The Value of Twins for Health and Medical Research: A Third of a Century of Progress.

In 1984, Hrubec and Robinette published what was arguably the first review of the role of twins in medical research. The authors acknowledged a growing distinction between two categories of twin studies: those aimed at assessing genetic contributions to disease and those aimed at assessing environmental contributions while controlling for genetic variation. They concluded with a brief section on recently founded twin registries that had begun to provide unprecedented access to twins for medical research. Here we offer an overview of the twin research that, in our estimation, best represents the field has progress since 1984. We start by summarizing what we know about twinning. We then focus on the value of twin study designs to differentiate between genetic and environmental influences on health and on emerging applications of twins in multiple areas of medical research. We finish by describing how twin registries and networks are accelerating twin research worldwide.

Management of congenital midline nasofrontal dermoid cysts in two identical twins: Case report.

Midline dermoid cysts are uncommon lesions that can lead to severe complications when an intracranial extension exists. We report the cases of two twin sisters referred to surgery for removal of the masses and the intracranial extension. They represent an additional example of familial nasal dermoid cysts, providing further support for a genetic basis for the disorder.

Acardiac twinning: High resolution three-dimensional reconstruction of a low resistance case.

BACKGROUND: Acardiac twinning is a rare anomaly of monochorionic twin pregnancies. Acardiac fetuses lack a functional heart but are passively perfused by arterial blood from their pump co-twin. Although four acardiac morphological types have been classified, the various paths of anatomical and circulatory acardiac twin development, and the potential influence of acardiac size and perfusion flow as possible predictors of pump twin morbidity and mortality are poorly understood. This report presents the first high resolution three-dimensional reconstruction of the vasculature of an acardiac twin by cryomicrotome imaging. CASE: A small, approximately 7.5-cm-diameter ball-shaped acardius amorphous of 30 5/7 weeks had caused pump twin cardiac decompensation that necessitated an emergency cesarian section. The pump twin survived well. The acardiac body had a partially intact vascular system with large diameter arteries and veins and multiple zones that appeared devoid of perfusion. The three-dimensional reconstruction showed neither recognizable organ structures nor identifiable blood vessels except for the umbilical artery and vein. CONCLUSION: Our case showed a small acardiac mass with large diameter vessels and consequential low outflow resistance that caused pump twin complications. This indicates that the development of a method that allows pump twin prognosis is likely more successful if based on the use of acardiac versus pump twin perfusion flows than on body volume ratios.

Premature newborns with fatal intrauterine herpes simplex virus-1 infection: first report of twins and review of the literature.

BACKGROUND: Neonates with blistering skin diseases are dermatologic emergencies. The pathologies involved can pose diagnostic difficulties and there exists a variety of potential life-threatening differential diagnoses. OBJECTIVE: description of the first case of intrauterine acquired herpes simplex virus (HSV) 1 infection in twins. METHODS: We present the case of two premature bicordial biamniotic twins (27th week of gestation) whose intrauterine growth retardation, fetal anaemia and cardiotocography abnormalities led to a caesarean emergency delivery. RESULTS: Accurate medical history revealed a maternal febrile gingivostomatitis at the 23rd week of gestation, which was neglected by the treating gynaecologist. Respiratory distress was present at delivery and intubation was necessary in both children. The whole skin showed extensive erosions and ulcerations and the mucosa of the eyes and genitals was also involved. Intrauterine Herpes simplex virus (HSV) 1 infection was confirmed by immunohistochemistry of skin Tzanck smear (HSV 1 positive, HSV 2 negative), real-time polymerase chain reaction of both serum and skin (HSV 1 positive; HSV 2 negative) and maternal serology positive for HSV 1 IgM and IgG. Siblings were immediately treated with high-dose endovenous acyclovir. Anaemia thrombocytopenia and hepatorenal values markedly deteriorated and both developed consequential hepatorenal failure. The third day live supportive measures were terminated after parental informed consent and both siblings deceased shortly after on their mother's breast. DISCUSSION: Intrauterine HSV infection is rare and accounts only for 5% of neonatal HSV infections. Literature reports only 64 cases and 90% of those are related to HSV-2. Transplacental viral transmission is highest during the first 20 weeks of gestation and has been observed in pregnant women with disseminated HSV infection. Mortality and morbidity of intrauterine herpetic infection are extremely high. CONCLUSION: Despite transplacental HSV transmission remains a rare event, the potential devastating outcome justifies immediate adequate antiviral treatment in a pregnant woman affected by primary HSV infection.

