Silver-Russell Syndrome Research Articles

The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature

Introduction: Among children born small for gestational age, 10–15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Methods: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <−2 SD for gestational age and life-minimum height <−2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. Results: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. Conclusions: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.

Computer-aided facial analysis as a tool to identify patients with Silver–Russell syndrome and Prader–Willi syndrome

Genetic syndromes often show facial features that provide clues for the diagnosis. However, memorizing these features is a challenging task for clinicians. In the last years, the app Face2Gene proved to be a helpful support for the diagnosis of genetic diseases by analyzing features detected in one or more facial images of affected individuals. Our aim was to evaluate the performance of the app in patients with Silver–Russell syndrome (SRS) and Prader–Willi syndrome (PWS). We enrolled 23 pediatric patients with clinically or genetically diagnosed SRS and 29 pediatric patients with genetically confirmed PWS. One frontal photo of each patient was acquired. Top 1, top 5, and top 10 sensitivities were analyzed. Correlation with the specific genetic diagnosis was investigated. When available, photos of the same patient at different ages were compared. In the SRS group, Face2Gene showed top 1, top 5, and top 10 sensitivities of 39%, 65%, and 91%, respectively. In 41% of patients with genetically confirmed SRS, SRS was the first syndrome suggested, while in clinically diagnosed patients, SRS was suggested as top 1 in 33% of cases (p = 0.74). Face2Gene performed better in younger patients with SRS: in all patients in whom a photo taken at a younger age than the age of enrollment was available, SRS was suggested as top 1, albeit with variable degree of probability. In the PWS group, the top 1, top 5, and top 10 sensitivities were 76%, 97%, and 100%, respectively. PWS was suggested as top 1 in 83% of patients genetically diagnosed with paternal deletion of chromosome 15q11-13 and in 60% of patients presenting with maternal uniparental disomy of chromosome 15 (p = 0.17). The performance was uniform throughout the investigated age range (1–15 years).Conclusion: In addition to a thorough medical history and detailed clinical examination, the Face2Gene app can be a useful tool to support clinicians in identifying children with a potential diagnosis of SRS or PWS.What is Known:• Several genetic syndromes present typical facial features that may provide clues for the diagnosis.• Memorizing all syndromic facial characteristics is a challenging task for clinicians.What is New:• Face2Gene may represent a useful support for pediatricians for the diagnosis of genetic syndromes.• Face2Gene app can be a useful tool to integrate in the diagnostic path of patients with SRS and PWS.

Action Induced Myoclonus in a 11-Year-Old Boy with Silver-Russell Syndrome.

Movement Disorders Clinical PracticeEarly View CLINICAL VIGNETTE Action Induced Myoclonus in a 11-Year-Old Boy with Silver-Russell Syndrome Laia Nou-Fontanet MD, Laia Nou-Fontanet MD orcid.org/0000-0001-7381-3983 Pediatric Neurology Department, Hospital Sant Joan de Déu Barcelona, Barcelona, SpainSearch for more papers by this authorDeyanira García-Navas MD, Deyanira García-Navas MD Department of Pediatric Neurology, Hospital Universitario San Pedro de Alcántara, Cáceres, SpainSearch for more papers by this authorHilario Gómez-Martín MD, Hilario Gómez-Martín MD Department of Pediatric Neurology, Hospital Universitario de Salamanca, Castilla y Leon, SpainSearch for more papers by this authorLoreto Martorell PhD, Loreto Martorell PhD Department of Genetic and Molecular Medicine-IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, SpainSearch for more papers by this authorJuan Darío Ortigoza-Escobar MD, PhD, Corresponding Author Juan Darío Ortigoza-Escobar MD, PhD [email protected] orcid.org/0000-0002-6320-2641 U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain Movement Disorders Unit, Pediatric Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain Correspondence to: Dr. Juan Darío Ortigoza-Escobar, Movement Disorders Unit, Pediatric Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Passeig Sant Joan de Déu 2, 08950, Barcelona, Spain; E-mail: [email protected]Search for more papers by this author Laia Nou-Fontanet MD, Laia Nou-Fontanet MD orcid.org/0000-0001-7381-3983 Pediatric Neurology Department, Hospital Sant Joan de Déu Barcelona, Barcelona, SpainSearch for more papers by this authorDeyanira García-Navas MD, Deyanira García-Navas MD Department of Pediatric Neurology, Hospital Universitario San Pedro de Alcántara, Cáceres, SpainSearch for more papers by this authorHilario Gómez-Martín MD, Hilario Gómez-Martín MD Department of Pediatric Neurology, Hospital Universitario de Salamanca, Castilla y Leon, SpainSearch for more papers by this authorLoreto Martorell PhD, Loreto Martorell PhD Department of Genetic and Molecular Medicine-IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, SpainSearch for more papers by this authorJuan Darío Ortigoza-Escobar MD, PhD, Corresponding Author Juan Darío Ortigoza-Escobar MD, PhD [email protected] orcid.org/0000-0002-6320-2641 U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain Movement Disorders Unit, Pediatric Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain Correspondence to: Dr. Juan Darío Ortigoza-Escobar, Movement Disorders Unit, Pediatric Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Passeig Sant Joan de Déu 2, 08950, Barcelona, Spain; E-mail: [email protected]Search for more papers by this author First published: 13 March 2023 https://doi.org/10.1002/mdc3.13724Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

