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Familial Premature Ovarian Failure in Female Premutated Carriers of Fragile X Syndrome: a Case Report and Literature Review
Y.S. Lin, M.L. Yang
■ SHORT COMMUNICATION ■
FAMILIAL PREMATURE OVARIAN FAILURE IN FEMALE PREMUTATED CARRIERS OF FRAGILE X SYNDROME: A CASE REPORT AND LITERATURE REVIEW Yu-Shiou Lin, Man-Li Yang* Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan.
SUMMARY Objective: The fragile X syndrome is the most common form of familial mental retardation. Most males with the FMR1 full mutation function in the mentally retarded range of intelligence. In contrast, females with the FMR1 full mutation show a broader range of intelligence. The most impressive somatic involvement that is consistently found among only premutated carrier females, not full-mutation carriers, is premature ovarian failure (POF). Case Report: We report a family of fragile X syndrome. All six daughters had POF and both of the grandsons born to the daughters showed mental retardation. Conclusion: We concluded that there was an association between fragile X syndrome premutation and POF, and established a model mechanism to explain the relationship. [Taiwanese J Obstet Gynecol 2006;45(1): 60–63] Key Words: fragile X syndrome, premutated carrier, premature ovarian failure, POF
Introduction Fragile X syndrome is the most common form of familial mental retardation. The carrier rate is 1/165 to 1/1,540 [1,2] and the occurrence of the full mutation is 1/1,000 to 1/4,000 in males and 1/2,000 to 1/9,000 in females [1,3]. The etiology is known to be an unstable gene, FMR1, on the X chromosome caused by a series of CGG (cytosine-guanine-guanine) repeats at Xq27.3 [4,5]. The number of repeats and the degree of methylation determine whether or not an individual is affected: 2–49 repeats (mean, 30) is phenotypically normal; 50– 199 repeats is called premutation, and such individuals
*Correspondence to: Dr. Man-Li Yang, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 201 Shih-Pai Road, Section 2, Taipei 112, Taiwan. E-mail: [email protected] Received: July 11, 2005 Revised: July 13, 2005 Accepted: July 14, 2005
60
do not usually exhibit overt clinical symptoms related to the mutation; and at least 200 repeats is called full mutation. Methylation of the CGG repeats and the surrounding promoter region inhibits FMR1 transcription and causes the absence of the RNA binding protein product. Of males with full mutation, 80% express mental retardation, with an intelligence quotient (IQ) of less than 30–45, while of females with full mutation, 50–70% have mental retardation with an IQ of 75–85 [1]. The most impressive somatic involvement that is consistently found among only premutated carrier females, not full-mutation carriers, is premature ovarian failure (POF). Of female premutated carriers, 20–28% have POF, whereas only 14% of full-mutation carriers and 6% of non-carriers have POF [1,6–8]. By convention, menopause that occurs between 40 and 45 years of age is considered early menopause and occurs in about 3–5% of women [9]. POF, defined as loss of ovarian follicles before 40 years of age, accounts for approximately 1% of the population [7,10]. The etiologies of POF are chromosomal anomalies, autoimmune diseases, metabolic diseases, familial heritance, infection, iatrogenic
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
Premature Ovarian Failure in Premutated Fragile X Syndrome
gene(s) escapes X-inactivation [9]. Second, molecular studies of ovarian dysfunction and Xq abnormalities from the last 10 years show that breakpoints are proximal at Xq13.3–q21.3 and Xq21.3–q22 and distal at Xq26–q28 [9,12]. The most common fragile X syndrome mutation is amplification of CGG repeats in the first exon of the FMR1 gene at Xq27.3. The premutation may affect a nearby gene(s) for ovarian function, inducing abnormal methylation so that fewer oocytes develop. Third, Sun et al reported non-random X inactivation and selection of fragile X full mutation in female fetal fibroblasts [13]. Fourth, an increase in twinning rates in premutated carriers has been observed by many investigators [6,14,15]. Partington et al suggested that fragile X carriers may produce fewer eggs, leading to premature menopause and an increased rate of dizygous twinning at an earlier age than usual; excess dizygous twinning could reflect a programmed excess hypothalamic stimulation of the ovaries resulting in excess follicular usage and earlier menopause [6,14– 16]. Fifth, endocrine profiles performed by Braat et al show abnormal serum follicle-stimulating hormone elevation on cycle day 1–2 in two of five premutated carriers [17]. From these five hypotheses, we suggest a possible mechanism, initiated by randomized and nonrandomized selection of X chromosome activation in premutated fragile X carriers and full mutation cases (Figures 2 and 3). Figure 4 shows a flow chart of this mechanism of POF in premutated fragile X carriers after randomized X chromosome activation selection. Finally, we used these five hypotheses to conclude that randomized selection of X chromosome activation in premutated fragile X carriers may lead to fewer oocytes and excess follicular usage, causing POF in fragile premutated carriers. Clinically, what can we do for females and their families affected by fragile X syn-
induction, and idiopathic cause. The common chromosomal anomalies causing impaired ovarian function are Turner syndrome (45X), 47XXX, and fragile X syndrome.
