Monozygotic Twin Sisters Research Articles

Images in Clinical Medicine: McCune-Albright Syndrome

Twelve years ago, the patient on the left (Figure 1), one of the 29-year-old single-placenta monozygotic twin sisters, underwent computed tomography after a relatively mild head trauma. As an incidental finding, the computed tomography scan (Figure 2) revealed that the skull structure was consistent with fibrous dysplasia, a characteristic finding for McCune-Albright syndrome. The pituitary gland was slightly enlarged. The second twin had no features of McCune-Albright syndrome. McCune-Albright syndrome is a sporadic disorder, caused by postzygotic activating mutations of the GNAS1 gene and characterized by polyostotic fibrous dysplasia, pigmented patches of skin, and endocrinological abnormalities (1). The extent and the nature of the abnormalities are highly variable, depending on the specific tissues involved in mosaicism. The affected twin had regular menses beginning at age 13. Her zygoma was very prominent on the left side, a manifestation of fibrous dysplasia, and the facial structure was typical of acromegaly (broad nose, elongated jaw, large mandible, and sharp facial features). There was an oval-shaped hyperpigmented lesion on the lower chest. Laboratory tests revealed high levels of serum prolactin, IGF-1, and GH (without oral glucose challenge test stimulation), which led to a diagnosis of acromegaly. The levels of TSH and T4 were normal. Molecular analysis of the GNAS1 gene from both twins did not reveal the cause of the discordance. Treatment of acromegaly was initiated with a somatostatin analog and a dopamine agonist, and fibrous dysplasia was managed with bisphosphonates. Under this treatment, GH and IGF-1 stabilized at slightly increased levels. Over the years, the phenotypic features of acromegaly became more prominent.

Identical twins:one with anti-glomerular basement membrane glomerulonephritis,the other with systemic lupus erythematosus

BackgroundAnti-glomerular basement membrane (GBM) glomerulonephritis and systemic lupus erythematosus (SLE) are both disorders of the immune system; however, they are known as distinct diseases. Till now no clinical evidence suggests the genetic relationship between these two diseases. Herein, we present two identical twins; one was diagnosed as anti-GBM glomerulonephritis, the other SLE. This is the first clinical report on the genetic relationship between these two diseases.Case presentationA 25-year-old female was admitted complaining of intermittent gross hematuria for 6 months and elevated serum creatinine for 1 month. She denied hemoptysis. Laboratory examinations showed hemoglobin 7.4 g/dL, serum creatinine 7.15 mg/dL and albumin 2.8 g/dL. Urinalysis showed hematuria (484 RBCs per high-power field) and proteinuria 4+. Antinuclear antibody, complement levels and ANCAs were all normal. Renal ultrasound showed normal-sized kidneys without obstruction or masses. Serum anti-GBM antibody assay showed 119.70 RU/mL (normal range, <20 RU/mL). Chest X-ray was normal. She was diagnosed as anti-GBM glomerulonephritis and received plasma exchange (2000-3000 ml plasma/exchange, 5 turns), methylprednisolone 0.5 g for three days, plus cyclophosphamide. Although serum anti-GBM antibodies decreased gradually to a normal range, her renal function did not improve. One month later, her identical twin sister was diagnosed as SLE based on malar erythema, arthralgia, antinuclear antibody positive with liter 1:1000, and Anti-Smith (Sm) antibody ++. Anti-GBM antibody and complements were within normal ranges. Further study showed these twins were HLA-DRB1*1501 homozygotes.ConclusionThe presence of identical twins having anti-GBM nephritis and SLE respectively provides clinical evidence to support that anti-GBM nephritis and lupus may share a common genetic background to some extent, while environment may contribute to disease evolution in part.

Correlation between FMR1 expression and clinical phenotype in discordant dichorionic–diamniotic monozygotic twin sisters with the fragile x mutation

BackgroundThe clinical phenotypes of females with fragile X full mutations vary drastically. Comparisons of discordant monozygotic twins provide opportunities to ascertain crucial factors that influence disease phenotype penetrance.ObjectiveTo identify crucial...