Increased prevalence of congenital heart defects in monozygotic and dizygotic twins.

BACKGROUND: Smaller studies and many case series reports indicate that congenital heart defects may be more common in monochorionic twins than in dichorionic twins and singletons. METHODS AND RESULTS: We investigated congenital heart defect occurrence in all twins and 5% of all singletons born in Denmark in 1977-2001 and followed through 2006 by linking the Danish Twin Registry and Statistics Denmark registers including the National Medical Birth Register and the Danish National Patient Register. Among 41 525 twin individuals, a total of 584 twins (1.4%) had a congenital heart defect registered in the Danish National Patient Register, whereas the corresponding numbers for singletons were 648 of 74 473 (0.87%; P<0.001; ie, a 63% [95% confidence interval, 45-82%] increased risk for congenital heart defect for twins). Patent ductus arteriosus and coarctation of aorta occurred >3 times as often in twins as in singletons, at 3.9 (95% confidence interval, 2.6-5.8) and 3.1 (95% confidence interval, 1.5-6.4), respectively. The increased occurrence in twins was also found in sensitivity analyses including only inpatients or only surgically treated cases regardless of whether preterm patent ductus arteriosus was included. We were not able to demonstrate a higher risk for congenital heart defect among monozygotic twins compared with dizygotic twins, and the congenital heart defect occurrence was also increased in dizygotic twins, who are all dichorionic. CONCLUSIONS: Congenital heart defect is more common in twins than in singletons, and the increased occurrence is not restricted to monochorionic twins. Intrauterine surveillance and a postnatal comprehensive cardiac assessment for both twins may be considered regardless of chorionicity and zygosity.

Discordant expression of a new WT1 gene mutation in a family with monozygotic twins presenting with congenital nephrotic syndrome.

Congenital nephrotic syndrome (CNS) is a heterogeneous group of diseases with different causes and prognoses. Two thirds of cases of NS in the first year of life are caused by mutations in four genes (NPHS1, NPHS2, WT1, and LAMB2). The mutation of WT1 gene can lead to Denys-Drash syndrome (DDS). We report on female monozygotic twins with CNS presenting at 7 and 8 weeks of age with anuric renal failure. Both twins were treated by peritoneal dialysis. Renal biopsy proved diffuse mesangial sclerosis. Genetic analysis detected a new heterozygote WT1 mutation R434P in both twins. One child developed a unilateral nephroblastoma. Both twins died because of complications of CNS (sepsis and extensive thrombosis of central venous system/sepsis and sudden heart failure) at ages 23 weeks/13.5 months, respectively. DNA analysis showed the same WT1 mutation in the father, who showed at his age of 41 years no clinical consequences of this mutation and no signs of DDS. In conclusion, we report the third family with monozygotic twins with DDS due to WT1 mutation. The DDS has very rapidly led to end-stage renal failure and death in both twins which is in striking contrast to the manifestation in their father.

Identical twins with lethal congenital pulmonary airway malformation type 0 (acinar dysplasia): further evidence of familial tendency.