Case Report A 31-year-old female visited our gynecology department with the chief complaint of menopause at the age of 23. Her two older sisters had experienced the same condition, with menopause in their early thirties. One of her sisters had married and had a boy with mental retardation (IQ, 50). The boy had been diagnosed with fragile X syndrome with more than 200 CGG repeats. The patient and her sisters were diagnosed to be premutated carriers, with 80–100 CGG repeats. The pedigree is shown in Figure 1. The patient’s father had another family in mainland China and the family had the same situation: all females had POF and one of the three sisters had a son with mental retardation (unknown IQ). It appeared that these female cases had all been affected by premutation of CGG repeats.
Discussion What happens in the X chromosomes, and how can we give a reasonable explanation of POF in premutated fragile X carriers? Murray et al consider that an FMR1 isoform could be inappropriately expressed in the fetal ovaries of premutated females [11]. But this does not explain the lower incidence of POF in females with full-mutation fragile X. We reviewed recent reports and gathered five main hypotheses. First, ovarian dysgenesis develops in Turner syndrome and X monosomy (45X). A double dose of the ovarian development gene is necessary for normal ovarian development, and this In mainland China
In Taiwan Male carrier Unknown numbers of CGG repeats for premature ovarian failure in mainland China
POF
POF
POF
POF
POF
At 23 y-o
POF
80–100 CGG repeats for premature ovarian failure in Taiwan Full mutation male
30 y-o, MR
6 y-o, MR
Unknown IQ?
IQ 50
MR Mental retardation
Figure 1. Pedigree of familial premature ovarian failure (POF). POF developed in all six daughters and fragile X was transmitted to two males.
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
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Y.S. Lin, M.L. Yang
Activation of premutated X chromosome Premutation Randomized selection of active X chromosome
Reduced ovarian follicle production
POF
FMRI gene Normal follicle number production
Inactivation of premutated X chromosome Figure 2. Randomized selection of X chromosome activation in premutated fragile X carriers. Black bands, Xq13.3–21.3 and Xq26–28, represent ovarian function gene domain and promoter gene for ovarian function regulation separately. Full mutation
Full mutated X chromosome inactivation selection FMRI gene
Ovary genes on Xq13.3–21.3
Normal follicle number production
and Xq26–q28
Figure 3. Non-randomized inactivation selection of X chromosome in full-mutation fragile X syndrome carriers and noncarriers.
Premutated carriers with randomized X chromosome activation selection
CGG repeats in FMR1 promotor gene
Methylation of ovarian function gene(s)
Influence in FSH gene expression or estrogen receptor gene expression; even GnRH gene
Fewer oocytes in utero
A programmed hypothalamic over-stimulation of the ovaries
POF
High level of serum FSH; an increase in twinning rate and premature decline in the number of follicles
Figure 4. Hypothetical mechanism for premature ovarian failure (POF) in premutated female fragile X carriers after randomized selection of X chromosome activation (active selection of premutated X chromosome).
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drome, especially premutated carriers? It is important to provide prenatal counseling and prenatal diagnosis, to assist them in making reproductive decisions, and to take care of health issues (risk for osteoporosis due to POF and other complications of the menopause). Modern artificial reproductive techniques, such as frozen preservation of ovarian tissue or oocyte donation and hormonal therapy, may play a role [18]. Clinically, female carriers of fragile X premutations have no increased risk for additional diseases other than POF [19]. More research is needed to prove our hypothesis and discover the gene(s) that regulate normal ovarian function to avoid POF.
References 1. Scriver CR, Benaudet AL, Valle D, et al. The Metabolic and th Molecular Basis of Inherited Diseases, 8 edition. McGraw Hill, 2002;1257–88. 2. Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K. Prevalence of carriers of premutation-size alleles of the FMR1 gene and implications for the population genetics of the fragile X syndrome. Am J Med Genet 1995;57:1006–18.
