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November 1993, Vol 147, No. 11 >
Article | November 1993

A Study of the Physical, Behavioral, and Medical Phenotype, Including Anthropometric Measures, of Females With Fragile X Syndrome FREE

Claire Hull; Randi J. Hagerman, MD
[+] Author Affiliations

Accepted for publication July 16, 1993.

Reprint requests to Child Development Unit-B140, The Children's Hospital, 1056 E 19th Ave, Denver, CO 80218 (Dr Hagerman).


Am J Dis Child. 1993;147(11):1236-1241. doi:10.1001/archpedi.1993.02160350110017.
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• The physical features of fragile X, including a long face, prominent ears, and hyperextensible joints, are present in affected males and females. Cytogenetically negative heterozygotes have been considered to be unaffected by the fragile X mental retardation—1 (FMR-1) gene. This study investigated the penetrance of the FMR-1 gene in cytogenetically negative but DNA-positive heterozygotes with a premutation (cytosine guanine guanine [CGG] amplification in the 50 to 200 repeat range), compared with carriers with a full mutation (>200 CGG repeats) and control subjects. One hundred thirty-nine women with normal IQs between the ages of 18 and 45 years were studied. All underwent cytogenetic and DNA testing to determine their fragile X carrier status. A medical history-taking and a physical examination, including selected anthropometric measurements, were performed. Results indicate that the FMR-1 mutation mildly affects the physical phenotype of individuals even in the premutation state, although less dramatically than more affected heterozygotes. Carriers with a premutation differed significantly from control subjects in overall physical index score and in the anthropometric measure of ear prominence. These results suggest a phenotypic impact of the FMR-1 mutation even at the 50 to 200 CGG repeat length.

(AJDC. 1993;147:1236-1241)

