Monozygotic Twin Sisters Research Articles

A BRCA2 mutation carrier diagnosed with breast cancer using ultrasonography during surveillance after genetic testing following the discovery of breast cancer in her identical twin sister

A <I>BRCA2</I> mutation carrier diagnosed with breast cancer using ultrasonography during surveillance after genetic testing following the discovery of breast cancer in her identical twin sister

Changes in differential gene expression during a fatal stroke

We present a young woman (with an identical twin sister) who arrived at the Emergency Department (ED) within 1hour of her initial stroke symptoms. Previous microarray studies have demonstrated differential expression of multiple genes between stroke patients and healthy controls. However, for many of these studies there is a significant delay between the initial symptoms and collection of blood samples, potentially leaving the important early activators/regulators of the inflammatory response unrecognised. Blood samples were collected from the patient for an analysis of differential gene expression over time during the evolution of a fatal stroke. The time points for blood collection were ED arrival (T0) and 1, 3 and 24hours post ED arrival (T1, T3 and T24). This was compared to her identical twin and an additional two age and sex-matched healthy controls. When compared to the controls, the patient had 12 mRNA that were significantly upregulated at T0, and no downregulated mRNA (with a cut off fold change value ±1.5). Of the 12 upregulated mRNA at T0, granzyme B demonstrated the most marked upregulation on arrival, with expression steadily declining over time, whereas S100 calcium-binding protein A12 (S100A12) gene expression increased from T0 to T24, remaining >two-fold above that in the healthy controls at T24. Other genes, such as matrix metalloproteinase 9, high mobility group box 2 and interleukin-18 receptor I were not upregulated at T0, but they demonstrated clear upregulation from T1–T3, with gene expression declining by T24. A greater understanding of the underlying immunopathological mechanisms that are involved during the evolution of ischaemic stroke may help to distinguish between patients with stroke and stroke mimics.

A Case of Concordant Twins with Infant ALL and Discordant Clinical Outcome – Part I: the genetic basis – identification of DSC2 as a gene with prognostic impact in infant MLL-rearranged ALL

Infant acute lymphoblastic leukemia (ALL) is associated with an unfavorable prognosis due to a high proportion of early relapses. We report on a pair of monozygotic twin sisters diagnosed with ALL (MLL-ENL fusion) in early infancy. Despite good initial treatment responses in both twins, one sister developed very early relapse (Twin A) and succumbed to the disease. The other sister went into continuous complete remission (Twin B) and is alive after 9 years. We performed exome sequencing experiments to identify additional diverging mutations in the twins that may be connected to the different clinical outcomes. Results obtained were further complemented by sequencing analyses of xenografted twin leukemias from different disease time points providing insights into clonal evolution in this twin model of infant leukemia. Apart from an overall paucity of mutations, genetic alterations predicted to be relevant were detected only in leukemic cells of the survivor, Twin B. In particular, we show evidence for a heterozygous desmocollin 2 (DSC2) mutation which is absent in Twin A. Notably, high gene expression of DSC2 in a cohort of infant ALL patients harboring MLL-ENL and MLL-AF9 fusions conferred a poor prognosis characterized by a significantly increased relapse rate. Our data suggest that high levels of DSC2 expression in residual cells may be a pathogenic mechanism in relapsing infant ALL.

Identical Twins, Matching Symptoms: Hypersensitivity Pneumonitis

PRESENTATION Shortness of breath was first attributed to the patient’s extensive history of cardiac ills, but a detailed environmental history pointed to the true source. A 58-year-old Caucasian woman presented with a 12-month history of dyspnea, nonproductive cough, and wheezing. She had been born with Ebstein’s anomaly, for which she had undergone tricuspid valve replacement with a prosthetic valve and repair of a coexisting atrial septal defect. In addition, she had an implanted pacemaker for complete heart block. Her cardiologist was considering biventricular pacing as an intervention for her dyspnea and requested a pulmonary evaluation before proceeding. The patient, who was married and a nurse, had an unremarkable pulmonary history. None of her medications posed a risk for lung toxicity. She never smoked, drank alcohol, or used illicit drugs. An identical twin sister, who lived in Texas, had similar pulmonary complaints and a presumptive diagnosis of pulmonary fibrosis. The sister’s medical records were brought to the consultation due to concern for a genetic predisposition for this progressive lung disease.