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
Premature Ovarian Failure in Premutated Fragile X Syndrome
3. Turner G, Webb T, Wake S, Robinson H. Prevalence of fragile X syndrome. Am J Med Genet 1996;64:196–7. 4. 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;252:1097–102. 5. Kremer EJ, Pritchard M, Lynch M, et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence P(CGG)n. Science 1991;252:1711–4. 6. Partington MW, Moore DY, Turner GM. Confirmation of early menopause in fragile X carriers. Am J Med Genet 1996; 64:370–2. 7. Gersak K, Meden-Vrtovec H, Peterlin B. Fragile X premutation in women with sporadic premature ovarian failure in Slovenia. Hum Reprod 2003;18:1637–40. 8. Schwartz CE, Dean J, Howard-Peebles PN, et al. Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet 1994;51:400–2. 9. Christin-Maitre S, Vasseur C, Portnoi M-F, Bouchard P. Genes and premature ovarian failure. Mol Cell Endocrinol 1998;145:75–80. 10. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604–6. 11. Murray A, Conway GS, Jacobs PA. Premature ovarian failure and fragile X. Am J Med Genet 1996;64:15–20.
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
12. Vianna-Morgante AM, Costa SS, Pares AS, Verreschi ITN. FRAXA premutation association with premature ovarian failure. Am J Med Genet 1996;64:373–5. 13. Sun YJ, Baumer A. Nonradom X inactivation and selection of fragile X full mutation in fetal fibroblast. Am J Med Genet 1999;86:162–4. 14. Turner G, Robinson H, Wake S, Martin N. Dizygous twinning and premature menopause in fragile X syndrome (letter). Lancet 1994;344:1500. 15. Vianna-Morgante AM. Twinning and premature ovarian failure in premature fragile X carriers (letter). Am J Med Genet 1999;83:326. 16. Patsalis PC. FMR1 repeat analysis in patients with ovarian dysfunction or failure (letter). Am J Med Genet 1999;83: 329–30. 17. Braat DDM, Smits APT, Thomas CMG. Menstrual disorders and endocrine profiles in fragile X carriers prior to 40 years of age — a pilot study. Am J Med Genet 1999;83:327–8. 18. Davis SR. Premature ovarian failure. Clinical review. Maturitas 1996;23:1–8. 19. Hundscheid RDL, Smits APT, Thomas CMG, Kiemeney LALM, Braat DDM. Female carriers of fragile X premutations have no increased risk for additional diseases other than premature ovarian failure. Am J Med Genet 2003;117A:6–9.
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■ SHORT COMMUNICATION ■
FAMILIAL PREMATURE OVARIAN FAILURE IN FEMALE PREMUTATED CARRIERS OF FRAGILE X SYNDROME: A CASE REPORT AND LITERATURE REVIEW Yu-Shiou Lin, Man-Li Yang* Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan.
SUMMARY Objective: The fragile X syndrome is the most common form of familial mental retardation. Most males with the FMR1 full mutation function in the mentally retarded range of intelligence. In contrast, females with the FMR1 full mutation show a broader range of intelligence. The most impressive somatic involvement that is consistently found among only premutated carrier females, not full-mutation carriers, is premature ovarian failure (POF). Case Report: We report a family of fragile X syndrome. All six daughters had POF and both of the grandsons born to the daughters showed mental retardation. Conclusion: We concluded that there was an association between fragile X syndrome premutation and POF, and established a model mechanism to explain the relationship. [Taiwanese J Obstet Gynecol 2006;45(1): 60–63] Key Words: fragile X syndrome, premutated carrier, premature ovarian failure, POF
Introduction Fragile X syndrome is the most common form of familial mental retardation. The carrier rate is 1/165 to 1/1,540 [1,2] and the occurrence of the full mutation is 1/1,000 to 1/4,000 in males and 1/2,000 to 1/9,000 in females [1,3]. The etiology is known to be an unstable gene, FMR1, on the X chromosome caused by a series of CGG (cytosine-guanine-guanine) repeats at Xq27.3 [4,5]. The number of repeats and the degree of methylation determine whether or not an individual is affected: 2–49 repeats (mean, 30) is phenotypically normal; 50– 199 repeats is called premutation, and such individuals
*Correspondence to: Dr. Man-Li Yang, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 201 Shih-Pai Road, Section 2, Taipei 112, Taiwan. E-mail: [email protected] Received: July 11, 2005 Revised: July 13, 2005 Accepted: July 14, 2005
60
