Fetus with multiple congenital anomaly syndrome caused by novel variant in ATP1A2.

We report a 32-year-old G3P1 at 35 weeks 3 days with a dichorionic, diamniotic twin gestation who presented for evaluation secondary to ventriculomegaly (VM) in one twin. Fetal ultrasound and MRI demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture, indicative of a prior insult in the affected twin. The co-twin was grossly normal. The family pursued a palliative care pathway for the affected twin and was delivered at 37 weeks and 6 days. The affected twin passed away within the first hour of life due to respiratory compromise. Postmortem trio exome sequencing identified a homozygous likely pathogenic variant in ATP1A2 (c.2439+1G>A). Although this variant is novel, it is predicted to affect the donor split site in intron 17, resulting in a frameshift and complete loss-of-function of the gene. Biallelic loss of function variants in this gene have been reported in seven individuals with multiple anomalies similar to those in the affected twin. However, only one other individual with a possible CDH has been previously reported. Our case suggests that CDH be included in the phenotypic spectrum of this disorder and reports the first frameshift mutation causing this autosomal recessive multiple congenital anomaly syndrome.

Complex Craniosynostosis in Pitt-Hopkins Syndrome: Case Report in Twins.

INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a rare genetic syndrome associated with neurodevelopmental disorders and craniofacial dysmorphisms caused by variations in the TCF4 transition factor. The aim of this article was to report the case of two twin infants diagnosed with PTHS, confirmed by the identification of a heterozygous pathogenic variant in the TCF4 gene through DNA extracted from a buccal swab. CASE PRESENTATION: Both infants presented with craniofacial asymmetry with a metopic crest and cranial deformity. During the diagnostic investigation, computed tomography with three-dimensional reconstruction of the skull showed premature fusion of the left coronal and metopic sutures in both twins. They underwent craniofacial reconstruction at the 9th month of age using a combination of techniques. The postoperative outcomes were satisfactory in both cases. CONCLUSION: To the best of our knowledge, this is the first case report to describe the occurrence of complex craniosynostosis (CCS) in children with PTHS. Further studies are needed to determine whether the co-occurrence of PTHS and CCS described here indicates an association or is explained by chance.

Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males.

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Episodic memory and cortical amyloid pathology: PET study in cognitively discordant twin pairs.

We studied the association between episodic memory and cortical fibrillar ß-amyloid pathology within twin pairs. Using telephone-administered cognitive screening of 1415 twin pairs in a population-based older Finnish Twin Cohort study, we identified 45 (mean [SD] age 72.9 [4.0] years, 40% women) cognitively discordant same-sex twin pairs (24 dizygotic and 21 monozygotic) without neurological or psychiatric disorders other than AD or mild cognitive impairment. In-person neuropsychological testing was conducted. Cortical amyloid was measured with carbon 11-labelled Pittsburgh compound B ([11C]PiB) positron emission tomography imaging and quantified as the average standardized uptake value ratio in cortical regions affected in AD. Larger within-twin pair differences in verbal immediate (r = -0.42) and delayed free recall (r = -0.41), and visual delayed free recall (r = -0.46) were associated with larger within-twin pair differences in [11C]PiB uptake (p's < 0.01). Correlations were not significantly different in dizygotic and monozygotic pairs suggesting that the episodic memory-cortical amyloid relationship is not confounded by genetic effects. However, larger samples are needed to draw more definitive conclusions.

Minimally invasive therapy for the resolution of a subcapsular hepatic hematoma in a newborn. / Terapia mínimamente invasiva para el manejo de un hematoma subcapsular hepático en un recién nacido.