Nur Fiona Önen Albring

Nur Fiona Onen Albring was born in Izmir, Turkey, with her identical twin sister on 17 December 1975. They were the much loved daughters of a Scottish mother and Turkish...

Post-operative Streptococcus pneumoniae meningoencephalitis complicating surgery for acromegaly in an identical twin

This case report provides provocative and useful data regarding two aspects of acromegaly and its management. The patient, who is one of a pair of identical twins, has no known hereditary, genetic or otherwise potentially etiologic factors as compared to her unaffected sister. Secondly, transsphenoidal surgery, which was ultimately successful, was complicated by pneumococcal meningitis, an unusual event with only four previously reported patients, three of whom ended in death or major neurologic deficits. In this case, a 57-year-old woman gradually developed classical signs and symptoms of acromegaly while her identical twin sister remained normal with no evidence of endocrine disease. Endoscopic transsphenoidal surgery was complicated by the development of meningitis 25days after surgery. This was controlled following a difficult hospital course. Streptococcus pneumoniae meningoencephalitis is a rare but life-threatening complication of transsphenoidal surgery. A high index of suspicion for incipient meningitis should be maintained when patients present with severe headache and increased intracranial pressure, even if they initially lack the typical symptoms and signs. Immediate and aggressive treatment is necessary to avoid significant neurologic deficit.

Aging and systemic hormonal status affects the circulating miR-21, miR-146a and FasL levels

MicroRNAs are small molecules, found in all cell types and body fluids, which most commonly affect negatively to gene expressions by translational repression. Their role in various physiological conditions and diseases has been emphasized during the last twenty years. In our recent studies with postmenopausal monozygotic twin sisters (n=11), we have investigated how different systemic hormonal status affects the levels of specific circulating microRNAs and other molecules related to inflammation and apoptosis, both processes associated with aging. Our results have shown that the systemic levels of miR-21, miR-146a and Fas ligand are lower within the postmenopausal women who are using estrogen-based hormonal replacement (HRT), compared to their non-using co-twins (p=0.018, p=0.039, p=0.021, respectively). To strengthen the aging effect, we also measured the same markers from the premenopausal control women (n=8), with natural hormonal status, and found out that the inflammatory profile was healthier among the young women and that the serum miR-21 profile was more similar with the HRT users than non-users, and miR-146 and FasL profile more similar to non-users. These findings demonstrate that HRT has effects on the circulating inflammation related regulatory molecules. Whether we can state that the effects are clearly positive or negative, needs further investigations and understanding of the regulatory system.

Fresh and cryopreserved ovary transplantation and resting follicle recruitment

Ovary cryopreservation and transplantation has garnered increasing interest as a possible method to preserve fertility for cancer patients and to study ovarian resting follicle recruitment. Eleven consecutive women underwent fresh donor ovary transplantation, and 11 underwent cryopreserved ovary auto-transplantation in the same centre, with the same surgeon. Of the 11 fresh transplant recipients, who were all young but menopausal, nine women had normal ovarian cortex transplanted from an identical twin sister, and two had a fresh allograft from a non-identical sister. In the second group, 11 women with cancer had ovarian tissue cryopreserved before bone marrow transplant, and then after years of therapeutically induced menopause, underwent cryopreserved ovarian cortex autotransplantation. Recovery of ovarian function and follicle recruitment was assessed in all 22 recipients, and the potential for pregnancy was further investigated in 19 (11 fresh and 8 cryopreserved) with over 1-year follow-up. In all recipients, normal FSH levels and menstruation returned by about 150 days, and anti-Müllerian hormone reached much greater than normal concentrations by about 170 days. Anti-Müllerian hormone levels then fell below normal by about 240 days and remained at that lower level. Seventeen babies have been born to these 11 fresh and eight cryopreserved ovary transplant recipients.