REFERENCES

1 +
Sherman SL, Jacobs PA, Morton NE, et al.  Further segregation analysis of the fragile X syndrome with special reference to transmitting males . Hum Genet . 1985;;69:289-299.
2 +
Verkerk AJMH, Pieretti M, Sutcliffe JS, et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome . Cell . 1991;;65:905-914.
3 +
Oberle I, Rousseau F, Heitz D, et al.  Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome . Science . 1991;; 252:1097-1102.
4 +
Hirst MC, Nakahori Y, Knight SJL, et al.  Genotype prediction in the fragile X syndrome . J Med Genet . 1991;;28:824-829.
5 +
Rousseau F, Heitz D, Biancalana V, et al.  Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation . N Engl J Med . 1991;; 325:1673-1681.
6 +
Yu S, Mulley J, Loesch D, et al.  Fragile X syndrome: unique genetics of the heritable unstable element . Am J Hum Genet . 1992;;50:968-980.
7 +
Fu Y-H, Kuhl DPA, Pizzuti A, et al.  Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman Paradox . Cell . 1991;;67:1047-1058.
8 +
Snow K, Doud L, Hagerman RJ, et al.  Analysis of mutations at the fragile X locus using the DNA probe Ox1.9 . Am J Med Genet . 1992;;43:244-254.
9 +
Mulley JC, Yu S, Gedeon AK, et al.  Experience with direct molecular diagnosis of fragile X . J Med Genet . 1992;;29:368-374.
10 +
Staley LW, Hull CE, Mazzocco MMM, et al.  Molecular-clinical correlations in children and adults with fragile X syndrome . AJDC . 1993;;147: 723-726.
11 +
Pieretti M, Zhang FP, Fu YH, et al.  Absence of expression of the FMR-1 gene in fragile X syndrome . Cell . 1992;;66:817-822.
12 +
Hagerman RJ, Jackson C, Amiri K, Cronister-Silverman A, O'Connor R, Sobesky W.  Girls with fragile X syndrome: physical and neurocognitive status and outcome . Pediatrics . 1992;;89:395-400.
13 +
Miezejeski CM, Hinton VJ.  Fragile X learning disability: neurobehavioral research, diagnostic methods and treatment options . In: Hagerman RJ, McKenzie P, eds. 1992 International Fragile X Conference Proceedings . Dillon, Colo: Spectra Publishing; 1992;:85-99.
14 +
Steyaert J, Borghgraef M, Gaulthier C, Fryns JP, Van den Berge H.  Cognitive profiles in adult, normal intelligent female fragile X carriers . Am J Med Genet . 1992;;43:116-119.
15 +
Mazzocco MMM, Hagerman RJ, Cronister-Silverman A, Pennington BF.  Specific frontal lobe deficits among women with the fragile X gene . J Am Acad Child Adolesc Psychiatry . 1992;;31:1141-1148.
16 +
Reiss AL, Freund L, Abrams MT, Boehm C, Kazazian H.  Neurobehavioral effects of the fragile X premutation in adult women: a controlled study . Am J Hum Genet . 1993;;52:884-894.
17 +
Brainard SS, Schreiner RA, Hagerman RJ.  Cognitive profiles of the adult carrier fra(X) female . Am J Med Genet . 1991;;38:505-508.
18 +
Reiss AL, Freund L, Vinogradov S, Hagerman RJ, Cronister A.  Parental inheritance and psychological disability in fragile X females . Am J Hum Genet . 1989;;45:697-705.
19 +
