Electro-clinical features in epileptic children with chromosome 15q duplication syndrome.

OBJECTIVE: We aimed to describe epilepsy and EEG patterns related to vigilance states and age, in chromosome15-long-arm-duplication-syndrome (dup15q) children with epilepsy, in both duplication types: interstitial (intdup15) and isodicentric (idic15). METHODS: Clinical data and 70 EEGs of 12 patients (5 intdup15, 7 idic15), followed from 4.5 m.o to 17y4m (median follow-up 8y3m), were retrospectively reviewed. EEGs were analyzed visually and using power spectrum analysis. RESULTS: Seventy video-EEGs were analyzed (1-16 per patient, median 6), follow-up lasting up to 8y10m (median 4y2m): 25 EEGs in intdup15 (8 m.o to 12y.o, median 4y6m) and 45 EEGs in idic15 (7 m.o to 12 y.o, median 15 m). Epilepsy: 6 West syndrome (WS) (2intdup15, 4idic15); 4 Lennox-Gastaut syndromes (LGS) (1 intdup15, 3 idic15), 2 evolving from WS; focal epilepsy (3 intdup15). In idic15, WS displayed additional myoclonic seizures (3), atypical (4) or no hypsarrhythmia (2) and posterior predominant spike and polyspike bursts (4). Beta-band rapid-rhythms (RR): present in 11 patients, power decreased during non-REM-sleep, localization shifted from diffuse to anterior, peak frequency increased with age. CONCLUSION: WS with peculiar electro-clinical features and LGS, along with beta-band RR decreasing in non-REM-sleep and shifting from diffuse to anterior localization with age are recognizable features pointing towards dup15q diagnosis in children with autism spectrum disorder and developmental delay. SIGNIFICANCE: This study describes electroclinical features in both interstitial and isodicentric duplications of chromosome 15q, in epileptic children, including some recent extensions regarding sleep features; and illustrates how the temporo-spatial organization of beta oscillations can be of significant help in directing towards dup15q diagnosis hypothesis.

Prenatal detection of terminal 9p24.3 microduplication encompassing DOCK8 gene: A variant of likely benign.

ABSTRACT: Trisomy 9p is one of the most common chromosomal partial trisomies in newborns. However, reports on prenatal 9p microduplications are rare in the clinic. This study aimed to examine the genotype-phenotype correlation and assess the clinical significance of 9p24.3 microduplication encompassing the DOCK8 gene. Eight pregnant women underwent amniocentesis for cytogenetic and genetic testing for various indications for prenatal diagnosis from January 2019 to January 2020. Chromosomal karyotypic analysis was performed on G-band metaphases that were prepared from cultured amniotic fluid cells. Chromosomal microarray analysis was carried out to detect chromosomal copy number variations. We also performed a literature review on clinical data on similar 9p24.3 microduplications to determine the genotype-phenotype correlation. We detected 123-248-kb microduplications in the region of 9p24.3 (chr9: 208454-469022), involving part of or the entire DOCK8 gene. The indications for prenatal diagnosis mainly focused on the risk of maternal serum screening for trisomy 21/18, advanced maternal age, and increased nuchal translucency. No evident structural abnormalities were observed for all fetuses, except for case 5 who presented with increased nuchal translucency in prenatal ultrasound findings. Follow-up of postnatal health was performed and showed no apparent abnormalities for cases 1 to 6 after birth. The parents of case 7 chose to terminate the pregnancy while the parents of case 8 chose to continue the pregnancy. We propose that 9p24.3 microduplications that encompass part of or the entire DOCK8 gene are variants that might be benign. However, further large-scale studies are necessary to evaluate the clinical pathogenicity. For prenatal cases with 9p24.3 microduplication, postnatal health and growth should be followed up and assessed regularly from childhood to adulthood.

Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.

BACKGROUND: Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X. CASE PRESENTATION: A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever　for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin. CONCLUSIONS: An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.

Trisomy 8 mosaicism in the placenta: A Danish cohort study of 37 cases and a literature review.