We report a case of identical twins with lethal congenital pulmonary airway malformation (CPAM) type 0. Twin A expired several hours after birth, and twin B was sustained by extra-corporeal membrane oxygenation (ECMO) support; however, care was withdrawn from twin B following the autopsy of twin A, which revealed a diagnosis of CPAM type 0. Both twins showed pulmonary hypoplasia, histologically consistent with CPAM type 0 and pulmonary hypertension. Furthermore, the family also had a previous male who presented with pulmonary hypoplasia and respiratory failure and died shortly after birth; however, no autopsy was performed to confirm a diagnosis of CPAM. Here, in discussing our case, as well as previously reported cases, we demonstrate CPAM type 0's high prevalence among females (9:1 ratio). From the reported cases, it appears that CPAM type 0's tendency to recur in families is up to 40%, suggesting an autosomal recessive inheritance pattern. However, the actual tendency of familial recurrence is hard to assess due to the rarity of the disease and the potential lack of reporting CPAM type 0 cases. To our knowledge, our report represents the first description of CPAM type 0 in identical twins.

Twin pregnancies complicated by a single malformed fetus: chorionicity, outcome and management.

The objective of this study was to evaluate the impact of one abnormal fetus in a twin pregnancy, to compare impact of chorionicity and clinical outcome of intervention and expectant management. Thirty-seven dichorionic (DC) twins and 18 monochorionic (MC) twins complicated with one malformed fetus were evaluated for gestational age, birthweight and perinatal outcome. Six hundred and forty-two twin pregnancies were evaluated in the database. The control groups consisted of 429 DC and 86 MC twins without anomalous fetus. Mean birthweight and gestational age at birth for DC control group were (n = 429; 2137g and 34.71 weeks), DC study group, n = 37; 2117g (p = .338) and 33.97 weeks (p = .311), and DC study group with major malformations, n = 30; 2019g (p = .289) and 33.3 weeks (p = .01), and showed only significance for gestational age. There was no statistical significance between MC control group, n = 86; 2097g and 34.93 weeks, and MC study group, n = 18; 2237g (p = .338), and 34.42 weeks (p = .502). Because of limited data, the preliminary evaluation for expectant management and intervention, and survival of at least one normal fetus showed no impact. We conclude that, although, all DC twin pregnancies have a risk for preterm delivery, DC twins complicated with major malformation of one twin, have a lower mean gestational age at birth. Preliminary results for intervention does not improve fetal outcome for DC and MC twins and needs further evaluation with greater studies of impact or review.

MFM/geneticist view on prenatal management of twins.

Twin pregnancies are associated with an increase in both fetal and maternal morbidity and mortality. Health care supervision is complex, increasingly requiring care from maternal-fetal medicine specialists. This review discusses optimal twin prenatal management, which includes recognizing increased twin pregnancy risks specific to twin-types; counseling families regarding fetal complications, ranging from prematurity to cerebral palsy; screening for aneuploidy and open neural tube defects; specific twin guidelines for diagnostic testing, including chorionic villus sampling and amniocentesis; and monitoring for maternal complications.

Twin-reversed arterial perfusion sequence: pre- and postoperative cardiovascular findings in the 'pump' twin.

OBJECTIVES: To assess cardiovascular findings in twin-reversed arterial perfusion (TRAP) sequence pre- and post-therapy and compare these findings to traditional obstetric markers, defined as acardius to pump twin weight ratio and presence of polyhydramnios. METHODS: This was a retrospective review of 27 cases of TRAP sequence diagnosed between 2004 and 2008. Echocardiographic data included indexed cardiac output and functional and anatomic parameters. Ultrasound reports were reviewed for acardius to pump twin weight ratio and polyhydramnios. We assessed the relationship between cardiac output and the remaining cardiac/obstetric variables obtained pre- and post-treatment. RESULTS: Twenty-three subjects had complete echocardiographic data sets at initial evaluation (mean gestational age, 20.4 +/- 2.5 weeks) and, of these, post-treatment echocardiographic evaluation was available in 10. Six of seven (86%) pump twins with elevated indexed cardiac output had significant cardiovascular compromise. Most fetuses with abnormal cardiac output or right ventricular dysfunction normalized post-therapy. There was no relationship between cardiac output and obstetric markers. CONCLUSIONS: Elevated indexed cardiac output is strongly associated with cardiovascular compromise. Traditional obstetric prognosticators do not correlate with cardiovascular derangements. In pump twins with cardiac compromise, postoperative cardiovascular status improves acutely. Given this analysis, we conclude that assessment of cardiovascular findings should be incorporated into the management and treatment of TRAP sequence.