Reiss AL, Hagerman RJ, Vinogradov S, Abrams M, King RJ.  Psychiatric disability in females carriers of fragile X chromosome . Arch Gen Psychiatry . 1988;;45:25-30.
20 +
Hagerman RJ, Sobesky WE.  Psychopathology in fragile X syndrome . Am J Orthopsychiatry . 1989;;59:142-152.
21 +
Borghgraef M, Fryns JP, Van den Berghe H.  The female and the fragile X syndrome: data on clinical and psychological findings in fragile X carriers . Clin Genet . 1990;;37:341-346.
22 +
Cronister A, Schreiner R, Wittenberger M, Amiri K, Harris K, Hagerman RJ.  Heterozygous fragile X female: historical, physical, cognitive and cytogenetic features . Am J Med Genet . 1991;;38:269-274.
23 +
Sobesky WE, Hull CE, Hagerman RJ.  The emotional phenotype in mildly affected carriers . In: Hagerman RJ, McKenzie P, eds. 1992 International Fragile X Conference Proceedings . Dillon, Colo: Spectra Publishing; 1992;:99-106.
24 +
Hagerman RJ, Smith ACM.  The heterozygous female . In: Hagerman RJ, McBogg P, eds. The Fragile X Syndrome: Diagnosis, Biochemistry and Intervention . Dillon, Colo: Spectra Publishing; 1983;:83-94.
25 +
Fryns JP.  The female and the fragile X: a study of 144 obligate female carriers . Am J Med Genet . 1986;;23:157-169.
26 +
Hagerman RJ.  Physical and behavioral phenotype . In: Hagerman RJ, Cronister-Silverman A, eds. Fragile X Syndrome: Diagnosis, Treatment and Research . Baltimore, Md: Johns Hopkins University Press; 1991;:3-68.
27 +
Butler MG, Allen GA, Haynes JL, Singh DN, Watson MS, Breg WR.  Anthropometric comparison of mentally retarded males with and without the fragile X syndrome . Am J Med Genet . 1991;;38:260-268.
28 +
Butler MG, Allen A, Singh D, Carpenter NJ, Hall BD.  Preliminary communication: photoanthropometric analyses of individuals with the fragile X syndrome . Am J Med Genet . 1988;;30:165-168.
29 +
Butler MG, Brunschwig A, Miller LK, Hagerman RJ.  Standards for selected anthropometric measurements in males with the fragile X syndrome . Pediatrics . 1992;;89:1059-1062.
30 +
Butler MG, Pratesi R, Watson MS, Breg WR, Singh DN.  Anthropometric and craniofacial patterns in mentally retarded males with and without fragile X syndrome . In: Hagerman RJ, McKenzie P, eds. 1992 International Fragile X Conference Proceedings . Dillon, Colo: Spectra Publishing; 1992;: 37-49.
31 +
Meryash DL, Cronk CE, Sacks B, Gerald PS.  An anthropometric study of males with the fragile X syndrome . Am J Med Genet . 1984;;17:159-174.
32 +
Heitz D, Devys D, Imbert G, Kretz C, Mandel J-L.  Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation . J Med Genet . 1992;;29:794-801.
33 +
Pergolizzi RG, Erster SH, Goonewardena P, Brown WT.  Detection of full fragile X mutation . Lancet . 1992;;339:271-272.
34 +
Farkas LG. Anthropometry of the Head and Face in Medicine . New York, NY: Elsevier Science Publishers; 1981;.
35 +
Hollingshead AB. Two Factor Index of Social Position . New Haven: Hollingshead; 1957;.
36 +
Richards RI, Holman K, Friend K, et al.  Evidence of founder chromosomes in fragile X syndrome . Nat Genet . 1992;;1:257-260.