do not usually exhibit overt clinical symptoms related to the mutation; and at least 200 repeats is called full mutation. Methylation of the CGG repeats and the surrounding promoter region inhibits FMR1 transcription and causes the absence of the RNA binding protein product. Of males with full mutation, 80% express mental retardation, with an intelligence quotient (IQ) of less than 30–45, while of females with full mutation, 50–70% have mental retardation with an IQ of 75–85 [1]. The most impressive somatic involvement that is consistently found among only premutated carrier females, not full-mutation carriers, is premature ovarian failure (POF). Of female premutated carriers, 20–28% have POF, whereas only 14% of full-mutation carriers and 6% of non-carriers have POF [1,6–8]. By convention, menopause that occurs between 40 and 45 years of age is considered early menopause and occurs in about 3–5% of women [9]. POF, defined as loss of ovarian follicles before 40 years of age, accounts for approximately 1% of the population [7,10]. The etiologies of POF are chromosomal anomalies, autoimmune diseases, metabolic diseases, familial heritance, infection, iatrogenic
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
Premature Ovarian Failure in Premutated Fragile X Syndrome
gene(s) escapes X-inactivation [9]. Second, molecular studies of ovarian dysfunction and Xq abnormalities from the last 10 years show that breakpoints are proximal at Xq13.3–q21.3 and Xq21.3–q22 and distal at Xq26–q28 [9,12]. The most common fragile X syndrome mutation is amplification of CGG repeats in the first exon of the FMR1 gene at Xq27.3. The premutation may affect a nearby gene(s) for ovarian function, inducing abnormal methylation so that fewer oocytes develop. Third, Sun et al reported non-random X inactivation and selection of fragile X full mutation in female fetal fibroblasts [13]. Fourth, an increase in twinning rates in premutated carriers has been observed by many investigators [6,14,15]. Partington et al suggested that fragile X carriers may produce fewer eggs, leading to premature menopause and an increased rate of dizygous twinning at an earlier age than usual; excess dizygous twinning could reflect a programmed excess hypothalamic stimulation of the ovaries resulting in excess follicular usage and earlier menopause [6,14– 16]. Fifth, endocrine profiles performed by Braat et al show abnormal serum follicle-stimulating hormone elevation on cycle day 1–2 in two of five premutated carriers [17]. From these five hypotheses, we suggest a possible mechanism, initiated by randomized and nonrandomized selection of X chromosome activation in premutated fragile X carriers and full mutation cases (Figures 2 and 3). Figure 4 shows a flow chart of this mechanism of POF in premutated fragile X carriers after randomized X chromosome activation selection. Finally, we used these five hypotheses to conclude that randomized selection of X chromosome activation in premutated fragile X carriers may lead to fewer oocytes and excess follicular usage, causing POF in fragile premutated carriers. Clinically, what can we do for females and their families affected by fragile X syn-
induction, and idiopathic cause. The common chromosomal anomalies causing impaired ovarian function are Turner syndrome (45X), 47XXX, and fragile X syndrome.
Case Report A 31-year-old female visited our gynecology department with the chief complaint of menopause at the age of 23. Her two older sisters had experienced the same condition, with menopause in their early thirties. One of her sisters had married and had a boy with mental retardation (IQ, 50). The boy had been diagnosed with fragile X syndrome with more than 200 CGG repeats. The patient and her sisters were diagnosed to be premutated carriers, with 80–100 CGG repeats. The pedigree is shown in Figure 1. The patient’s father had another family in mainland China and the family had the same situation: all females had POF and one of the three sisters had a son with mental retardation (unknown IQ). It appeared that these female cases had all been affected by premutation of CGG repeats.
Discussion What happens in the X chromosomes, and how can we give a reasonable explanation of POF in premutated fragile X carriers? Murray et al consider that an FMR1 isoform could be inappropriately expressed in the fetal ovaries of premutated females [11]. But this does not explain the lower incidence of POF in females with full-mutation fragile X. We reviewed recent reports and gathered five main hypotheses. First, ovarian dysgenesis develops in Turner syndrome and X monosomy (45X). A double dose of the ovarian development gene is necessary for normal ovarian development, and this In mainland China
In Taiwan Male carrier Unknown numbers of CGG repeats for premature ovarian failure in mainland China
POF
POF
POF
POF
POF
At 23 y-o
POF
80–100 CGG repeats for premature ovarian failure in Taiwan Full mutation male
30 y-o, MR
6 y-o, MR
Unknown IQ?
IQ 50
MR Mental retardation
Figure 1. Pedigree of familial premature ovarian failure (POF). POF developed in all six daughters and fragile X was transmitted to two males.