Monozygotic twin sisters discordant for familial hemiplegic migraine

BackgroundThe high concordance rate of migraine in monozygotic twin pairs has long been recognised. In the current study, we present a monozygotic twin pair discordant for familial hemiplegic migraine (FHM).Case presentationsWe evaluated 12 adult family members in 2012. The twin pair was separately examined by neurologists at different time points. Mutation screening was performed for known FHM-related genes. The monozygosity of the twins was verified. Eleven individuals had a history of migraine or paroxysmal neurological symptoms, including four patients with motor aura. No mutations were detected in the CACNA1A, ATP1A2, SCN1A, PRRT2 or NOTCH3 genes. The monozygotic twin sisters, aged 52, were discordant for age of onset, motor aura and neuropsychological aura (forced thinking). Overall, the family members presented a wide range of phenotypical features.ConclusionsFamilial hemiplegic migraine is a monogenic disorder that is distinct from migraine with typical aura. However, in certain families with motor aura, such as this one, it is possible that the most severe phenotype is caused by an unlikely combination of polygenic traits and non-genetic factors. In these kindreds, we propose that hemiplegic aura is only a severe and complex form of typical aura.

MTOR Inhibition and Tuberous Sclerosis Prevention

Investigators at Children's Memorial Health Institute, Warsaw, Poland, report monozygotic twin sisters with tuberous sclerosis complex (TSC), one treated with the mTOR inhibitor everolimus since age 4 years.

Possible Prevention of Tuberous Sclerosis Complex Lesions

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by mammalian target of rapamycin (mTOR) activation and growth of benign tumors. Some TSC lesions, such as cardiac rhabdomyomas and cortical tubers in the brain, occur in fetuses, and some, such as renal angiomyolipomas (AMLs) and skin angiofibromas, develop over years. Recently, the mTOR inhibitor everolimus was shown to be effective in the treatment of subependymal giant cell astrocytomas (a brain tumor) and renal AMLs (kidney tumors) in TSC patients. We present monozygotic twin sisters affected with TSC. Since age 4 years, 1 of the sisters has been treated with everolimus; the other sister received no mTOR inhibitor treatment. After 24-month follow-up, everolimus treatment resulted in a significant brain tumor volume decrease in the treated twin. This child presents no facial angiofibroma, and no renal AMLs. The brain tumor in the nontreated sister is stable in size, but in the meantime, she has developed significant facial angiofibroma and renal AMLs. This observation indicates that early mTOR inhibition in TSC patients may prevent the development of TSC lesions and alter the natural history of the disease.

Breast Cancer in Monozygotic Twins

Breast cancer is a multifactorial disease. Twin studies comparing the disease concordance rate in identical twin pairs serve to differentiate the influence of genetic and environmental factors in the disease development. To assess breast cancer risk for an identical twin sister of a patient with breast cancer. Five monozygotic twin families were examined during 2005- 2011 in which at least one of the monozygotic sisters developed breast cancer.In 4 breast cancer women from 4 families, molecular genetic analysis of BRCA1 and BRCA2 genes was performed. The median followup period was 12.6 years (7 to 24 years). No pair of monozygotic sisters was concordant for breast cancer. Familial breast/ ovarian cancer syndrome due to BRCA1 gene mutation was confirmed in one pair. These twins were phenotypically discordant, the first one developing breast cancer at the age of 54 years, her co sister suffering from ovarian cancer at the age of 43 years. In the other 4 nonBRCA families, breast cancer was diagnosed at the age of 38- 50 years (median 44 years) in one of the sisters; the other twins remain healthy through the followup period. We did not observe concordance for breast cancer in 5 pairs of monozygotic twins. Based on results of published studies, the life time breast cancer risk for a healthy identical twin of a breast cancer nonBRCA woman is around 20- 30 %. Other nonhereditary risk factors must exist to explain the discordant phenotype. This highlights that environmental factors play an important role in breast cancer development. In case of BRCA associated breast cancer, breast cancer risk for the healthy co twin is the same as that for other BRCA mutation carriers, i.e. 45- 85%.

Assessment of a symptomatic Duchenne muscular dystrophy carrier 20years after myoblast transplantation from her asymptomatic identical twin sister

Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects.