Acute osteomyelitis of the iliac bone presenting with gluteal syndrome in a newborn.

Acute osteomyelitis in neonates, although rare, represents a diagnostic and therapeutic challenge. We herein report an extremely rare case of congenital nonsyphilitic iliac bone osteomyelitis caused by methicilline-sensitive Staphylococcus aureus and presenting with gluteal syndrome in a near-term infant. To our knowledge, this represents the second report with iliac osteomyelitis and the first report with gluteal syndrome in neonatal period. A high index of suspicion is necessary to make an early diagnosis. Early diagnosis is essential to prevent catastrophic sequelae in such cases. We report this case because of its unusual clinical presentation and rarity.

Precalcaneal congenital fibrolipomatous hamartoma.

Precalcaneal congenital fibrolipomatous hamartoma (PCFH) is a condition that is seldom reported in the paediatric literature and rarely in the dermatological literature. It has other disparate and confusing names and as histology is rarely obtained, the condition may be under-reported. We describe this disorder in the male twin of a pair of nonidentical twins.

A classic twin study of lower urinary tract obstruction: Report of 3 cases and literature review.

OBJECTIVE: The aim of the present study was to investigate genetic effects in the formation of congenital lower urinary tract obstruction (LUTO) comprising posterior urethral valves (PUV), urethral atresia, and urethras with variable degrees of stenosis. METHODS: A classic twin study was performed by assessing LUTO twin pairs from the literature. Furthermore, data regarding 3 previously unreported twin pairs with PUV from University of Bonn, Essen and Wroclaws own in-house databases were added. Both pair- and probandwise concordance rates were calculated and compared for monozygotic (MZ) and dizygotic (DZ) twin pairs. RESULTS: The pairwise concordance rates for all LUTO were 53% (95% confidence interval [CI] 32%-73%) and 17% (95% CI 3%-56%) for MZ and DZ twin pairs, respectively (P = .180). The probandwise concordance rates were 69% (95% CI 51%-83%) and 29% (CI 95% 8%-64%) for MZ and DZ twin pairs respectively (P = .084). The MZ/DZ ratios of the pair- and probandwise concordance rates were 3.1 and 2.4, respectively. CONCLUSION: The present study did not show significant differences in comparisons of concordance rates of MZ and DZ twin pairs, probably due to the small number of twin pairs reported. However, the more than 2-fold higher pair- and probandwise concordance rates for MZ versus DZ twin pairs are very suggestive of a contribution of genetic factors to the development of LUTO.

Discordant immune complete heart block and growth restriction in dichorionic twin pregnancy with permanent pacemaker implantation of an 1140 g neonate.

Fetal atrioventricular block is a rare pathology, mostly due to placental transmission of maternal SSA/Ro and SSB/La antibodies, and can lead to severe fetal or neonatal outcomes. We report a case of dichorionic, diamniotic twin pregnancy, with maternal SSA/Ro antibodies. Isolated complete atrioventricular block was diagnosed at 23 weeks in one fetus (Twin A), while the second fetus (Twin B) remained in normal sinus rhythm. Severe asymmetric intrauterine growth restriction occurred in Twin A. Delivery was by caesarean section at 32 + 2 weeks. Neonatal permanent pacemaker was inserted on the first day after birth in 1140 g neonate. Discordant heart block in twin pregnancy has already been reported in a few dichorionic pregnancies, but the pathway of discordant disease expression remains unclear. Extraction decision is a dilemma between cardiac failure prevention and prematurity associated twin morbidity. This case shows a successful pacing in a very low birth weight neonate.

Discordant prenatal phenotype and karyotype of monozygotic twins characterized by the unequal distribution of two cell lines investigated by different methods: a review.