OBJECTIVE: To describe an innovative alternative to exploratory laparotomy in a newborn with a sub capsular hepatic hematoma secondary to umbilical vein catheterization. CLINICAL CASE: A preterm baby with a history of hyaline membrane disease, pulmonary hypertension, and large patent ductus arteriosus, requiring mechanical ventilation and the use of vasoactive drugs. Umbilical catheters were inserted and through an abdomen X-ray, we observed their proper position. The patient evolved with greater requirements of vasoactive drugs, abdominal wall pallor, and abdominal distention. Abdominal ultrasound showed a subcapsular hepatic hematoma, with no signs of active bleeding, so expectant management was decided. The patient required increased vasoactive drugs and presented a decrease in hematocrit. New ultrasound showed a larger subcapsular hematoma, abundant perihe patic fluid, and the intraparenchymal position of the umbilical catheter was confirmed. Endovascular embolization was performed through the umbilical catheter with Gelita®, achieving occlusion of the capsular path. Posterior ultrasound showed a reduction of the hematoma. CONCLUSIONS: The use of embolization through angiography is not commonly used in pediatric emergencies. It is a procedure with fewer comorbidities and complications than exploratory laparotomy, therefore it should be considered as first-line therapy in patients like the one presented above. The limitation for its routine performance is the lack of available angiography operating room and trained interventional radio logy team.

Excessive Prenatal Supplementation of Iodine and Fetal Goiter: Report of Two Cases Using Three-dimensional Ultrasound and Magnetic Resonance Imaging.

Fetal thyroid complications in pregnancy are uncommon, and are commonly related to the passage of substances through the placenta. The excessive iodine intake during the pregnancy is a well-known mechanism of fetal thyroid enlargement or goiter, and invasive procedures have been proposed for the treatment of fetal thyroid pathologies. In the present report, we demonstrate two cases from different centers of prenatal diagnosis of fetal thyroid enlargement and/or goiter in three fetuses (one pair of twins, wherein both fetuses were affected, and one singleton pregnancy). The anamnesis revealed the ingestion of iodine by the patients, prescribed from inadequate vitamin supplementation. In both cases, the cessation of iodine supplement intake resulted in a marked reduction of the volume of the fetal thyroid glands, demonstrating that conservative treatment may be an option in those cases. Also, clinicians must be aware that patients may be exposed to harmful dosages or substances during pregnancy.

As complicações fetais da tireoide na gravidez são incomuns e são comumente relacionadas à passagem de substâncias pela placenta. A ingestão excessiva de iodo durante a gravidez é um mecanismo bem conhecido de aumento da tireoide ou bócio fetal, e procedimentos invasivos foram propostos para o tratamento de patologias da tireoide fetal. No presente relato de caso, demonstramos dois casos de diferentes centros de diagnóstico pré-natal de aumento da tireoide fetal e/ou bócio em três fetos (um par de gêmeos, em que ambos os fetos foram afetados, e uma gravidez única). A anamnese revelou a ingestão de iodo pelos pacientes prescrita por suplementação inadequada de vitaminas. Nos dois casos, a interrupção da ingestão de suplemento de iodo resultou em uma redução acentuada do volume das glândulas tireoides fetais, demonstrando que o tratamento conservador pode ser uma opção nestes casos. Além disso, os médicos devem estar cientes de que as pacientes podem ser expostas a doses ou substâncias nocivas durante a gravidez.

Association between intrauterine growth restriction and patent ductus arteriosus: Use of a dichorionic twin pregnancy model.

OBJECTIVE: To evaluate the association between intrauterine growth restriction (IUGR) and the incidence of fetuses with patent ductus arteriosus (PDA) and Hemodynamically significant PDA (Hs-PDA) in dichorionic twins (DC) with selective IUGR. MATERIALS AND METHODS: This is an observational cohort study and retrospective case assessment, involved twins born at Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan between 2013 and 2018. DC twins with selective IUGR (sIUGR) were defined as the presence of a birth weight discordance of >25% and a smaller twin with a birth weight below the tenth percentile. PDA was diagnosed using echocardiography between postnatal day 3 and 7. Hs-PDA was defined as PDA plus increased pulmonary circulation, poor systemic perfusion, cardiomegaly, pulmonary edema, or hypotension requiring pharmacotherapeutic intervention. RESULT: A total of 1187 twins were delivered during the study period, and 53 DC twins with selective IUGR were included in this study. DC twins with PDA have higher rate of preterm birth, lower gestational age of delivery, and lower mean birth weight of both twins compared with DC twins without PDA. In a comparison of the sIUGR twin with the appropriate for gestational age co-twin, both the incidences of PDA (28.30% vs. 7.55%, respectively; P = 0.003) and Hs-PDA (24.53% vs. 5.66%, respectively; P = 0.002) were higher in sIUGR fetuses than in the appropriate for gestational age co-twins. Small gestational age of delivery was the only variable to predict PDA and Hs-PDA [p = 0.002, Odds ratio = 0.57 (0.39-0.82), p = 0.009, Odds ratio = 0.71 (0.55-0.92), respectively]. CONCLUSION: An analysis of dichorionic twins with sIUGR indicated that IUGR increased the risk of PDA and hemodynamically significant PDA.