Congenital absence of the bilateral long heads of the biceps brachii tendons in a patient with Silver-Russell syndrome

Agenesis of the long head of biceps tendon (LHBT) is a congenital anomaly not commonly reported in the literature, and bilateral absence of the LHBT is even more rare. Most cases of LHBT agenesis are found incidentally at arthroscopy or are diagnosed by magnetic resonance imaging after a history of insidious shoulder pain or anterior shoulder instability. We present the magnetic resonance imaging findings of bilateral congenital absence of the LHBT in a 37-year-old male with Silver-Russell syndrome who presented with progressive, bilateral anterior shoulder pain after failing conservative treatment strategies. This case report describes bilateral agenesis of the LHBT in association with a congenital growth disorder that has not been described previously in the literature. We provide a description of key MR imaging findings to assist in making the diagnosis, along with a discussion of potential differential diagnoses, and a review of the current literature on this topic.

Executive functioning in adolescents and adults with Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by prenatal and postnatal growth retardation. The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Knowledge of the neuropsychological profile of SRS remains sparse and incomplete even if several difficulties related to attention and learning have been reported both in the literature and by patients with SRS. These difficulties could be the result of troubles in different cognitive domains, but also of executive dysfunction. Nevertheless, executive functioning has never been investigated, even though executive functions play an essential role in psychological development, and are extensively involved in daily life. The present study explored the executive functioning of individuals with SRS due to UPD(7)mat or 11p15 LOM. A battery of executive tasks assessing cognitive flexibility, inhibitory control, and working memory, together with a task assessing sustained attention, was administered to 19 individuals with SRS (13-39 years) and 19 healthy controls. The Behavior Rating Inventory of Executive Function was also completed by the participants' families. The results showed that participants with SRS had similar performance (z-scores) to our controls, in a context of normal intellectual efficiency. Group comparisons with Bayesian statistics showed a single difference between the 11p15 LOM and control groups: the completion time for part A of the Trail Making Test appeared to be longer in the 11p15 LOM group than in the control group. However, at the clinical level, several participants with SRS had clinically significant scores on various measures of EFs. Thus, the cognitive phenotype of SRS did not appear to be characterized by executive dysfunction, but individuals with SRS could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder. These results provide new insights into the neuropsychological profile of individuals with SRS.

Management of Two Years Old Child with Russell-Silver Syndrome - A Case Report

Russell-Silver syndrome (RSS) is a rare genetic malformation characterized by the growth of a 2-year-old male child with RSS who underwent hip spica surgery under general anesthesia. The patient had a history of mild developmental delay, failure to gain weight, and frequent vomiting. Anesthetic implications of RSS, including airway management, glucose homeostasis, hypothermia, and pharmacological considerations, were considered during the patient's pre-operative assessment and intraoperative management. The patient was induced with propofol and fentanyl, and maintenance anesthesia was achieved with sevoflurane. The patient's airway was safely secured, and extubation was performed smoothly. The anesthetic management proceeded without complications, ensuring a successful outcome. This case report highlights the importance of considering the specific anesthetic implications of RSS in the perioperative management of patients with this rare genetic syndrome.

Silver–Russell syndrome in siblings with orthodontic management

Silver–Russell syndrome (SRS) is a rare congenital abnormality. The incidence ranges from 1 in 3000 to 100,000 live births. It is characterized by low birth weight, asymmetric limb, relative macrocephaly, high forehead, small triangular-shaped face with small jaws, and dental malocclusion. The etiology of SRS is still unclear, but genetic alterations and family history have been attributed. The diagnosis of SRS is mainly based on physical characteristics and appearance. This article enlightens clinical versatility in dental features of SRS in two siblings and discusses the orthodontic management for dental malocclusion in the elder one.

