Monozygotic Twin Brothers Research Articles

Evaluation of transitional changes of sub-gingival bacterial species in twins with gingival fibromatosis

Gingival fibromatosis is a condition of uncommon gingival overgrowth, with hereditary causes regarded to be associated with the most common form. The condition is generally non-inflammatory, though secondary gingival inflammation occurs in some cases due to formation of anaerobic spaces between gingiva and teeth. We present a case of identical twin brothers aged 11 years 9 months who came to our clinic with complaints of gingival esthetic problems. They were both diagnosed with hereditary gingival fibromatosis and gingivectomies were performed. At 14 years 11 months of age, they returned with gingival swelling, though the inflammation and corresponding conditions were significantly different from those seen at the first visit, as the older twin showed severe gingival inflammation, while the younger had moderate inflammation. A microbiological analysis was carried out using a PCR technique, which specifically identified Porphyromonas gingivalis , Treponema denticola , and Tannerella forsythensis in plaque samples taken from sites of severe inflammation in both patients. The numbers of periodontitis-related species decreased as gingival conditions improved with treatment, including removal of calculus and tooth brushing instruction, and microbiological findings were correlated with clinical conditions. Our findings show that monitoring of periodontitis-related bacterial species is beneficial for evaluating the effects of periodontal treatment with a scientific basis.

TINF2, a Component of the Shelterin Telomere Protection Complex, Is Mutated in Dyskeratosis Congenita.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the triad of abnormal nails, lacey reticular skin pigmentation, and oral leukoplakia. Patients with DC are at high risk of developing aplastic anemia, myelodysplastic syndrome and leukemia. Diagnosis of DC is challenging due to variability of the triad and heterogeneous clinical findings such as pulmonary and liver disease, avascular necrosis, esophageal or urethral stenosis and development delay. The unifying feature in DC is exceedingly short telomere lengths and defects in telomere biology. Gene mutations have been identified in DKC1 (X-linked), TERC and TERT (dominant, AD) and NOP10 (recessive), but approximately 60% of DC patients lack a known mutation. We identified a non-consanguineous family with AD DC and no mutations in DKCI, TERC or TERT. The first DC cases were monozygotic twin brothers (now deceased). Telomere length was determined by flow-FISH on the twins' children (6 affected, 4 unaffected), wives, their 8 siblings and parents. Despite variable clinical phenotypes, the 6 affected individuals (1 female, 5 male) all had very short telomere lengths (<1st%ile for age). Unaffected relatives had normal telomere lengths. A single nucleotide polymorphism (SNP) genome-wide linkage screen (Human Linkage IVb, Illumina, Inc) was conducted using telomere length <1st%ile as the affected phenotype. SNPLINK was used to remove SNPs in linkage disequilibrium (D′=0.7, R2=0.4). Data were analyzed with GeneHunter under a parametric, AD, rare, highly-penetrant disease model. Evidence favoring linkage was found in a 17 megabase (Mb) region on chromosome 2p and a 3.1 Mb region on chromosome14q (LOD score=2.62 at both sites). Bi-directional sequence analysis of the two best candidate genes, DDX1 (2p) and TINF2 (14q) was conducted to identify mutations. A novel mutation, K280E, in TINF2 (protein name TIN2) was identified in the 6 living, affected family members but not in the 8 unaffected relatives, suggesting inheritance from the affected fathers. There were no mutations in DDX1. TINF2 was sequenced in 8 additional, unrelated DC probands without DKCI, TERC or TERT mutations and 7 with known mutations. An R282H mutation was present in 3 unrelated DC probands (1 Hoyeraal-Hreidarsson, 1 Revesz Syndrome). Another DC patient had an R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC or TERT, or 298 controls. The mutation prevalence in DC probands represented in our cohort of patients with DC are DKC1 (18.8%), TERC (18.8%), TERT (6.2%), and TINF2 (31.2%). As a component of shelterin, the protein complex that stabilizes telomeres, TIN2 is highly evolutionarily conserved. It serves as a bridge between the three primary telomere DNA-binding proteins, TRF1, TRF2 and POT1 (via TPP1). In silico analyses predict that K280E, R282H and R282S are deleterious mutations. Functional studies are underway to characterize possible effects of these mutations on shelterin protein interactions. By focusing on telomere length as the affected phenotype, instead of the heterogeneous clinical features present in DC patients, we identified mutations in TINF2 and further validated telomere length as a diagnostic test for DC. This study demonstrates that TINF2 is the 5th gene mutated in DC, the 1st in Revesz Syndrome, and the 1st shelterin complex gene mutated in human disease.