OBJECTIVE: To evaluate the risk of fetal involvement when trisomy 8 mosaicism (T8M) is detected in chorionic villus samples (CVS). METHODS: A retrospective descriptive study of registered pregnancies in Denmark with T8M in CVS identified through a database search and a review of published cases of T8M found through a systematic literature search and inclusion of cross references. Pregnancies with T8M in CVS and no additional numerical chromosomal aberrations were included. RESULTS: A total of 37 Danish cases and 60 published cases were included. T8M detected in a CVS was associated with fetal involvement in 18 out of 97 pregnancies (18.6% [95%CI: 11.4-27.7]). Eight out of 70 (11.4% [95%CI: 5.1-21.3]) interpreted prenatally to be confined placental mosaicism (CPM) were subsequently found to be true fetal mosaicisms (TFM). CONCLUSION: T8M detected in CVS poses a significant risk of fetal involvement, and examination of amniotic fluid (AF) and/or fetal tissue should be offered. However, a normal result of AF still has a considerable residual risk of fetal involvement. Genetic counselling at an early gestational age is essential, and follow-up ultrasonography should be performed to predict fetal involvement if possible.

Adaptive functioning in children and adolescents with Trisomy X: An exploratory analysis.

Identifying the factors related to adaptive functioning will improve the information available to families and providers of females with Trisomy X. Cognitive and behavioral features were assessed in 50 females ages 12.2 ± 3.6 years using the Behavior Assessment System for Children Second Edition (BASC-2) and Wechsler Scales of Intelligence. Executive functioning, social skills, and autistic traits were evaluated in a subset. Adaptive functioning was assessed using the BASC-2 adaptive skills composite score (ASC). Participants were classified as average adaptive skills (ASC T-score > 40) or deficits (ASC T-score < 40). Group comparisons were conducted. Multiple linear regression examined which factors contributed to ASC score. Twenty-eight females (55.6%) had adaptive skills deficits with functional communication being the most commonly affected adaptive domain. The group with ASC in the average range had higher verbal IQ (VIQ) and lower rates of numerous behavioral concerns. Internalizing behavior composite, DSM-IV inattentive symptoms score, and VIQ were significant predictors of ASC. Prenatally diagnosed females comprised over 70% of those with average adaptive skills. In this study, internalizing behaviors, inattentive ADHD symptoms, and VIQ were associated with poorer adaptive functioning. Early interventions targeting internalizing behaviors, attention/executive functioning, and communication skills may improve adaptive skills and deserve further study.

Early neurodevelopmental and medical profile in children with sex chromosome trisomies: Background for the prospective eXtraordinarY babies study to identify early risk factors and targets for intervention.

Sex chromosome trisomies (SCT), including Klinefelter syndrome/XXY, Trisomy X, and XYY syndrome, occur in 1 of every 500 births. The past decades of research have resulted in a broadening of known associated medical comorbidities as well as advances in psychological research. This review summarizes what is known about early neurodevelopmental, behavioral, and medical manifestations in young children with SCT. We focus on recent research and unanswered questions related to the risk for neurodevelopmental disorders that commonly present in the first years of life and discuss the medical and endocrine manifestations of SCT at this young age. The increasing rate of prenatal SCT diagnoses provides the opportunity to address gaps in the existing literature in a new birth cohort, leading to development of the eXtraordinarY Babies Study. This study aims to better describe and compare the natural history of SCT conditions, identify predictors of positive and negative outcomes in SCT, evaluate developmental and autism screening measures commonly used in primary care practices for the SCT population, and build a rich data set linked to a bank of biological samples for future study. Results from this study and ongoing international research efforts will inform evidence-based care and improve health and neurodevelopmental outcomes.

The behavioral profile of children aged 1-5 years with sex chromosome trisomy (47,XXX, 47,XXY, 47,XYY).