Imaging diagnosis and legal implications of brain injury in survivors following single intrauterine fetal demise from monochorionic twins - a review of the literature.

Brain injury of the surviving twin from monochorionic pregnancies following intrauterine fetal demise during the second and third trimesters is a rare but severe complication. Monochorionicity and gestational age at the time of stillbirth seem to be decisive factors in terms of long-term neurologic outcome prediction for the survivor. Magnetic resonance imaging (MRI), diffusion weighted imaging (DWI) in particular, seem to bring the earliest and most accurate diagnosis. Ultrasound detection of brain damage is possible in later stages of fetal brain injury. It is essential to provide early diagnosis and multidisciplinary counsel to the parents to ensure informed decision making. For couples who choose to terminate pregnancy legislation related to late abortion might lead to further distress. Our paper aims to stress the importance of MRI DWI in the evaluation of surviving twins following single intrauterine fetal demise in monochorionic pregnancies and the delicate context of the medical professionals and parents facing this clinical situation, sometimes complicated by legal constraints.

Excessive prenatal supplementation of iodine and fetal goiter: report of two cases using three-dimensional ultrasound and magnetic resonance imaging / Suplementação pré-natal excessiva de iodo e bócio fetal: Relato de dois casos utilizando ultrassonografia tridimensional e ressonância magnética

Abstract Fetal thyroid complications in pregnancy are uncommon, and are commonly related to the passage of substances through the placenta. The excessive iodine intake during the pregnancy is a well-known mechanism of fetal thyroid enlargement or goiter, and invasive procedures have been proposed for the treatment of fetal thyroid pathologies. In the present report, we demonstrate two cases from different centers of prenatal diagnosis of fetal thyroid enlargement and/or goiter in three fetuses (one pair of twins, wherein both fetuses were affected, and one singleton pregnancy). The anamnesis revealed the ingestion of iodine by the patients, prescribed from inadequate vitamin supplementation. In both cases, the cessation of iodine supplement intake resulted in a marked reduction of the volume of the fetal thyroid glands, demonstrating that conservative treatmentmay be an option in those cases. Also, clinicians must be aware that patients may be exposed to harmful dosages or substances during pregnancy.

Resumo As complicações fetais da tireoide na gravidez são incomuns e são comumente relacionadas à passagem de substâncias pela placenta. A ingestão excessiva de iodo durante a gravidez é um mecanismo bem conhecido de aumento da tireoide ou bócio fetal, e procedimentos invasivos foram propostos para o tratamento de patologias da tireoide fetal. No presente relato de caso, demonstramos dois casos de diferentes centros de diagnóstico pré-natal de aumento da tireoide fetal e/ou bócio em três fetos (um par de gêmeos, em que ambos os fetos foram afetados, e uma gravidez única). A anamnese revelou a ingestão de iodo pelos pacientes prescrita por suplementação inadequada de vitaminas. Nos dois casos, a interrupção da ingestão de suplemento de iodo resultou em uma redução acentuada do volume das glândulas tireoides fetais, demonstrando que o tratamento conservador pode ser uma opção nestes casos. Além disso, os médicos devem estar cientes de que as pacientes podem ser expostas a doses ou substâncias nocivas durante a gravidez.