Agency in Adaptation

Agency in Adaptation

Coronary Flow Characteristics of Multiple Coronary Artery-Left Ventricular Microfistulae in Young Monozygotic Twins

Coronary artery multiple fistulae of the left ventricular chamber are extremely rare congenital malformations. We report on 13-year-old monozygotic twin brothers who have identical abnormalities of coronary flow reserve as well as the same morphological findings of multiple coronary fistulae of the 3 major coronary arteries to the left ventricular chamber. The left circumflex coronary artery (LCX) had abundant fine communications with the left ventricular chamber and had a higher flow rate than the left anterior-descending coronary artery. The coronary flow reserve obtained from the LCX was lower than the normal value matched for the same age group. The increased shunt flow resulted in enlargement of the left ventricular chamber. This is the first report of coronary flow characteristics in children with multiple coronary fistulae.

David Graham Lloyd. 20 June 1937 — 30 May 2007

David Graham Lloyd was born on 20 June 1937 at Manaia, Taranaki, New Zealand, slightly ahead of his identical twin brother, Peter. The births caused surprise to the family because twins were not expected. His father was a dairy farmer, and David's early years were immersed in country life and helping on the farm. David's mother died of cancer when he was eight years old and his father brought up the twins, as well as his elder siblings, Judith and Trevor, with the help of their grandparents, who farmed next door. Although the death of their mother was a sad loss, David seems to have had a happy childhood and to have excelled at primary school before moving to boarding school with Peter in 1950. At New Plymouth Boys High School, David was most interested in the sciences and also in sports, for which the school was well known. Although relatively small in stature, he played in the first team at rugby, was a tenacious tackler, and also excelled at sprinting and long jump.

Hyperbaric oxygen therapy of angiopathic changes in patients with inherited gene imbalance

Phenotype match inherited by genes is in most cases present in monozygotic twins. Their phenotypic resemblance is unfortunately characterized by strong susceptibility for the development of chronic non-infectious diseases. One of the most common non-infectious chronic diseases that are phenotipically represented in twins is diabetes mellitus. Genetic imbalance is, in most cases, placed in 2, 3, 7, 8, 11, 12, 19 and 20 chromosomal pair of the human genome. This study describes a pair of monozygotic twins, aged 54, who were diagnosed for diabetes type 2 ten years earlier. The first patient had trophic changes of muscles and skin tissues of the lower limb, and a necrotic wound on his right leg tibial region with the claudication distance of 50 m. After arteriography, he was referred by a vascular surgeon for hyperbaric oxygen therapy (HBO). HBO protocol implied 70 min. application of 100% oxygen at 2.5 absolute atmospheres. After the first series of HBO therapies consisting of 20 HBO treatments, claudication was eliminated and the necrotic wound healed. Next, surgical aortofemoral bypass was done. During the second HBO treatment, his monozygotic twin brother presented with angiopathic changes due to diabetes. In both patients, biochemical parameters corresponded to the expected level for diabetes type 2 imbalance, and the localization of the chromosomal defect (placed on 3, 11 and 19 chromosomal pair) was also in accordance with the respective disorder. After they were included into next 10 HBO treatments, Doppler imaging of the major arteries of limbs revealed normal findings. Identical genetic impairment in monozygotic twins can lead to identical somatic changes with resultant consequences. HBO treatment of such patients associated with other therapeutic procedures (conducted by diabetologist, vascular surgeon and physiatrist) can postpone or prevent irreversible changes occurring due to blood vessel disorders.