Children with SCT have an increased risk of suboptimal neurodevelopment. Previous studies have shown an elevated risk for neurobehavioral problems in individuals with SCT. However, not much is known about neurobehavioral problems in very young children; knowledge that could help with early identification of children at risk for suboptimal development, and that could help establish targets for early intervention. This study addressed the question of what the behavioral profile of children with SCT aged 1-5 years looks like. In total, 182 children aged 1-5 years participated in this study (NSCT =87, Nnonclinical controls = 95). Recruitment and assessment took place in the Netherlands and the United States. The SCT group was recruited through prospective follow-up (50%), information seeking parents (31%), and clinical referral (18%). Behavioral profiles were assessed with the child behavior checklist and the ages-and-stages social-emotional questionnaire. Levels of parent-rated problem behavior were higher in children with SCT. Difficulties with overall social-emotional functioning were already present in 1-year-olds, and elevated scores were persistent across the full age range. Affective and pervasive developmental behaviors were seen in late toddlerhood and prominent at preschool age. Anxiety, attention deficit, and oppositional defiant behaviors were seen in preschool-aged children. Within this cross-sectional study, the developmental trajectory of affective, pervasive developmental, and oppositional defiant behaviors seemed to be different for SCT children than nonclinical controls. Collectively, these results demonstrate the importance of behavioral screening for behavioral problems in routine clinical care for children with SCT from a young age. Social-emotional problems may require special attention, as these problems seem most prominent, showing increased risk across the full age range, and with these problems occurring regardless of the timing of diagnosis, and across all three SCT karyotypes.

Motor Development and Health-Related Fitness in Trisomy X: A Case Report.

PURPOSE: This case study provides information regarding the motor development and health-related fitness level of a female with 47,XXX. The Movement Assessment Battery for Children-Second Edition (MABC-2) and the Test of Gross Motor Development-Second Edition (TGMD-2) batteries were used to assess motor competence and gross motor development, respectively. Cardiorespiratory, muscular fitness, and flexibility were assessed by means of field-based tests. Two groups of children developing typically were used for comparison purposes. SUMMARY OF KEY POINTS: Results from the MABC-2 indicated that the participant was placed in the 37th percentile, whereas the comparison group was placed in the 68th percentile. The participant scored above the 50th percentile in the TGMD-2 and showed lower fitness values than those in the comparison group. RECOMMENDATIONS FOR CLINICAL PRACTICE: Contrary to what is generally expected, supernumerary 47,XXX does not have to negatively impact motor competence, although a low health-related physical fitness can be present.

Two Abnormal Cell Lines of Trisomy 14 and t(X;14) with Skewed X-Inactivation.

Trisomy 14 is incompatible with live, but there are several patients reported with mosaic trisomy 14. We aimed to study the pattern of X inactivation and its effect on a translocated autosome and to find out an explanation of the involvement of chromosome 14 in 2 different structural chromosomal abnormalities. We report on a girl with frontal bossing, hypertelorism, low-set ears, micrognathia, cleft palate, congenital heart disease, and abnormal skin pigmentations. The patient displayed iris, choroidal, and retinal coloboma and agenesis of the corpus callosum and cerebellar vermis hypoplasia. Cytogenetic analysis revealed a karyotype 45,X,der(X)t(X;14)(q24;q11)[85]/46,XX,rob(14;14)(q10;q10),+14[35]. Array-CGH for blood and buccal mucosa showed high mosaic trisomy 14 and an Xq deletion. MLPA detected trisomy 14 in blood and buccal mucosa and also showed normal methylation of the imprinting center. FISH analysis confirmed the cell line with trisomy 14 (30%) and demonstrated the mosaic deletion of the Xq subtelomere in both tissues. There was 100% skewed X inactivation for the t(X;14). SNP analysis of the patient showed no region of loss of heterozygosity on chromosome 14. Also, genotype call analysis of the patient and her parents showed heterozygous alleles of chromosome 14 with no evidence of uniparental disomy. Our patient had a severe form of mosaic trisomy 14. We suggest that this cytogenetic unique finding that involved 2 cell lines with structural abnormalities of chromosome 14 occurred in an early postzygotic division. These 2 events may have happened separately or maybe there is a kind of trisomy or monosomy rescue due to dynamic cytogenetic interaction between different cell lines to compensate for gene dosage.

Influence of allelic differences in Down syndrome.

Both trisomic and non-trisomic genes may affect the incidence and severity of phenotypes associated with Down syndrome (DS). The importance of extra (trisomic) genetic material is emphasized in DS, with less emphasis to the allelic composition of candidate trisomic genes in defining the trisomic gene-phenotype relationship in DS. Allelic differences in non-trisomic genes have been shown to be important moderators of cardiac, leukemia, and developmental phenotypes associated with DS. Trisomic mouse models provide an in vivo genetic platform for examining the gene-phenotype relationship, including the influence of allelic variants, on DS-like phenotypes. DS mouse models have differing trisomic genetic makeup, and optimal development, viability and translational value of these mouse models may require a non-inbred genetic background with heterogeneity at many loci. Additionally, understanding the contribution of specific genes or regions to DS phenotypes often requires the utilization of genetically manipulated mice that may be established on a different inbred background than the trisomic mice. The impact of allelic differences of trisomic and background genes in human and model systems may offer insight into the variability in occurrence and severity of trisomic phenotypes.

Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome.

Altered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.

Hidradenitis suppurativa in a patient with Warkany syndrome: Sustainability of adalimumab treatment.

Mental retardation is a potential limitation to self-administration of innovative biologic treatment, which is otherwise very effective for devastating chronic inflammatory conditions, such as hidradenitis suppurativa (HS). We report our successful experience with a 34-year-old woman, who was genetically affected by Warkany syndrome, which causes intellectual disability. This patient was unable to maintain long-term antibiotic regimen and was disappointed by the limited results in her 12 years' history of painful draining fistulae and abscesses; however, she enthusiastically adhered to adalimumab 40 mg/once weekly treatment. After 52 weeks, treatment compliance is excellent, the patient is satisfied with the HS improvements, and no adverse effects have been reported.

Trisomy 9p. A brief clinical, diagnostic and therapeutic description. / Trisomía 9p. Una breve descripción clínica, diagnóstica y terapéutica.

Trisomy 9p is characterized by the partial or complete duplication of the short arm of chromosome 9. It is one of the most common autosomal structural abnormalities in newborn infants. This is a relatively poor gene region, so it may be more compatible with survival. It is characterized by delayed mental and psychomotor growth, craniofacial dysmorphisms, skeletal alterations, central nervous system abnormalities, congenital heart disease, and, to a lesser extent, kidney disorders. To establish a diagnosis, it is necessary to perform a cytogenetic study with G bands and, if available, fluorescence in situ hybridization complemented with comparative genomic hybridization for a better understanding of the genotype-phenotype correlation. Assessment should be interdisciplinary and encompassing a timely family genetic counseling, together with available therapeutic options in an early manner.

La trisomía del 9p se caracteriza por la duplicación de todo o de algún segmento del brazo corto del cromosoma 9. Es una de las anomalías autosómicas estructurales más frecuentes en recién nacidos. Esta región es relativamente pobre en genes, por lo que puede ser más compatible con la supervivencia. Se caracteriza por presentar retraso del crecimiento, psicomotor y mental, dismorfias cráneo-faciales, alteraciones esqueléticas, así como anomalías en el sistema nervioso central, cardiopatías congénitas y alteraciones renales en menor frecuencia. Para realizar el diagnóstico, debe desarrollarse el estudio citogenético mediante la técnica de banda G, y, si está disponible, se recomienda la hibridación por fluorescencia in situ, complementada por la hibridación genómica comparativa, para la mejor comprensión de la correlación genotipo-fenotipo. La evaluación debe ser interdisciplinaria, en la que se incluya un oportuno asesoramiento genético familiar y, con ello, las opciones terapéuticas disponibles y de forma precoz.

Mosaic trisomy 20 and mitigation in capital crimes sentencing: A review and case report.

Trisomy 20 is a genetic abnormality in which individuals have an extra copy of chromosome 20. Complete trisomy 20 is rare and believed to be incompatible with life. A mosaic form of trisomy 20, in which only some cells or tissues contain the extra chromosome, is a relatively commonly encountered chromosomal abnormality found during prenatal testing, and c. 90% result in a normal phenotype. However, despite the absence of a consistent phenotype, certain findings have been reported across multiple cases of mosaic trisomy 20. These include an array of morphological findings, developmental delays, and learning disabilities. Beyond physical manifestations, a wide range of developmental and learning delays have also been reported. In this work, we provide an overview of the trisomy 20 literature and a case report of a young adult male with mosaic trisomy 20 who committed homicide. His developmental and life history, eventual diagnosis of mosaic trisomy 20, similarities and differences in his condition compared with prior research findings, and potentially new phenotypic findings associated with trisomy 20 that he manifested (childhood visual hallucinations, self-injury, polydactyly) are presented. Additionally, the potential role of this genetic diagnosis in his neuropsychiatric history and its successful application as a mitigating factor at his capital sentencing trial are described. We did not identify other similar cases during our search of major scientific and legal databases. As a backdrop, the use of genetics in criminal trials is on the rise, and courts are increasingly likely to accept behavioral genetics evidence; therefore, it is crucial that the legal system is well acquainted with the opportunities and limitations of these approaches.