Intramuscular sex steroid hormones are associated with skeletal muscle strength and power in women with different hormonal status.

Estrogen (E2)-responsive peripheral tissues, such as skeletal muscle, may suffer from hormone deficiency after menopause potentially contributing to the aging of muscle. However, recently E2 was shown to be synthesized by muscle and its systemic and intramuscular hormone levels are unequal. The objective of the study was to examine the association between intramuscular steroid hormones and muscle characteristics in premenopausal women (n = 8) and in postmenopausal monozygotic twin sister pairs (n = 16 co-twins from eight pairs) discordant for the use of E2-based hormone replacement. Isometric skeletal muscle strength was assessed by measuring knee extension strength. Explosive lower body muscle power was assessed as vertical jump height. Due to sequential nature of enzymatic conversion of biologically inactive dehydroepiandrosterone (DHEA) to testosterone (T) and subsequently to E2 or dihydrotestosterone (DHT), separate linear regression models were used to estimate the association of each hormone with muscle characteristics. Intramuscular E2, T, DHT, and DHEA proved to be significant, independent predictors of strength and power explaining 59–64% of the variation in knee extension strength and 80–83% of the variation of vertical jumping height in women (P < 0.005 for all models). The models were adjusted for age, systemic E2, and total body fat mass. The statistics used took into account the lack of statistical independence of twin sisters. Furthermore, muscle cells were shown to take up and actively synthesize hormones. Present study suggests intramuscular sex steroids to associate with strength and power regulation in female muscle providing novel insight to the field of muscle aging.

Sea of Shadows: Age of Legends by K. Armstrong

Armstrong, Kelley. Sea of Shadows: Age of Legends. Toronto: Doubleday Canada, 2014. Print.This Young Adult fantasy novel tells the story of identical twin sisters Moria and Ashyn. In this mythical world, twin girls are special, because they can sometimes communicate with spirits. This means that when they are babies, twins are submitted to a ritual to see if they are destined to become Keeper and Seeker – magical roles that require the girls to quiet the souls of the damned, and protect the rest of the empire. Bond beasts accompany the twins – a giant wildcat for the Keeper, and a giant hound for the Seeker.Moria and Ashyn live in the village of Edgewood by the Forest of the Dead. Moria is a fiery warrior with a penchant for telling scary stories, and Ashyn is a shy romantic who often doubts herself, although both sisters are very close. The Wastes separate the Forest of the Dead, where criminals are often exiled from the rest of the empire. Every year, during the ritual of the Seeking, the Seeker and her hound must find all the restless spirits of the dead in the Forest, and quiet their souls. Often the dead are exiled criminals or are angry because they were not granted justice in life. The imperial court’s Keeper and Seeker have trained Moria and Ashyn for this ritual, and this is the first year they will perform the Seeking alone.During the Seeking, things quickly go wrong due to forces beyond the girls’ control. As a result, the girls’ village is destroyed, and their friends and family are killed by evil spirits. In the aftermath, Ashyn is separated from her sister. With the few remaining village survivors, Ashyn decides to set out with Ronan, a young thief she met in the Forest of the Dead. She hopes to take her people to safety. Moria follows her sister’s trail with the help of the last of the village guards, the stubborn Gavril, who is himself descended from sorcerers.Along the way, both sisters face mythical beasts, and discover their own strengths and weaknesses. They also deal with loss, and the harshness of a world beyond their village through encounters with bandits, kidnappers, and outcasts. Once the girls reunite, they learn that the failed ritual and the destruction of their village were not accidents. They are forced to warn the emperor and travel to court, where they must learn to navigate the politics of the realm. They also discover one of their companions may not be what he seems.This book is the first in a trilogy, although the journey of the two sisters is a complete story. The novel is told through the viewpoints of both sisters. Many deaths occur, and there are several violent scenes. The story also features creatures from horror stories that might frighten younger readers. Overall, it is a story well suited to young adult audiences, featuring interesting characters and mythology.Recommended: 3 out of 4 starsReviewer: Colette LeungColette Leung is a graduate student at the University of Alberta, working in the fields of Library and Information science and Humanities Computing who loves reading, cats, and tea. Her research interests focus around how digital tools can be used to explore fields such as literature, language, and history in new and innovative ways.

