Female twin with hunter disease due to nonrandom inactivation of the X‐chromosome: A consequence of twinning

Winchester, Bryan; Young, Elisabeth; Geddes, Stella; Genet, S; Hurst, Jane A.; Middelton‐Price, Helen; Williams, Nicola; Webb, Michael R.; Habel, Alex; Malcolm, S

doi:10.1002/ajmg.1320440625

Cited by 58 publications

(32 citation statements)

References 18 publications

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“…Several MZ twin pairs have been reported where one twin is healthy and the co-twin severely aVected with an X-linked disorder. This discordance has been attributed to skewed XCI in the aVected twin in several cases, such as Duchenne muscular dystrophy (Burn et al 1986;Richards et al 1990;Lupski et al 1991;Tiberio 1994), Hunter disease (Winchester et al 1992), Fabry disease (Marguery et al 1993;Redonnet-Vernhet et al 1996) and hemophilia A (Bennett et al 2008). It has been speculated that skewed X inactivation of the inner cell mass may lead to MZ twinning (Nance 1990;Lubinsky and Hall 1991).…”

Section: Monozygotic Twinsmentioning

confidence: 95%

X chromosome inactivation in clinical practice

Ørstavik

2009

Hum Genet

111

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X chromosome inactivation (XCI) is the transcriptional silencing of the majority of genes on one of the two X chromosomes in mammalian females. Females are, therefore, mosaics for two cell lines, one with the maternal X and one with the paternal X as the active chromosome. The relative proportion of the two cell lines, the X inactivation pattern, may be analyzed by simple assays in DNA from available tissues. This review focuses on medical issues related to XCI in X-linked disorders, and on the value of X inactivation analysis in clinical practice.

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Section: Monozygotic Twinsmentioning

confidence: 95%

X chromosome inactivation in clinical practice

Ørstavik

2009

Hum Genet

111

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“…However, anecdotal examples of discordant female MC-MZ twins have been reported where the affected twin exhibited a selective inactivation of the normal X chromosome while her normal co-twin showed either random X inactivation or skewing toward the mutant X chromosome. [19][20][21][22] Several theoretical explanations for such "mirror-image" inactivation have been proposed. It was initially suggested that random X inactivation followed by asymetric splitting of the inner cell mass would result in only one affected twin because she received a majority of cells in which the normal allele had been inactivated.…”

mentioning

confidence: 99%

Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A

Valleix

Vinciguerra

Lavergne

et al. 2002

Blood

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This study describes the genetic mechanisms responsible for the de novo occurrence of severe and mild hemophilia A in monozygotic twin females. Both twins were found to carry a previously known factor VIII mutation (Tyr16Cys) in the heterozygous state which most probably arose in the paternal germ line. Both twins showed concordant skewing of X inactivation toward the maternally derived normal X chromosome, the most severely affected twin exhibiting a higher percentage of inactivation of the normal X chromosome. The degree of skewing of X inactivation closely correlated with both the coagulation parameters and the clinical phenotype of the twins. Since these twins were monochorionic, such results suggest that the twinning event in this case has occurred after the onset of the X-inactivation period. IntroductionHemophilia A is an X-linked recessive bleeding disorder caused by deficiency of factor VIII (FVIII) which occurs in 1/5000 male births. 1 Clinical severity is inversely related to residual factor VIII activity (FVIII:C) such that patients with less than 1%, 1%-5%, and 5%-30% FVIII:C are classified as severe, moderate, or mild, respectively. The molecular basis underlying hemophilia A is well characterized, and about half of severely affected individuals have large genomic inversions disrupting the FVIII gene (F8). [2][3][4] In the remaining cases, different heterogeneous point mutations, insertions, and deletions are found scattered throughout the 26 exons, as well as in the introns of F8. 5 Hemophilia A is transmitted by heterozygous females denoted as carriers, who are generally asymptomatic since random X inactivation results in approximately equal proportions of somatic cells in which either the normal X or the mutated X chromosome is active. 6 Even though the disease in females is extremely rare, a few cases have been documented, resulting from different pathophysiologic mechanisms. [7][8][9][10][11][12][13] Here, we report monozygotic (MZ) twin girls both carrying the same F8 mutation which results in severe hemophilia A in one twin and mild phenotype in her co-twin. Although they exhibited a different clinical and biologic severity, they both showed concordant skewing of X inactivation toward the normal X chromosome. In this respect, they differed from some pairs of MZ twin females who typically showed a "mirror-image" pattern of X inactivation. As the twins were classified as monochorionic (MC) at birth, our data strongly support the hypothesis that the splitting event in MC-MZ twin pairs occurs after the onset of X-inactivation period. Study design Case reportThe family is presented in Figure 1. Coagulation studies showed FVIII:C of less than 1% for proposita II.2 and 12% for II.3 on repeated measurements, with normal VWF:Ag and VWF:RCo levels in both cases. None of the other family members (I.1, I.2, and II.1) exhibited hemophilia or had abnormal values of plasma FVIII:C and von Willebrand factor (VWF), suggesting an absence of familial inheritance for the disease. Binding of FVIII to VWF was fo...

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“…Another possible explanation for discordant MZ female twins is skewed X-chromosome inactivation, which is the proposed mechanism for the discordance in MZ twins with Duchenne-muscular dystrophy (DMD) [Richards et al, 1990], red-green color blindness [Jorgensen et al, 1992], and Hunter disease [Winchester et al, 1992]. However, the twins reported here had similar X-inactivation patterns and we conclude that discrepant X-inactivation is an unlikely cause for the phenotypic discordance.…”

Section: Mechanisms Of Discordance Of Ofd1 In Twinsmentioning

confidence: 40%

Discordance of oral-facial-digital syndrome type 1 in monozygotic twin girls

et al. 1999

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The oral-facial-digital syndrome type 1 (OFD1) includes limb, facial, intraoral malformations and the gene for the disorder was recently mapped to Xp22.3-p22.2. We report on monozygotic twin girls discordant for OFD1. Monozygosity is supported by placental pathology (monochorionic diamniotic) and molecular studies with probability of dizygosity <1 x 10(-6). The affected twin has oral cavity abnormalities including median cleft lip, cleft palate, lobulated hamartomatous tongue, aberrant hyperplastic oral frenula, alveolar notches, and absent lateral incisors. Facial manifestations include telecanthus, hypoplastic alae nasi, and transient neonatal facial milia. The patient also has short and deviated fingers with partial cutaneous syndactyly. At 10 years, she has not had central nervous system or kidney problems. X-inactivation study revealed similar X-inactivation patterns in the lymphoblasts of both twins. We conclude that skewed X-inactivation is an unlikely cause for the discordance, which is more likely due to a postzygotic mutation in the affected twin.

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Female twin with hunter disease due to nonrandom inactivation of the X‐chromosome: A consequence of twinning

Cited by 58 publications

References 18 publications

X chromosome inactivation in clinical practice

X chromosome inactivation in clinical practice

Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A

Discordance of oral-facial-digital syndrome type 1 in monozygotic twin girls

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