Ductus Venosus Agenesis as a Marker of Pallister-Killian Syndrome.

The ductus venosus (DV) is a shunt that allows the direct flow of well-oxygenated blood from the umbilical vein (UV) to the coronary and cerebral circulation through the foramen ovale. Its agenesis has been associated with chromosomal abnormalities and rare genetic syndromes, structural defects, intrauterine growth restriction (IUGR) and even antepartum fetal demise. Pallister-Killian Syndrome (PKS) is a rare sporadic disorder with specific tissue mosaic distribution of an extra 12p isochromosome (i(12p)). Its main clinical features are moderate to severe intellectual disability/neuromotor delay, skin pigmentation abnormalities, typical facial appearance, variable association with multiple congenital malformations and epilepsy. Though prenatal findings (including congenital diaphragmatic hernia, ventriculomegaly, congenital heart disease, polyhydramnios, and rhizomelic shortening) have been described in literature, prenatal diagnosis is difficult as there are no associated identification signs no distinctive or pathognomonic signs, and some of these malformations are hard to identify prenatally. The tissue mosaicism linked to this syndrome and the decrease of the abnormal clone carrier of the i(p12) after successive trypsinizations of cultured cells makes the diagnosis even more challenging. We present the case of a 27.5 weeks pregnant woman with a fetal ductus venosus agenesis (DVA) as the main guide marker. To our knowledge this is the first case published in literature reporting a DVA as a guide sign to diagnose a complex condition as Pallister-Killian syndrome. We also underscore the key role of new genetic techniques as microarrays to avoid misdiagnosis when only a subtle sonographic sign is present in complex conditions like this.

A Spontaneous Pregnancy in a Patient with Turner Syndrome with 45,X/47,XXX Mosaicism: A Case Report and Review of the Literature.

BACKGROUND: Turner syndrome is a chromosomal abnormality, due to a total or partial loss of 1 of the X chromosomes and is mostly characterized clinically by short stature and primary ovarian insufficiency. Spontaneous pregnancies are rare (5%) and of relatively high risk. This is 1 of few reported cases of spontaneous conception and favorable prognosis in a patient with Turner syndrome and a 45,X/47,XXX karyotype. CASE: A 21-year-old woman with Turner mosaicism (45,X/47,XXX) who had a full-term, uncomplicated pregnancy after spontaneous conception, gave birth to a healthy female (46,XX) infant. SUMMARY AND CONCLUSION: Spontaneous pregnancies in women with Turner syndrome are a rarity. Fertility preservation methods are being discussed. Due to the high reported incidence of neonatal, obstetric, maternal, and especially cardiovascular complications in those pregnancies, close monitoring is essential.

Sex chromosome trisomies are not associated with atypical lateralization for language.

AIM: To test the hypothesis that sex chromosome trisomies (SCTs) are associated with reduced left lateralization for language. METHOD: Using a cross-sectional design, language laterality was measured during an animation description task using functional transcranial Doppler ultrasonography. Data were available for 75 children with an SCT (47,XXX females [n=26], 47,XXY males [n=25], 47,XYY males [n=24]; mean age 11y 4mo [SD 3y 10mo]) and 132 comparison children with typical karyotypes (69 males, 63 females; mean age 9y 1mo [SD 1y 7mo]). RESULTS: Lateralization for language did not differ between the SCT and comparison groups, either in mean laterality index or relative frequency of each laterality category. There were no differences when splitting the group with an SCT by trisomy. Handedness showed no group effects. INTERPRETATION: Our data provide no evidence for disrupted lateralization for language in SCTs. The brain basis of the cognitive phenotype in SCTs is unlikely to be a failure of the left hemisphere to specialize for language, as previously suggested. WHAT THIS PAPER ADDS: Children with a sex chromosome trisomy (SCT) have typically lateralized language. This disproves theories linking language problems to hemispheric specialization in SCTs.