Presentación inusual de teratomas ováricos bilaterales en gemelas / Bilateral ovarian mature teratomas in twins: an unsual presentation

RESUMEN Los teratomas maduros son los tumores ováricos más frecuentes en edad pediátrica. A la fecha, se han descrito escasos reportes sobre su aparición en gemelas. Se presenta el caso de teratomas ováricos bilaterales en gemelas bicoriales, tratadas con tumorectomía laparoscópica. A los 45 días post-operatorios, ambas presentan recurrencia bilateral con marcadores tumorales negativos. Se realiza una nueva tumorectomía laparoscópica, cuyo estudio histopatológico confirma teratomas maduros. Presentan segunda recurrencia evidenciada en control imagenológico a los 2 meses post-quirúrgicos. Se plantea la posible asociación genética y/o familiar en la aparición de teratomas ováricos, la cual, hasta el momento, es prácticamente desconocida.

ABSTRACT Mature cystic teratomas are the most frequent ovarian tumor in children. There are few reports describing mature teratoma in twins to date. We present a case of bicorial twins with bilateral ovaric mature cystic teratoma treated with laparoscopic tumorectomy. 45 days after surgery, both present bilateral recurrence with negative tumor markers. The patients underwent a new laparoscopic tumor resection, where histopathological diagnosis confirms mature teratomas. Ultrasound control describes second recurrence 2 months after surgery. There is a possible genetic and/or family association in the presentation of ovarian teratomas, which currently, is unknown.

Gran feto acardio: diagnóstico tardío de gestacion gemelar monocorial biamniótica complicada por secuencia TRAP: reporte de un caso y revisión de la literatura / Great acardiac fetus: late diagnosis of monochorionic diamniotic twin pregnancy complicated by sequence TRAP: case report and review of the literature

OBJETIVOS: reportar el caso de una paciente con gestación gemelar monocorial-biamniótica complicada por secuencia TRAP que dio lugar al nacimiento de un feto bomba de 1932 gramos sin malformaciones anatómicas y de un feto acardio anceps de 1800 gramos, y realizar una revisión sobre esta patología y la importancia de su diagnóstico y tratamiento precoces. MATERIALES Y MÉTODOS: se presenta el caso de un feto acardio en una gestante con embarazo sin control estricto en el Hospital San Pedro de Logroño en el año 2019, de interés por su diagnóstico tardío y elevado peso al nacimiento del feto acardio. Se realizó una búsqueda de la literatura en las bases de datos Medline vía PubMed, OVID, Embase y SciE-LO con las palabras clave DeCS y términos MeSH. Como criterios de inclusión se consideraron artículos tipo series y reportes de casos y artículos de revisión desde enero de 1950 hasta enero de 2020. RESULTADOS: la búsqueda incluyó 39 referencias bibliográficas sobre las que se repasaron las principales cuestiones teóricas a exponer. El peso del feto acardio de nuestro caso fue muy elevado sin provocar repercusión en el feto sano, en comparación con la bibliografía, lo que aporta singularidad al caso, siendo sólo equiparable la serie de casos de Brassard et al (1999), con pesos de los fetos acardio por encima de 1700 gramos y diferenciándose en 100 gramos del feto bomba. CONCLUSIONES: el feto acardio es una complicación infrecuente de embarazos gemelares monocoriales. Se requiere la presencia de anastomosis vasculares placentarias entre ambas circulaciones. El diagnóstico precoz es importante para disminuir la morbilidad y usar, en la medida de lo posible, técnicas terapéuticas no invasivas.

OBJECTIVES: to report the case of a patient with a monochorionic-biamniotic twin gestation complicated by TRAP sequence that gave rise to the birth of a pump fetus without anatomical malformations (1932 g) and an acardiac anceps fetus (1800 g), and to review this pathology and the importance of its early diagnosis and management. MATERIAL AND METHODS: the case of an acardiac fetus is presented in a pregnant woman without strict control at the Hospital San Pedro de Logroño in 2019, worthwhile because of its late diagnosis and high birth weight. A search of the literature was carried out in the Medline databases via PubMed, OVID, Embase and SciELO with the MeSH terms. As inclusion criteria, we considered series-type articles and case reports, cohorts and review articles from January 1950 to January 2020. RESULTS: 39 bibliographic references were included with the main theoretical questions to be reviewed. Our acardiac fetus weight was very high comparing with the bibiography and without causing repercussion in the healthy fetus, which contributes to the uniqueness of the case, only the series report by Brassard et al (1999) is comparable, with weights of the acardiac fetus above 1700 grams and differing by 100 grams from the pump fetus. CONCLUSIONS: the acardiac fetus is an infrequent complication of monochorionic twin pregnancies. The presence of placental vascular anastomoses between both circulations is required. Early diagnosis is important to decrease morbidity and to use, as far as possible, non-invasive therapeutic techniques.

