Hum Genet 60:278-280.

    of mentally retarded males. Hum Genet 63:153-157.

    chromosomes. Clin Genet 26:44S-447.

    27 males with the fragile site at Xq28. J Ment Defic Res 27:211-226.

    linked mental retardation. Am J Med Genet 17:5-94.

    type of tissue culture medium. Science 197:265-266.

    Press.

    survey of 75 autistic males (Letter). N Engl J Med 310: 1462.

    schoolchildren in Coventry. J Med Genct 23:396-399.

    age population with special reference to fragile sites, J Ment Defic Res 31:61-71.

    Edited by John M. Opitz and James F. Reynolds

Recommended

View more >