Molecular analyses in Indonesian individuals with intellectual disability and microcephaly

Background Intellectual disability (ID) often coincides with anabnormal head circumference (HC). Since the HC is a reflectionof brain size, abnormalities in HC may be a sign of a brain anomaly.Although microcephaly is often secondary to ID, hereditary(autosomal recessive) forms of primary microcephaly (MCPH)exist that result in ID.Objective To investigate mutations in MCPH genes in patientswith ID and microcephaly.Methods From a population of 527 Indonesian individuals withID, 48 patients with microcephaly (9.1 %) were selected. Thesepatients were previously found to be normal upon conventionalkaryotyping, fragile X mental retardation 1 (FMRl) gene analysis,subtelomeric deletion, and duplication multiplex ligationdependentprobe amplification (MLPA). Sanger sequencing forabnormal spindle-like microcephaly-associated (ASPM) and WDrepeat domain 62 (WDR62) was performed in all 48 subjects, whilesequencing for microcephalin (MCPHl), cyclin-dependent kinase5 (CDK5) regulatory subunit-associated protein 2 (CD5KRAP2) ,centromere protein} (CENPJ), and SCUfALl interrupting locus(STIL) was conducted in only the subjects with an orbitofrontalcortex (OFC) below -4 SD.Results In all genes investigated, 66 single nucleotide polymorphisms(SNPs) and 15 unclassified variants which were predictedas unlikely to be pathogenic (lN2), were identified. Possiblepathogenic variants (lN3) were identified in ASPM. However,since none of the patients harboured compound heterozygouslikely pathogenic mutations, no molecular MCPH diagnosis couldbe established. Interestingly, one of the patients harboured thesame variants as her unaffected monozygotic twin sister, indicatingthat our cohort included a discordant twin.Conclusions This study is the first to investigate for possible geneticcauses ofMCPH in the Indonesian population. The absenceof causative pathogenic mutations in the MCPH genes tested may originate from several factors. The identification of UV2and UV3 variants as well as the absence of causative pathogenicmutations calls for further investigations.

Posterior Spinal Fusion for Friedreich Ataxia-Related Scoliosis in Twin Girls

Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia with an incidence of two in 100,000 Caucasians1. Caused by a triplet expansion mutation of the frataxin gene, which is located on chromosome 9q13, it is the most common recessively inherited ataxia2. Early symptoms include tabetocerebellar ataxia, generalized clumsiness, scoliosis, and pes cavus or equinovarus1,2. Later, dysarthria, nystagmus, hypertrophic cardiomyopathy, and diabetes mellitus may arise1. Symptoms begin within the first two decades of life, and most people with FRDA lose the ability to walk within fifteen years3. Cardiomyopathy may lead to arrhythmia, congestive heart failure, and premature death by the third or fourth decade4. Scoliosis has been reported in 63% to 100% of people with FRDA2,5-8. Curve classification is varied, with most now recognizing a neuromuscular pattern5-8. Bracing does not halt the progression of these curves and can further hinder mobility5-7, so surgical treatment is indicated7,8. A report in the recent literature demonstrated enhanced stability with use of segmental pedicle screw fixation7. Despite the familial nature of FRDA, there have been no reports, to our knowledge, of posterior spinal fusion in twins with FRDA-related scoliosis. We present the case of twin girls with FRDA and scoliosis. We highlight the similarity of phenotype in these twins, with respect to scoliosis curve type, onset, and progression, as well as the timing and success of surgical intervention. Both patients and their guardians were informed that data concerning their cases would be submitted for publication, and they all provided consent. Fourteen-year-old identical twin sisters with FRDA and scoliosis were referred to our center. Genetic testing showed homozygous mutation of the frataxin …

Maternal age at first birth and offspring criminality: Using the children of twins design to test causal hypotheses

Teenage childbirth is a risk factor for poor offspring outcomes, particularly offspring antisocial behavior. It is not clear, however, if maternal age at first birth (MAFB) is causally associated with offspring antisocial behavior or if this association is due to selection factors that influence both the likelihood that a young woman gives birth early and that her offspring engage in antisocial behavior. The current study addresses the limitations of previous research by using longitudinal data from Swedish national registries and children of siblings and children of twins comparisons to identify the extent to which the association between MAFB and offspring criminal convictions is consistent with a causal influence and confounded by genetic or environmental factors that make cousins similar. We found offspring born to mothers who began childbearing earlier were more likely to be convicted of a crime than offspring born to mothers who delayed childbearing. The results from comparisons of differentially exposed cousins, especially born to discordant monozygotic twin sisters, provide support for a causal association between MAFB and offspring criminal convictions. The analyses also found little evidence for genetic confounding due to passive gene-environment correlation. Future studies are needed to replicate these findings and to identify environmental risk factors that mediate this causal association.