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
61
Y.S. Lin, M.L. Yang
Activation of premutated X chromosome Premutation Randomized selection of active X chromosome
Reduced ovarian follicle production
POF
FMRI gene Normal follicle number production
Inactivation of premutated X chromosome Figure 2. Randomized selection of X chromosome activation in premutated fragile X carriers. Black bands, Xq13.3–21.3 and Xq26–28, represent ovarian function gene domain and promoter gene for ovarian function regulation separately. Full mutation
Full mutated X chromosome inactivation selection FMRI gene
Ovary genes on Xq13.3–21.3
Normal follicle number production
and Xq26–q28
Figure 3. Non-randomized inactivation selection of X chromosome in full-mutation fragile X syndrome carriers and noncarriers.
Premutated carriers with randomized X chromosome activation selection
CGG repeats in FMR1 promotor gene
Methylation of ovarian function gene(s)
Influence in FSH gene expression or estrogen receptor gene expression; even GnRH gene
Fewer oocytes in utero
A programmed hypothalamic over-stimulation of the ovaries
POF
High level of serum FSH; an increase in twinning rate and premature decline in the number of follicles
Figure 4. Hypothetical mechanism for premature ovarian failure (POF) in premutated female fragile X carriers after randomized selection of X chromosome activation (active selection of premutated X chromosome).
62
drome, especially premutated carriers? It is important to provide prenatal counseling and prenatal diagnosis, to assist them in making reproductive decisions, and to take care of health issues (risk for osteoporosis due to POF and other complications of the menopause). Modern artificial reproductive techniques, such as frozen preservation of ovarian tissue or oocyte donation and hormonal therapy, may play a role [18]. Clinically, female carriers of fragile X premutations have no increased risk for additional diseases other than POF [19]. More research is needed to prove our hypothesis and discover the gene(s) that regulate normal ovarian function to avoid POF.
References 1. Scriver CR, Benaudet AL, Valle D, et al. The Metabolic and th Molecular Basis of Inherited Diseases, 8 edition. McGraw Hill, 2002;1257–88. 2. Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K. Prevalence of carriers of premutation-size alleles of the FMR1 gene and implications for the population genetics of the fragile X syndrome. Am J Med Genet 1995;57:1006–18.
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
Premature Ovarian Failure in Premutated Fragile X Syndrome
3. Turner G, Webb T, Wake S, Robinson H. Prevalence of fragile X syndrome. Am J Med Genet 1996;64:196–7. 4. 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;252:1097–102. 5. Kremer EJ, Pritchard M, Lynch M, et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence P(CGG)n. Science 1991;252:1711–4. 6. Partington MW, Moore DY, Turner GM. Confirmation of early menopause in fragile X carriers. Am J Med Genet 1996; 64:370–2. 7. Gersak K, Meden-Vrtovec H, Peterlin B. Fragile X premutation in women with sporadic premature ovarian failure in Slovenia. Hum Reprod 2003;18:1637–40. 8. Schwartz CE, Dean J, Howard-Peebles PN, et al. Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet 1994;51:400–2. 9. Christin-Maitre S, Vasseur C, Portnoi M-F, Bouchard P. Genes and premature ovarian failure. Mol Cell Endocrinol 1998;145:75–80. 10. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604–6. 11. Murray A, Conway GS, Jacobs PA. Premature ovarian failure and fragile X. Am J Med Genet 1996;64:15–20.
Taiwanese J Obstet Gynecol • March 2006 • Vol 45 • No 1
12. Vianna-Morgante AM, Costa SS, Pares AS, Verreschi ITN. FRAXA premutation association with premature ovarian failure. Am J Med Genet 1996;64:373–5. 13. Sun YJ, Baumer A. Nonradom X inactivation and selection of fragile X full mutation in fetal fibroblast. Am J Med Genet 1999;86:162–4. 14. Turner G, Robinson H, Wake S, Martin N. Dizygous twinning and premature menopause in fragile X syndrome (letter). Lancet 1994;344:1500. 15. Vianna-Morgante AM. Twinning and premature ovarian failure in premature fragile X carriers (letter). Am J Med Genet 1999;83:326. 16. Patsalis PC. FMR1 repeat analysis in patients with ovarian dysfunction or failure (letter). Am J Med Genet 1999;83: 329–30. 17. Braat DDM, Smits APT, Thomas CMG. Menstrual disorders and endocrine profiles in fragile X carriers prior to 40 years of age — a pilot study. Am J Med Genet 1999;83:327–8. 18. Davis SR. Premature ovarian failure. Clinical review. Maturitas 1996;23:1–8. 19. Hundscheid RDL, Smits APT, Thomas CMG, Kiemeney LALM, Braat DDM. Female carriers of fragile X premutations have no increased risk for additional diseases other than premature ovarian failure. Am J Med Genet 2003;117A:6–9.
63