We present the case of a monozygotic twin pregnancy discordant for phenotype and karyotype. A chorionic villus sample was performed at the 11th week of gestation in a primigravida because of cystic hygroma detected by ultrasound in one twin of a monochorionic, biamniotic pregnancy. Rapid testing by means of quantitative fluorescence polymerase chain reaction and conventional karyotyping, obtained by both short- and long-term culture, revealed a homogeneous monosomy X (45,X). Amniocentesis was performed separately for both twins before termination and showed an homogeneous monosomy X in one sample and a 46,X,del(X)(p11.1) karyotype in the other one. Postmortem fetal tissues culture confirmed the discordant karyotype between the two embryos. Placental samples obtained after termination revealed the cell line which was not detected at chorionic villus sampling. Based on this and previous reports, we suggest that in cases of a phenotypic discordance detected at ultrasound in the first trimester, it is advisable to perform a karyotype analysis on amniocytes because it better reflects fetal constitution rather than chorionic villi or lymphocytes in case of heterokaryotipic monosomy X monochorionic twins.

[Periorbital, blue tumour in newborn twins]. / Periorbitale, blauwe zwelling bij pasgeboren tweeling.

Newborn twins both had a blue, smooth tumour in the inner angle of the orbit; one of them had two such tumours. They were diagnosed with congenital dacryocystoceles. If decompression into the nose is not effective, patients should undergo probing early in life to reduce the incidence of dacryocystitis and orbital cellulitis.

Congenital tuberculosis after in vitro fertilization: suggestion for tuberculosis tests in infertile women in developing countries.

Congenital tuberculosis (CTB) after in vitro fertilization (IVF) is a major new problem in developing countries. Only 16 cases of CTB after IVF have been reported, and no tuberculosis (TB) tests were performed before IVF in these cases. However, on the basis of data in the literature and from the World Health Organization, the incidence of CTB has been substantially underestimated. We describe two cases of CTB after IVF in detail in our center and provide new insight into the important issue of controlling TB vertical transmission in developing countries. Performing an early diagnosis of CTB, mostly based on evidence of maternal infection and a high index of clinical suspicion, is a challenge. However, most mothers have no symptoms of TB infection during prepartum, and infertility may be the only symptom. Infertility caused by genital TB is common in countries with a high TB burden, and IVF is considered to be an effective treatment to improve their fertility. Therefore, this may lead to more CTB cases without thorough TB tests before IVF. We suggest that thorough TB tests should be conducted in infertile women before IVF to prevent CTB.

Poor oral intake in a late preterm twin - usual symptom with an unusual diagnosis.

BACKGROUND: At three weeks of age, a previous 34 weeks' gestation male infant (twin A) was transferred to our regional perinatal center (RPC) with complaints of poor oral feeding and intermittent tachypnea. Twin B was discharged at 37 weeks with an uneventful course. CASE: Twin A briefly required respiratory support but continued to have difficulty transitioning from gavage to oral feeding. Initially, his inability to feed orally was thought to be secondary to nasal congestion and prematurity, but with worsening respiratory distress he was transferred for further evaluation and management. DIAGNOSIS & CONCLUSION: On admission to RPC, the examination prompted a cardiac assessment which revealed a large aortic-pulmonary window type II. After surgery, the infant quickly improved and went home on-demand oral feeds. Cardiac lesions are more common in monochorionic twins but should be suspected in dichorionic twins especially if one twin has a normal course.

Dizygotic twins with congenital malalignment of the great toenails: reappraisal of the pathogenesis.

Congenital malalignment of the great toenails (CMGTN) is a heritable disorder, in which the longitudinal axis of the nail plate is not parallel to the corresponding axis of the distal phalanx of the hallux, but laterally deviated. We describe a pair of 1(1/2)-month-old dizygotic twins with laterally deviated nail plates of the great toenails since birth. By the time the infants were 10 months of age, significant realignment was observed. Adult pedigree members also showed slight similar deviations of the nail plates. We suggest that desynchronization of growth between the nail and the adherent end-phalanx of the hallux may result in temporarily larger nail plates, which are gliding outwards, in order to fit into the underlying bony space. During postnatal life, spontaneous realignment is usually observed, probably as a result of a faster growing end-phalanx.