Symptomatic Charcot?Marie-Tooth? A pair of concordant monozygotic twins

A pair of monozygotic twin brothers were referred due to hereditary peripheral neuropathy resembling late onset Charcot-Marie-Tooth (CMT). Diagnostic classification of the twin pair. Clinical, neurological, genetical and neurophysiological examination, and molecular genetic testing. The clinic and neurophysiology was compatible with CMT disease with late onset. Molecular genetic analysis excluded mutations in PMP22, connexin32, MPZ, LITAF and MFNZ genes, as well as duplication and deletion of PMP22. The twins were employed in PVC production and developed symptoms after 14 years of massive exposure. We think that the heavy exposure to various neurotoxic compounds caused symptoms that mimic late-onset CMT. However, the twins had distal dysesthesia which is unusual in inherited neuropathies. This illustrates the importance of an occupational history even in the molecular genetic era.

Genetic and Environmental Correlates of Semen Quality

The influences of environmental factors on the male reproductive system have been much debated over the last 3 decades. We studied the impact of genes and environment on semen quality, sex hormone levels, and sperm chromatin stability by using a twin design. The study population consisted of monozygotic and dizygotic twins from the population-based Danish Twin Registry and a random selection of pairs of singleton brothers from the Danish Civil Registration System. All men were 20 to 45 years of age. The study population comprised 100 monozygotic twin brothers (50 pairs), 102 dizygotic twins (51 pairs), and 102 single-born brothers (51 pairs). A semen sample and blood sample were collected from all participants. Heritability was estimated to account for 20% (95% confidence interval = 0% to 68%) of the variation in sperm density. A higher heritability was found for the hormones reflecting Sertoli cell function (inhibin B, 76% [36% to 84%] and follicle-stimulating hormone, 81% [40% to 88%]) and for percent morphologic normal cells (41% [0% to 60%] and sperm chromatin parameters (mean alphaT, 68% [34% to 81%] and COMP alphaT, 72% [25% to 82%], respectively). Our study indicates a substantial hereditary component in plasma levels of hormones reflecting Sertoli cell function and in sperm cell chromatin stability and morphology. The environmental contribution (including the prenatal environment) appeared to be largest for sperm count.

Anophthalmia‐esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes

The clinical combination of anophthalmia/microphthalmia and esophageal atresia was first recognized in 1988 as a distinct variable multi-system malformation syndrome and since then at least 17 cases of the disease have been described, all of them sporadic in occurrence. We report a heterozygous SOX2 gene mutation underlying the syndrome of anophthalmia/microphthalmia-esophageal atresia and demonstrate that this entity can be associated to considerable clinical variability as shown by the discordant ocular phenotype observed in monozygotic twin brothers carrying an SOX2 deletion. This is the first report describing a strikingly discordant eye phenotype in monozygotic twins with the condition, with one of our patients being the first reported individual carrying an SOX2 lesion associated with unilateral eye defect. We discuss the probable sources for this remarkable phenotypic heterogeneity of the anophthalmia/microphthalmia syndrome in individuals with an identical genetic constitution.

TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions

Monozygotic twin brothers with a subtelomeric 6q deletion presented with mental retardation, microcephaly, seizures, an enlarged cisterna magna, dimpling at elbows, a high arched palate and a thin upper lip. The same subtelomeric deletion was detected in the mother of the patients, presenting with a milder phenotype. We narrowed down the breakpoint to a region of approximately 100 kb and estimated the size of the terminal deletion to be 1.2 Mb. This region contains four known and seven putative genes. Comparison of the deletion with other reported patients showed TBP was the most plausible candidate gene for the mental retardation in this syndrome. We verified that the TBP gene expression was halved in our patients using real-time PCR. Cognitive and behavioural tests performed on previously described heterozygous tbp mice suggested that TBP is potentially involved in cognitive development.