Analyses of a Pair of Concordant Twins with Infant ALL and Discordant Clinical Outcome Reveals Immunoescape As a Mechanism of Disease Persistence in MLL-Rearranged Leukemia

MLL-fusion is the most common genetic abnormality in acute lymphoblastic leukemia (ALL) of infancy and occurs in approximately 80% of the cases. Infant ALL represents a biologically distinctive entity with a highly immature pro-B immunophenotype associated with a particularly unfavorable prognosis due to a high proportion of early relapses. This may be due to the survival of dormant residual disease protected by the bone marrow niche.We have characterized a pair of monozygotic twin sisters diagnosed with ALL in early infancy. Tumor cells from both children carried the t(11;19) translocation (MLL-ENL fusion) and both patients were treated according to the ALL-BFM 2000 protocol. Despite good initial treatment responses in both twins, one sister developed very early relapse (twin A) and succumbed to the disease. The other went into continuous complete remission (twin B) and, as of today, is alive after 9 years. The clinical data of the 2 patients are presented in Table 1.Diagnostic bone marrow (BM) aspirates of both sisters were injected into the femoral bones of NOD SCID gamma (NSG) mice. Survival of xenografted mice bearing twin A was significantly longer due to a lower proliferative capacity of twin A as compared to twin B cells. In vivo Bromodeoxyuridine (BrdU) assays revealed that twin B cells were proliferating equally fast in BM and spleen, while in twin A cells, the BM markedly suppressed entry into S-phase. Flow cytometry from xenograft BM identified a large CD34+ population in twin A cells that was almost absent in twin B cells. Furthermore, BM of twin A xenografts showed a CD34+/CD38-/CD19- stem cell like population undetectable in twin B animals. Most interestingly, injection of minimal residual disease (MRD) negative remission bone marrow (PCR for Ig-gene rearrangements and the MLL-fusion gene) of both sisters into NSG mice resulted in a full-blown xenograft leukemia in animals bearing twin A but not twin B. Taken together, these data suggest that fatal relapse in twin A may be due to a quiescent stem cell like population kept in check by unknown mechanisms.Next, we performed gene expression analyses on xenografted leukemias from twin A (initial, leukemia amplified from remission BM, relapse) and from twin B (initial). STRING analysis of gene expression differences revealed that, amongst other findings related to cell cycle regulation and DNA-repair, twin A cells downregulated genes indicating a reduced interferon pathway activity (CXCL10, IFI30, TRAIL, STAT1, OAS1, MX1) and several genes connected to TYRO protein kinase binding protein (TYROBP) shown previously to regulate the activity of natural killer (NK) cells. This suggests that twin A cells may evade immunosurveillance as a mechanism of disease persistence. 51Chromium-release assays with IL-2 stimulated allogeneic NK cells from two healthy donors and the xenografted twin cells showed that twin A cells were significantly less sensitive to NK cell mediated lysis as compared to twin B cells. Whether the tumor cells also display differential susceptibility to antibody-dependent cell-mediated cytotoxicity is currently investigated.While the extensive genomic characterization of the twin leukemias is under way, we show evidence from xenograft experiments, gene expression profiles and functional in vitro experiments that dormant residual cells in MLL-rearranged ALL can evade immunosurveillance. These findings serve as a rationale to employ immunotherapeutic approaches in infant ALL patients in order to improve their dismal prognosis. Finally, we report the first monozygotic twin pair with MLL-rearranged ALL and discordant clinical outcomes. This provides a unique opportunity and a model to gain insight into the clonal composition of infant leukemia and the origins of leukemia relapse.Table 1:Patient characteristics of the MLL-ENL positive twin pair. WBC, white blood cells; BM, bone marrow; CNS, central nervous system; MRD, minimal residual disease.ParameterTwin ATwin BAge at diagnosis (days)98147WBC (initial)/µl334.000103.000Blasts (Peripheral Blood) %9791Blasts (BM) %9897CNS involvementNot determinedNegativeImmunophenotypePro-BPro-BCytogeneticst(11;19)t(11;19)Prednisone-ResponsePoorGoodBlasts (BM), day 15 %321MRD day 33NegativeNegativeMRD day 78Negative<10-4 *Event-free survival227 days>9 yearsTime to relapse227 daysn/aOverall survival390 days>9 years*low positive, not quantifiable DisclosuresNo relevant conflicts of interest to declare.