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References

1 +
Sherman SL, Jacobs PA, Morton NE, et al.  Further segregation analysis of the fragile X syndrome with special reference to transmitting males . Hum Genet . 1985;;69:289-299.
2 +
Verkerk AJMH, Pieretti M, Sutcliffe JS, et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome . Cell . 1991;;65:905-914.
3 +
Oberle I, Rousseau F, Heitz D, et al.  Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome . Science . 1991;; 252:1097-1102.
4 +
Hirst MC, Nakahori Y, Knight SJL, et al.  Genotype prediction in the fragile X syndrome . J Med Genet . 1991;;28:824-829.
5 +
Rousseau F, Heitz D, Biancalana V, et al.  Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation . N Engl J Med . 1991;; 325:1673-1681.
6 +
Yu S, Mulley J, Loesch D, et al.  Fragile X syndrome: unique genetics of the heritable unstable element . Am J Hum Genet . 1992;;50:968-980.
7 +
Fu Y-H, Kuhl DPA, Pizzuti A, et al.  Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman Paradox . Cell . 1991;;67:1047-1058.
8 +
Snow K, Doud L, Hagerman RJ, et al.  Analysis of mutations at the fragile X locus using the DNA probe Ox1.9 . Am J Med Genet . 1992;;43:244-254.
9 +
Mulley JC, Yu S, Gedeon AK, et al.  Experience with direct molecular diagnosis of fragile X . J Med Genet . 1992;;29:368-374.
10 +
Staley LW, Hull CE, Mazzocco MMM, et al.  Molecular-clinical correlations in children and adults with fragile X syndrome . AJDC . 1993;;147: 723-726.
11 +
Pieretti M, Zhang FP, Fu YH, et al.  Absence of expression of the FMR-1 gene in fragile X syndrome . Cell . 1992;;66:817-822.
12 +
Hagerman RJ, Jackson C, Amiri K, Cronister-Silverman A, O'Connor R, Sobesky W.  Girls with fragile X syndrome: physical and neurocognitive status and outcome . Pediatrics . 1992;;89:395-400.
13 +
Miezejeski CM, Hinton VJ.  Fragile X learning disability: neurobehavioral research, diagnostic methods and treatment options . In: Hagerman RJ, McKenzie P, eds. 1992 International Fragile X Conference Proceedings . Dillon, Colo: Spectra Publishing; 1992;:85-99.
14 +
Steyaert J, Borghgraef M, Gaulthier C, Fryns JP, Van den Berge H.  Cognitive profiles in adult, normal intelligent female fragile X carriers . Am J Med Genet . 1992;;43:116-119.
15 +
Mazzocco MMM, Hagerman RJ, Cronister-Silverman A, Pennington BF.  Specific frontal lobe deficits among women with the fragile X gene . J Am Acad Child Adolesc Psychiatry . 1992;;31:1141-1148.
16 +
Reiss AL, Freund L, Abrams MT, Boehm C, Kazazian H.  Neurobehavioral effects of the fragile X premutation in adult women: a controlled study . Am J Hum Genet . 1993;;52:884-894.
17 +
Brainard SS, Schreiner RA, Hagerman RJ.  Cognitive profiles of the adult carrier fra(X) female . Am J Med Genet . 1991;;38:505-508.
18 +
Reiss AL, Freund L, Vinogradov S, Hagerman RJ, Cronister A.  Parental inheritance and psychological disability in fragile X females . Am J Hum Genet . 1989;;45:697-705.
19 +
Reiss AL, Hagerman RJ, Vinogradov S, Abrams M, King RJ.  Psychiatric disability in females carriers of fragile X chromosome . Arch Gen Psychiatry . 1988;;45:25-30.
20 +
Hagerman RJ, Sobesky WE.  Psychopathology in fragile X syndrome . Am J Orthopsychiatry . 1989;;59:142-152.
21 +
Borghgraef M, Fryns JP, Van den Berghe H.  The female and the fragile X syndrome: data on clinical and psychological findings in fragile X carriers . Clin Genet . 1990;;37:341-346.
22 +
Cronister A, Schreiner R, Wittenberger M, Amiri K, Harris K, Hagerman RJ.  Heterozygous fragile X female: historical, physical, cognitive and cytogenetic features . Am J Med Genet . 1991;;38:269-274.
23 +
Sobesky WE, Hull CE, Hagerman RJ.  The emotional phenotype in mildly affected carriers . In: Hagerman RJ, McKenzie P, eds. 1992 International Fragile X Conference Proceedings . Dillon, Colo: Spectra Publishing; 1992;:99-106.
24 +
Hagerman RJ, Smith ACM.  The heterozygous female . In: Hagerman RJ, McBogg P, eds. The Fragile X Syndrome: Diagnosis, Biochemistry and Intervention . Dillon, Colo: Spectra Publishing; 1983;:83-94.
25 +
Fryns JP.  The female and the fragile X: a study of 144 obligate female carriers . Am J Med Genet . 1986;;23:157-169.
26 +
Hagerman RJ.  Physical and behavioral phenotype . In: Hagerman RJ, Cronister-Silverman A, eds. Fragile X Syndrome: Diagnosis, Treatment and Research . Baltimore, Md: Johns Hopkins University Press; 1991;:3-68.
27 +
Butler MG, Allen GA, Haynes JL, Singh DN, Watson MS, Breg WR.  Anthropometric comparison of mentally retarded males with and without the fragile X syndrome . Am J Med Genet . 1991;;38:260-268.
28 +
Butler MG, Allen A, Singh D, Carpenter NJ, Hall BD.  Preliminary communication: photoanthropometric analyses of individuals with the fragile X syndrome . Am J Med Genet . 1988;;30:165-168.
29 +
Butler MG, Brunschwig A, Miller LK, Hagerman RJ.  Standards for selected anthropometric measurements in males with the fragile X syndrome . Pediatrics . 1992;;89:1059-1062.
30 +
Butler MG, Pratesi R, Watson MS, Breg WR, Singh DN.  Anthropometric and craniofacial patterns in mentally retarded males with and without fragile X syndrome . In: Hagerman RJ, McKenzie P, eds. 1992 International Fragile X Conference Proceedings . Dillon, Colo: Spectra Publishing; 1992;: 37-49.
31 +
Meryash DL, Cronk CE, Sacks B, Gerald PS.  An anthropometric study of males with the fragile X syndrome . Am J Med Genet . 1984;;17:159-174.
32 +
Heitz D, Devys D, Imbert G, Kretz C, Mandel J-L.  Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation . J Med Genet . 1992;;29:794-801.
33 +
Pergolizzi RG, Erster SH, Goonewardena P, Brown WT.  Detection of full fragile X mutation . Lancet . 1992;;339:271-272.
34 +
Farkas LG. Anthropometry of the Head and Face in Medicine . New York, NY: Elsevier Science Publishers; 1981;.
35 +
Hollingshead AB. Two Factor Index of Social Position . New Haven: Hollingshead; 1957;.
36 +
Richards RI, Holman K, Friend K, et al.  Evidence of founder chromosomes in fragile X syndrome . Nat Genet . 1992;;1:257-260.

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