Successful identical-twin living donor small bowel transplant for necrotizing enterovasculitis secondary to Churg-Strauss syndrome

Churg-Strauss syndrome (CSS) is a granulomatous small-vessel vasculitis with unknown etiology. Extra-pulmonary manifestations of CSS are currently treated with a combination of steroids and Cyclophosphamide. Its gastrointestinal complications may be devastating, occasionally requiring extensive bowel resection resulting in short-gut syndrome. Living-related small bowel transplantation (LRSBTx) is a relatively standardized procedure that, not only represents a valid alternative to cadaver bowel transplant in selected cases, but also portraits excellent results when performed in experienced centers. The availability of an identical twin as a donor, which allows avoidance of immunosuppressive therapy, is a major indication for this procedure. We present the case of a young individual affected by gastrointestinal necrotizing vasculitis that lost almost his entire small bowel requiring the immediate institution of total parenteral nutrition (TPN). However, within few weeks a significant hepatic dysfunction ensued. An identical twin-brother, not affected with CSS, became an immediate, optimal donor-candidate for LRSBTx, the first of this kind in a patient affected with CSS. Following the procedure, two main concerns were addressed: the recipient's ability to recover a regular intestinal function without immunosuppression and the possible recurrence of the primary disease. Twenty-seven months post-transplant, the patient enjoys a regular lifestyle without any clinical, endoscopic and histologic evidences of recurrent disease in the transplanted graft.

Transplantation at 100 Years: Alexis Carrel, Pioneer Surgeon

n December 23, 1954, Ronald Herrick became the first ealthy human being to subject himself to a major urgical procedure for the benefit of someone other than imself. He was the donor of a kidney to his identical win brother, Richard, who was dying of end-stage renal isease. His brother’s donated kidney allowed Richard to urvive for another 8 years [1]. The surgeon, Dr Joseph urray of the Peter Brigham Hospital in Boston, had one extensive preliminary experimental work and coninued to be a leader not only in clinical transplantation, ut also in the study of the immune phenomena surounding transplantation. Dr Murray, along with E. Donall Thomas, was awarded the Nobel Prize in Physiology r Medicine in 1990, “for their discoveries concerning rgan and cell transplantation in the treatment of human isease” [2]. Last year, the semi-centennial anniversary of the proedure was widely celebrated as the beginning of clinical rgan transplantation. Although the 1954 procedure aunched clinical transplantation, the science of organ ransplantation actually began a half-century earlier. The ear 2005 marks the centennial anniversary of Alexis arrel’s publication of his first article on successful organ ransplantation in October 1905 [3]. The critical technical prerequisite for successful translantation surgery was the development of techniques or suturing blood vessels. Such methods had not been eveloped yet in 1894 when the president of France, Sadi arnot, was assassinated in Lyon. Carnot was stabbed in he abdomen and bled to death from a laceration of the ortal vein. Surgical opinion held that the president ould not have been saved because of the nature of his njury. A young medical student at the University of yon, Alexis Carrel, argued to the contrary that Carnot ould have been saved if surgeons could repair blood essels as they repaired other tissues. In 1896, Carrel was n intern at Lyon’s Hotel Dieu, and he was aware that atthieu Jaboulay at the University of Lyon had successully repaired a divided carotid artery experimentally, sing everting interrupted mattress sutures. However, is method did not work in the repair of small blood essels. In that year, Carrel started his own experiments, nd before long his work gained local notoriety. He ecognized that extremely fine needles and thread were eeded, and he found what he needed, but not in surgical

Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability

Background: Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder with hypersensitivity to ionising radiation. The clinical phenotype is characterised by congenital microcephaly, mild dysmorphic facial appearance, growth...

Insights into the Structure and Regulation of Glucokinase from a Novel Mutation (V62M), Which Causes Maturity-onset Diabetes of the Young

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mM). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val62 has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of beta-cells and hepatocytes.

Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder characterized by the absence of ganglion cells in the nerve plexuses of the lower digestive tract, resulting in intestinal obstruction in neonates. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. In this study, we collected genomic DNA samples from 55 HSCR patients in central Taiwan and analyzed the coding regions of the RET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, an A to G transition was detected in two (identical twin brothers). The mutation was at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site for the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, 11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were detected. The differences between patients and controls in allele distribution of the five RET polymorphic sites were statistically significant. The most frequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with the highest percentage of heterozygotes) was AA/GG in patients, which was different from the AG/GT in the normal controls. Transmission disequilibrium was observed in exons 2, 7, and 13, indicating nonrandom association of the susceptibility alleles with the disease in the patients. This study represents the first comprehensive genetic analysis of HSCR disease in Taiwan.

Discordant phenotypic expression of Alport syndrome in monozygotic twins

Alport syndrome is a genetically heterogeneous disorder, but most patients showed the X-linked form resulting from mutations in the COL4A5 gene. A few cases of mosaicism in Alport syndrome have been reported. We describe the case of an 8-year-old boy with mosaicism in Alport syndrome. Punch skin biopsies were obtained from the patient's mother and monozygotic twin brother. Five biopsy specimens from non-Alport patients were used as controls. Immunohistochemical analysis was performed using rat monoclonal antibodies towards individual collagen IV(NC) domains. Kidney tissue of the patient showed: mosaic expression of alpha3(IV), alpha4(IV) and alpha5(IV) in the glomerular basement membrane (GBM), distal tubular basement membrane (TBM) and Bowman's capsule; mosaic alpha6(IV) expression in the Bowman's capsule and distal TBM; and well-preserved expression of alpha1(IV) and alpha2(IV). The patient's skin exhibited mosaic alpha5(IV) expression. His mother and monozygotic twin brother disclosed a normal linear staining of alpha5(IV) in their epidermal basement membranes. This unusual mosaicism of alpha3(IV), alpha4(IV), alpha5(IV) and alpha6(IV) is consistent with a pattern of female heterozygotes of Alport syndrome. This discordant phenotypic expression of Alport syndrome in monozygotic twins with unaffected parents suggests possible somatic mosaicism in the COL4A5 gene.

Cardiac transplantation in twins with autosomal dominant Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder resulting in progressive muscle weakness, contractures, and cardiomyopathy. We report successful cardiac transplantation in identical twin brothers with autosomal dominant EDMD, complicated by ventricular arrhythmias and end-stage cardiomyopathy. Early recognition of progressive cardiac disease and subsequent cardiac transplantation are lifesaving in children with EDMD.

Gémellité, traumatismes, vulnérabilité et résilience : approche comparative

This article has the aim to study resilience in a specific context (twins) with an original methodology to compare the productions of monozygotic twin brothers, which had to face traumatic environmental conditions. We have used interview procedure and projective methodology (Rorschach Test, Tales’ test). Results show that resiliency and vulnerability are associated with different external conditions (especially maternal libidinal investment in spite of her pathology) and intrapsychic differences (related to quality of mentalization).

Monozygotic twin sisters suffering from cluster headache and migraine without aura

In general, cluster headache (CH) is considered a sporadic disease. However, epidemiologic studies and twin case reports point to an increased familial risk of CH.1 Five sets of monozygotic twin brothers suffering from CH have been reported so far. This is the first report on affected monozygotic twin sisters suffering from CH and additionally from migraine without aura. The first-born, 38-year-old twin suffers from episodic CH since aged 24 years. The attacks, which are of excruciating intensity, are located behind the left eye, radiating to the left ear and the left mandible. They are usually accompanied by conjunctival injection and lacrimation. Attacks occur twice or thrice every night, often with clockwise regularity, and last 30 to 45 minutes. To alleviate the pain, the twin paces. Episodes last 4 to 6 weeks and have occurred every 3 years so far. Results of neurologic examination and brain imaging (cMRT) …

A Case Report of Cutis Laxa in One of Identical Twins

A 29-year-old man with cutis laxa presented requesting surgery to improve his appearance. The patient had an unaffected identical twin brother which allowed us to compare how he had changed over the years in relation to his sibling and this also provided us with a gold standard for any surgery performed. The patient underwent staged surgery including upper lid blepharoplasties and two facelifts.