Abstract 17378: Familial Spontaneous Coronary Artery Dissection - Evidence for Genetic Susceptibility

Background: Spontaneous coronary artery dissection (SCAD) typically presents as acute coronary syndrome in young women with no cardiovascular risk factors. It is associated with high morbidity and mortality, and is underdiagnosed. Despite this, risk factors and pathophysiology associated with SCAD are not completely understood. The objective of the present case series was to assess family history as a risk factor in patients with SCAD. Methods: We reviewed the medical records and questionnaires of 335 participants in the Mayo Clinic SCAD Registry for history of MI, SCAD or CAD in another family member. Coronary angiograms of all affected family members were reviewed by a senior interventional cardiologist. Results: We identified 4 familial cases of SCAD comprised of affected mother-daughter, identical twin sister, sister and aunt-niece pairs, implicating both recessive and dominant modes of inheritance. The mother-daughter pair also reported history of fatal MI in 3 maternal relatives including grandmother, great grandmother and great aunt. One of the affected twin sisters died of SCAD, which was confirmed on autopsy. None of the subjects had other potential risk factors for SCAD including extreme exercise, polycystic kidney disease, connective tissue disorder, peripartum status or diagnosed non-coronary fibromuscular dysplasia. The details of their demographics, risk factors, presentation, location of SCAD and management are presented in the table. Conclusions: This series is the first to identify a familial association in SCAD suggesting a genetic predisposition. Recognition of SCAD as a heritable disorder has implications for at-risk family members and furthers our understanding of the pathophysiology of this complex disease. Whole exome sequencing in these families provides a unique opportunity to identify the molecular underpinnings of SCAD susceptibility.

SYMPTOMS OF MITOCHONDRIAL DISEASE FALLING ON DEAF EARS

<h3>Case report</h3> Mitochondrial diseases show a broad phenotypic spectrum and are underdiagnosed. We present a 37-year-old woman referred to our neurology clinic after an incidental finding of bilateral caudate, lentiform and pulvinar calcification during workup for cochlear implant surgery. She was born at 30 weeks9 gestation with her identical twin sister and was found to have progressive sensorineural hearing loss from eight years of age. She had had no seizures, ataxia, weakness, psychosis or involuntary movements. Her mother had diabetes mellitus. On examination, she was areflexic but otherwise normal. Neurophysiology showed a mild sensory neuropathy. Mitochondrial gene testing showed heteroplasmy for m.3243A&gt;G mutation. <h3>Discussion</h3> Our patient was seen by a number of different specialists for her deafness and the possibility of mitochondrial diseases was never explored. Pathogenic mitochondrial gene mutations are present in up to 0.5% of the general population. The m.3243A&gt;G mutation is associated with deafness and diabetes mellitus. Neurologists see it in MELAS syndrome. Radiologically, it is associated with basal ganglia calcification. Reaching a diagnosis allows the patient and family to understand their illness and prognosis, to undergo predictive testing if wished and to undergo screening for other affected organ systems.