Perinatal outcome of monochorionic diamniotic twin pregnancy complicated by selective intrauterine growth restriction according to umbilical artery Doppler flow pattern: single-center study using strict fetal surveillance protocol.

OBJECTIVE: To determine the perinatal outcome of monochorionic diamniotic (MCDA) twin pregnancies complicated by selective intrauterine growth restriction (sIUGR), which were classified according to the umbilical artery (UA) Doppler flow pattern of the IUGR twin. METHODS: This was a retrospective cohort study of all MCDA twin pregnancies diagnosed with sIUGR and managed at a single tertiary referral center between 2012 and 2018. Cases were classified according to the UA Doppler flow pattern of the IUGR twin as Type I (positive end-diastolic flow), Type II (persistently absent/reversed end-diastolic flow) or Type III (intermittently absent/reversed end-diastolic flow). Patients with Type-II or -III sIUGR were hospitalized at 26-28 weeks of gestation for increased fetal surveillance. Perinatal and immediate and long-term neurodevelopmental outcomes were stratified according to the UA Doppler flow pattern at the final examination. Intact survival rate was defined as the number of infants surviving without neurological impairment, divided by the total number of fetuses. Composite adverse outcome, defined as any mortality, presence of severe brain lesions on postnatal transcranial ultrasound or severe neurological morbidity, was also assessed. RESULTS: Of 88 MCDA twin pregnancies with sIUGR included in the study, 28 underwent selective termination by cord occlusion using radiofrequency ablation, resulting in a perinatal survival rate of 89.3% and a median gestational age (GA) at delivery of 33.8 (interquartile range (IQR), 28.8-38.2) weeks for the large cotwin. Expectant management was employed in 60 cases. In 26 (43.3%) cases in the expectant-management group, the classification according to the UA Doppler flow pattern changed during gestation, resulting in 26 (43.3%) cases of Type-I, 22 (36.7%) cases of Type-II and 12 (20.0%) cases of Type-III sIUGR at the final examination. The perinatal survival rate of both twins with sIUGR Types I, II and III at the final examination was 100%, 81.8% and 75.0%, respectively (P = 0.04). Two cases of double fetal death and one case of single fetal death occurred 1-4 weeks after the Doppler pattern had changed from Type I or Type II to Type III. The median GA at delivery was 34.8 (IQR, 33.1-35.7) weeks in Type I, 30.3 (IQR, 28.6-32.1) weeks in Type II and 32.0 (IQR, 31.3-32.6) weeks in Type III (P < 0.01). The total intact survival rate was 100% for Type I, 77.3% for Type II and 75.0% for Type III (P < 0.001). Multivariate analysis demonstrated that early GA at diagnosis (odds ratio (OR), 0.83 (95% CI, 0.69-0.99); P = 0.04) and the presence of Type II or III vs Type I at the last examination (OR, 13.16 (95% CI, 1.53-113.32); P = 0.02) were associated with preterm birth < 32 weeks' gestation. Early GA at diagnosis was also associated with the composite adverse outcome (OR, 0.60 (95% CI, 0.36-0.99); P = 0.04). CONCLUSIONS: The classification system of MCDA pregnancy complicated by sIUGR, according to the UA Doppler flow pattern of the IUGR twin at final examination, is associated with perinatal outcome. Importantly, the UA Doppler flow pattern can change during gestation, which has an impact on the risk of fetal death. Nevertheless, under strict fetal surveillance, the perinatal outcome of these pregnancies is favorable. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Mirror-image phenomenon in Turkish monozygotic twins: A report of 3 cases.