両側性唇顎口蓋裂と片側性唇顎裂を示した一卵性双生児姉妹の治療経験

The incidence of monozygotic twins with cleft lip and palate is very low, and there have been few studies of longitudinal observations. The observation of monozygotic twins with different types of cleft lip and palate from the perspective of jaw growth facilitates comparison and evaluation of the effects of extrinsic and intrinsic factors. In this study, we observed monozygotic twin sisters with bilateral cleft lip and palate (BCLP) and unilateral cleft lip and alveolus (UCLA). In the child with BCLP in whom collapse occurred during jaw development, we placed a palatal plate and maxillary expansion appliance in infancy, and longitudinally compared her with her sister with UCLA. Although there were no marked differences in the growth or development of the middle face between the sister with BCLP, in whom jaw guidance was performed from birth, and the sister with UCLA at the age of 7 years and 11 months, mandibular growth in the inferior direction was noted in the sister with BCLP.The results suggest that careful follow-up of both patients, including occlusal control, is necessary.

Hormone therapy is associated with better body composition and adipokine/glucose profiles

The aim of this study was to evaluate the possibility of preventing the metabolic health consequences of postmenopausal hypogonadism with the use of long-term hormone therapy (HT). We used a monozygotic co-twin control design including 10 twin pairs (aged 56-62 y) discordant for HT (duration of HT, 2-10 y). In addition, 14 premenopausal women (aged 29-35 y) who did not use HT were studied to evaluate the differences in metabolic health between the premenopausal and postmenopausal states. Body composition was determined, and waist-to-hip ratio was used as an estimate for fat distribution. Serum sex steroids, sex hormone-binding globulin, and serum lipid and glucose profiles were analyzed. The serum levels of adiponectin, monocyte chemotactic protein-1, and leptin, as well as their local transcript levels in adipose tissue, skeletal muscle, and leukocytes, were measured. Long-term HT was associated with a healthier amount and distribution of body fat. No difference was seen in serum lipid concentrations between HT users and their nonusing identical twin sisters, but fasting serum glucose and glycated hemoglobin levels were 5% and 3% lower in HT users than in nonusers, respectively. Among the adipokines analyzed, the most notable finding was a 15% lower level of monocyte chemotactic protein-1 in HT users, particularly with respect to its suggested mediator role between obesity and insulin resistance. Long-term HT is associated with healthier amount and distribution of body fat and better adipocytokine profile, with concomitant signs of improved insulin sensitivity.

Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation

Renal coloboma syndrome (RCS) is a highly variable syndrome characterized by renal and ocular abnormalities. It is associated in about 50 % of cases with mutations of PAX2, a gene encoding a transcription factor required during development. The case study involves two monozygotic twin sisters with RCS showing highly discordant phenotypes. Twin 1 was antenatally diagnosed with multiple cysts in the right kidney. She had complicated vacuum-assisted delivery with acute renal failure. She developed proteinuria at age 4 years, followed by a progressive rise in serum creatinine requiring renal replacement therapy at age 22. No ocular abnormalities have been detected. Twin 2 experienced rapidly reversible acute renal failure without renal morphological abnormalities at birth. At age 2 years, complete visual acuity loss of the left eye secondary to an optic disc coloboma was diagnosed. No significant events occurred until the age of 20, when clinical proteinuria was detected. Proteinuria remission was obtained by multidrug treatment. In both patients, a novel de novo mutation of PAX2 was detected, which leads to the substitution of a highly conserved cysteine (p.C52Y). The patients described provide an extreme example of clinical variability in RCS. The role of environmental, genetic, and epigenetic factors is discussed.

Adult with sacral lipomyelomeningocele covered by an anomalous bone articulated with iliac bone: Computed tomography and magnetic resonance images

The present paper reports and discusses a case of sacral lipomyelomeningocele with an anomalous long bone articulating with the left iliac bone in a 40-year-old female. That patient had a monozygotic twin sister who had normal spine. The findings were incidental during an evaluation for a urinary tract infection. The computed tomography (CT) and magnetic resonance (MR) images revealed sacral dysraphism, lipomyelomeningocele, tethered spinal cord, and profound subcutaneous fat in the sacrococcygeal region. In addition, an anomalous bony strut was demonstrated on the posterior aspect of the sacrum, covering the sacral defect and the associated lipomyelomeningocele. The 3-D CT images of the anomalous bone associated with the sacral lipomyelomeningocele and the putative embryologic process are presented with a review of the literature.