Papillary Thyroid Cancer in Identical Adolescent Twins with Osteogenesis Imperfecta and Hashimoto's Thyroiditis: Is There a Genetic Link?

The relationship between Hashimoto's thyroiditis (HT) and papillary thyroid cancer (PTC) remains controversial. Researchers have identified multiple genes that could put patients with HT at risk for PTC. None are related to osteogenesis imperfecta (OI). We present identical twin sisters with OI who developed PTC in the setting HT.

Neuropathic pain in two-generation twins carrying the sodium channel Nav1.7 functional variant R1150W

We present clinical, neuropathological, and molecular genetic findings of a family with a new pain phenotype of the sodium channel gene SCN9A polymorphism R1150W. A 46-year-old woman presented with a 5-year history of episodic temperature- and exercise-dependent burning pain of the feet and lower legs associated with numbness of the distal upper and lower limbs. Her monozygotic twin sister and their mother and her twin presented similar symptoms. Clinical evaluation was normal except for a mild distal sensory deficit in fingers and feet. Electrophysiological testing was unremarkable, as were serum and cerebrospinal fluid laboratory findings. Skin biopsies of the distal lower limbs revealed an epidermal nerve fiber density at the lower limit of normal. Myelinated dermal nerve fibers showed elongated nodes of Ranvier, but normal distribution of nodal and paranodal proteins. Genetic testing for ion channel-associated pain disorders revealed an amino acid R1150W substitution of the Nav1.7 sodium channel. The combination of a Nav1.7 polymorphism with dysmyelinating features in small-caliber peripheral nerves has not been described before and may suggest an explanation for the clinical syndrome in our patients. Treatment with the sodium channel blocker lamotrigine provided some relief, consistent with a role of sodium channel dysfunction in the pain syndrome of this family.

Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs.

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen’s causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes’ IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.

FRI0354 Effects of Carbamylation and Citrullination of B and T Epitopes of Human Type II Collagen on Lymphocytes from Dr4+ Monozygotic Twins Discordant for Rheumatoid Arthritis

BackgroundRheumatoid arthritis (RA) susceptibility is linked to HLA DR4 and DR1. T cells in RA recognize the DR4/DR1-restricted epitope 261-273 of the human type II collagen, whereas B cells recognize...

Case of rudimentary meningocele in identical twin sisters

Case of rudimentary meningocele in identical twin sisters

Anti-N-Methyl-Aspartate Receptor Encephalitis in Identical Twin Sisters

Anti-N-methyl-aspartate receptor encephalitis is a potentially fatal form of encephalitis and frequently associated with ovarian teratomas. Surgical removal of ovarian teratomas improves clinical outcome, but it is unclear whether bilateral salpingo-oophorectomy for normal-appearing ovaries is of clinical benefit. Our report describes a unique clinical scenario of identical twin sisters with anti-N-methyl-aspartate receptor encephalitis. Neither patient responded to immunosuppressive therapy. Imaging studies showed normal-appearing ovaries. The first twin continued on medical therapy only and died of the disease. The second twin underwent a bilateral salpingo-oophorectomy followed by gradual recovery. Based on our experience in two genetically identical individuals, we suggest considering the removal of normal-appearing ovaries in patients with anti-N-methyl-aspartate receptor encephalitis who fail to respond to medical treatment.

Atlantoaxial instability in monozygotic twin sisters: degenerative or congenital disease?

The authors report on two 70-year-old monozygotic twin sisters who both suffered severe nontraumatic atlantoaxial instability. If either had been a solitary case, degenerative atlantoaxial instability would have been the most straightforward diagnosis. In this case report the authors attempt to answer the question of whether an underlying congenital predisposition might be involved.