Due to the special circumstances and the pre-natal environment in twin gestations, disruptions in the development of the embryo are more frequently observed in twin births as compared to singleton births. Twin research provides an excellent model to explore the etiology of disruptions in craniofacial biology. Mirror imaging (MI) is a special manifestation of twinning, and the elucidation of the etiology of this phenomenon is important to understand the biological mechanisms which underlie congenital defects, like orofacial clefts, and to provide insight into left-right asymmetry. The aim of this paper was, therefore, to present 3 pairs of Turkish monozygotic (MZ) twins with MI dental features, and to contribute to the knowledge of the MI phenomenon in the literature. We examined 2 male and 1 female MZ twin pairs clinically and radiographically in terms of their MI features. Mirrorimage features in dental and other ectodermal structures were detected in all the twins. Understanding the biological mechanisms of MI provides broad insight into preventive measures and treatment protocols. Furthermore, the presence of MI features may lead to the detection of other MI pathologies in twins.

Monozygotic twins with familial hypercholesterolemia and high lipoprotein(a) levels leading to identical cardiovascular outcomes: Case report and review of the literature.

Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal dominant disease that leads to premature cardiovascular disease (CVD). Since monozygotic twins share the intrauterine environment and have the same age and gene profile, they could represent a very special resource for the investigation of the causes and the natural course of FH. This report is a description of 36-year-old monozygotic twin brothers with almost identical early coronary artery involvement due to FH concomitant with high lipoprotein(a) (Lpa) levels and a review of the literature. Sequence analysis revealed that the twins were homozygous for the LDLR c.1060+10G>A (rs12710260) mutation and heterozygous for the LDLR c.542C>T (rs557344672) mutations. Both were also homozygous for the c.1060+7T>C (rs2738442) and c.1586+53A>G (rs1569372) mutations in the LDLR gene as well as c.4265A>T (rs568413) mutations in the APOB gene. In the literature, there are 7 twin cases with reported FH, but none with high Lpa levels. The HoFH twins in this case report had lower low-density lipoprotein (LDL) cholesterol levels than expected (before treatment 204 and 223 mg/dL), with almost identical coronary involvement. Both had an extremely high Lpa level (308 and 272 nmol/L) with a very low coronary calcium score (16 AU) and a good response to statins (>60%). There was a history of the first CVD event occurring at nearly the same age (32-34 years) in the family. This could be an important aspect of FH families as a result of the similar timing of cumulative LDL exposure exceeding the threshold of CVD events. In conclusion, this first report of monozygotic HoFH twins with elevated Lpa levels and almost identical early coronary artery involvement at the same age provides evidence to substantiate the hypothesis of lifetime cholesterol burden/exposure.

Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

Intrauterine growth discordance across gestation and birthweight discordance in dichorionic twins.

BACKGROUND: Although intertwin size difference is an important measure of fetal growth, the appropriate cut point to define discordance is unclear. Few studies have assessed intertwin differences in estimated fetal weight longitudinally or in relation to size differences at birth. OBJECTIVES: The objectives of the study were to estimate the magnitude of percentage differences in estimated fetal weight across gestation in dichorionic twins in relation to a fixed discordance cut point and compare classification of aberrant fetal growth by different measures (estimated fetal weight differences, birthweight discordance, small for gestational age). STUDY DESIGN: Women aged 18-45 years from 8 US centers with dichorionic twin pregnancies at 8 weeks 0 days to 13 weeks 6 days gestation planning to deliver in participating hospitals were recruited into the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Dichorionic Twins study and followed through delivery (n = 140; 2012-2013). Ultrasounds were conducted at 6 targeted study visits to obtain fetal biometrics and calculate estimated fetal weight. Percent estimated fetal weight and birthweight differences were calculated: ([weightlarger - weightsmaller]/weightlarger)*100; discordance was defined as ≥18% for illustration. Birth sizes for gestational age (both, 1, or neither small for gestational age) were determined; twins were categorized into combined birthweight plus small for gestational age groups: birthweight discordance ≥18% (yes, no) with both, 1, or neither small for gestational age. Linear mixed-models estimated percentiles of estimated fetal weight percent differences across gestation and compared estimated fetal weight differences between combined birthweight discordance and small for gestational age groups. A Fisher exact test compared birthweight discordance and small for gestational age classifications. RESULTS: Median estimated fetal weight percentage difference increased across gestation (5.9% at 15.0, 8.4% at 38.0 weeks), with greater disparities at higher percentiles (eg, 90th percentile: 15.6% at 15.0, 26.3% at 38.0 weeks). As gestation advanced, an increasing percentage of pregnancies were classified as discordant using a fixed cut point: 10% at 27.0, 15% at 34.0, and 20% at 38.0 weeks. Birthweight discordance and small for gestational age classifications differed (P = .002); for birthweight discordance ≥18% vs <18%: 44% vs 71% had neither small for gestational age; 56% vs 18% had 1 small for gestational age; no cases (0%) vs 11% had both small for gestational age, respectively. Estimated fetal weight percent difference varied across gestation by birthweight discordance plus small for gestational age classification (P = .040). Estimated fetal weight percentage difference increased with birthweight discordance ≥18% (neither small for gestational age: 0.46%/week [95% confidence interval, 0.08-0.84]; 1 small for gestational age: 0.57%/week [95% confidence interval, 0.25-0.90]) but less so without birthweight discordance (neither small for gestational age: 0.17%/week [95% confidence interval, 0.06-0.28]; 1 small for gestational age: 0.03%/week [95% confidence interval, -0.17 to 0.24]); both small for gestational age: 0.10%/week [95% confidence interval, -0.15 to 0.36]). CONCLUSION: The percentage of dichorionic pregnancies exceeding a fixed discordance cut point increased over gestation. A fixed cut point for defining twin discordance would identify an increasing percentage of twins as discordant as gestation advances. Small for gestational age and percentage weight differences assess distinct aspects of dichorionic twin growth. A percentile cut point may be more clinically useful for defining discordance, although further study is required to assess whether any specific percentile cut point correlates to adverse outcomes.