Novel insertion in exon 5 of the TCOF1 gene in twin sisters with Treacher Collins syndrome

Treacher Collins syndrome (TCS) is associated with an abnormal differentiation of the first and second pharyngeal arches during fetal development. This causes mostly craniofacial deformities, which require numerous corrective surgeries. TCS is an autosomal dominant disorder and it occurs in the general population at a frequency of 1 in 50,000 live births. The syndrome is caused by mutations in the TCOF1 gene, which encodes the serine/alanine-rich protein named Treacle. Over 120 mutations of the TCOF1 gene responsible for TCS have been described. About 70% of recognized mutations are deletions, which lead to a frame shift, formation of a termination codon, and shortening of the protein product of the gene. Herewith, a new heterozygotic insertion, c.484_668ins185bp, was described in two monozygotic twin sisters suffering from TCS. This mutation was absent in their father, brother, and uncle, indicating a de novo origin. The insertion causes a shift in the reading frame and premature termination of translation at 167 aa. The novel insertion is the longest ever found in the TCOF1 gene and the only one found among monozygotic twin sisters.

First language attrition in the speech of Dutch–English bilinguals: The case of monozygotic twin sisters

Recent years have seen a proliferation of research on attrition in L1 speech (de Leeuw, Mennen &amp; Scobbie, in press; de Leeuw, Schmid &amp; Mennen, 2010; Dmitrieva, Jongman &amp; Sereno, 2010; Mennen, 2004). Adding to this line of inquiry, the present study investigates the speech of a 62-year-old bilingual monozygotic twin who emigrated to an L2-speaking environment 30 years ago. Changes in L1 accent were assessed by comparing her speech to that of her identical twin sister who remained in the L1-speaking environment, thus providing a unique control setting. Acoustic analyses of voice onset time and vowels indicate pervasive changes to the emigrated twin's L1 accent, with attrition presenting in the form of cross-linguistic assimilation patterns. Interestingly, her L1 vowel space exhibited a systematic increase in first formant frequency, confirming claims that L1 and L2 sounds may be related to each other at a system-wide level (Chang, 2010, 2011; Guion, 2003). Implications for theoretical models of bilingual sound systems are discussed.

Postpartum Onset of Adult Celiac Disease in Identical Twin Sisters

Different risk factors for the onset of celiac disease have been enumerated, with the single most important factor being a known familial history of biopsy-defined disease (1). However, estimated rates of familial celiac disease have been difficult to determine due to the important phenomenon of clinical discordance, even in genetically identical twin pairs (2). In addition, nongenetic factors have been suspected to play a role in the clinical onset of adult celiac disease, including pregnancy and the puerperium (3,4).

Simultaneous Occurrence of Erythema Nodosum in Monozygotic Twin Sisters

Erythema nodosum (EN) is the most frequent clinicopathologic variant of panniculitis with painful red or violaceous nodules on the anterior surfaces of the legs. The condition is a cutaneous reaction that might be associated with a wide variety of disorders or might be caused by medications that produce painful nodules on the shins, and less commonly on the thighs and forearms. In this paper, we describe, for the first time in the world, erythema nodosum as the simultaneous presenting complaint of monozygotic twin sisters after streptococcal pharyngitis. This paper might support the effect of heredity in the occurrence of erythema nodosum.

Axenfeld-Rieger Syndrome in Monozygotic Twins

Two teenaged monozygotic twin sisters with Axenfeld-Rieger syndrome (ARS) were referred to our center for uncontrolled glaucoma from the local hospital in December 2006. At presentation, typical components of ARS could be found in both patients, including iris anomaly, maxillary hypoplasia, hypodontia, and umbilical skin fold. Both sisters received trabeculectomy in both the eyes later in our center. Intraocular pressure was well controlled in both the eyes in both patients 1 year after the surgeries. No mutations were found by direct sequencing of PITX2 and FOXC1 genes, in the twin sisters. As far as we know, no earlier report has described monozygotic twins with ARS in the international literature.