Acardius anceps with neck cyst and cleft palate: Three dimensional skeletal computed tomography reconstruction with discussion of the literature.

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 causing the acardiac body to be hypoxemic. In this report, we present an acardius anceps, therapeutically laser separated from its pump twin at 16 weeks. The healthy pump twin and macerated acardiac body were born at 40 3/7 weeks. A three dimensional (3D) reconstruction was made by CT images, showing cranial bones, spinal column, pelvis and lower extremities but absent arms. A cyst in the neck of the acardiac twin was identified by postnatal sonography; this was also described in four literature cases, and was additionally observed by us in two other acardiac twins. Median cleft palate was identified by oral cavity inspection but undetectable in the reconstruction. In the literature, we found 21 other acardiac anceps twins with a cleft palate. From the two larger published series, with 12 clefts in 21 acardiac anceps twins, a cleft palate occurs in over 50% during acardiac twinning. Our first hypothesis is that acardiac fetuses develop an oral cleft palate when acardiac onset starts prior to 11 weeks, because 11 weeks includes the period of embryonic oral cavity formation, and no cleft occurs when onset starts later than 11 weeks. Our second hypothesis is that cysts and cleft palates are more common in acardiac twins than currently known, likely reflecting that acardiac bodies are hypoxemic and that hypoxia contributes to the development of both cysts and clefts.

US Evaluation of Twin Pregnancies: Importance of Chorionicity and Amnionicity.

The twin birth rate is increasing in the United States. Twin pregnancies can be dichorionic or monochorionic (MC). MC twins account for 20% of twin pregnancies but 30% of all-cause pregnancy-related complications. This article describes the imaging findings that establish chorionicity and amnionicity. Ideally, these are established in the first trimester when accuracy is high, but they can also be determined later in pregnancy. Complications unique to MC twin pregnancy include twin-twin transfusion syndrome, twin anemia polycythemia sequence, twin reversed arterial perfusion sequence, and selective fetal growth restriction. The US features, staging systems, and management of these complications are reviewed, and the consequences of MC twin demise are illustrated. Ongoing surveillance for these conditions starts at 16 weeks gestation. Monoamniotic (MA) twins are a small subset of MC twins. In addition to all of the MC complications, specific MA complications include cord entanglement and conjoined twinning. Radiologists must be able to determine chorionicity and amnionicity and should be aware of potential complications so that patients may be referred to appropriate regional specialized centers. A proposed algorithm for referral to specialized fetal treatment centers is outlined. Online supplemental material is available for this article. ©RSNA, 2019.