P145: Microcephaly in atypical Silver-Russell syndrome caused by defects in PLAG1

P145: Microcephaly in atypical Silver-Russell syndrome caused by defects in PLAG1

Efficient generation of epigenetic disease model mice by epigenome editing using the piggyBac transposon system

BackgroundEpigenome-edited animal models enable direct demonstration of disease causing epigenetic mutations. Transgenic (TG) mice stably expressing epigenome-editing factors exhibit dramatic and stable changes in target epigenome modifications. Successful germline transmission of a transgene from founder mice to offspring will yield a sufficient number of epigenome-edited mice for phenotypic analysis; however, if the epigenetic mutation has a detrimental phenotypic effect, it can become difficult to obtain the next generation of animals. In this case, the phenotype of founder mice must be analyzed directly. Unfortunately, current TG mouse production efficiency (TG founders per pups born) is relatively low, and improvements would increase the versatility of this technology.ResultsIn the current study, we describe an approach to generate epigenome-edited TG mice using a combination of both the dCas9–SunTag and piggyBac (PB) transposon systems. Using this system, we successfully generated mice with demethylation of the differential methylated region of the H19 gene (H19-DMR), as a model for Silver–Russell syndrome (SRS). SRS is a disorder leading to growth retardation, resulting from low insulin-like growth factor 2 (IGF2) gene expression, often caused by epimutations at the H19-IGF2 locus. Under optimized conditions, the efficiency of TG mice production using the PB system was approximately threefold higher than that using the conventional method. TG mice generated by this system showed demethylation of the targeted DNA region and associated changes in gene expression. In addition, these mice exhibited some features of SRS, including intrauterine and postnatal growth retardation, due to demethylation of H19-DMR.ConclusionsThe dCas9–SunTag and PB systems serve as a simple and reliable platform for conducting direct experiments using epigenome-edited founder mice.

Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models.

Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 imprinting control region (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis.

Genetics for the pediatric endocrinologists – 2 Primordial short stature in children and adolescents

Primordial short stature (PSS) is an extremely rare group of monogenic disorders characterized by profound global growth failure commencing in the fetal life and continuing postnatally for the rest of the life. It is suspected when there is an extreme degree of proportionate short stature and global growth failure with or without microcephaly, and without any evidence of known skeletal dysplasia. The cardinal features of PSS include severe intrauterine and postnatal growth failure, severe postnatal short stature, primary microcephaly, characteristic facial features, and variable intellectual disability. The most common genetic etiology is monogenic except for Silver–Russell syndrome, where an epigenetic mechanism is a predominant cause of primordial dwarfism. This review demonstrates a holistic approach to the diagnosis and management of PSS in children and adolescents.

First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders

BackgroundImprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses.ResultsWe collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver–Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith–Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories.ConclusionsBased on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.

ODP373 A Tale of Two Syndromes: Coexistence of Russell-Silver and Klinefelter Syndrome

Abstract Background/Aims Klinefelter syndrome is a common condition characterized by an extra X chromosome, tall stature, gynecomastia, and hypogonadism. Russell-Silver syndrome is a rare disorder characterized by intrauterine growth restriction, poor growth after birth, and triangular facies. The coexistence of Russell-Silver and Klinefelter syndrome has so far not been reported in the literature. This study aimed to characterize the phenotype of such an individual. Methods Clinical and endocrinal investigations were performed and followed by pathogenic variant screening of candidate genes. Results An 8-year-old boy was evaluated for short stature. He was a former 27-week preemie who had postnatal growth failure. His mean parental height was5'6" (66 inches). His growth chart showed that he was below the 0. 01% percentile in both height and weight for age. He had behavioral issues. On physical exam, he had high riding prepubertal testes and proportional limbs. He was evaluated by both genetics and endocrine. His bone age was delayed by 4 years. He passed his growth hormone stimulation test. He had a nondiagnostic bone survey. His chromosomal microarray showed an XXY karyotype. Further testing was collected because it did not explain his short stature. He was found to have maternal uniparental disomy of 7q32.2. He was started on growth hormone and his most recent growth velocity was 4 cm a year. He continues to be below the 0. 01% percentile in both height and weight for age Conclusion: This is the first report on a patient with the coexistence of Russell-Silver and Klinefelter syndrome. It shows that the short stature and postnatal growth of Russell-Silver syndrome is the prevailing phenotype in this rare combination. Presentation: No date and time listed

Temple Syndrome: Clinical Findings, Body Composition and Cognition in 15 Patients.

Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated methylation defect of the MEG3-DMR. Studies on phenotypical characteristics in TS14 are scarce and patients with TS14 often experience delay in diagnosis, which has adverse effects on their health. TS14 is often characterized as either Prader-Willi-like, Silver-Russell-like or as a Silver-Russell spectrum disorder. This study describes 15 patients with TS14 who visited the Dutch Reference Center for Prader-Willi-like from December 2018 to January 2022. Eight patients had UPD(14)mat and seven a methylation defect. The most common symptoms were intra-uterine growth retardation (IUGR) (100%), hypotonia (100%), precocious puberty (89%), small for gestational age (SGA) birth (67%), tube feeding after birth (53%) and psycho-behavioral problems (53%). Median (interquartile range (IQR)) IQ was 91.5 (84.25; 100.0), whilst many patients were enrolled in special education (54%). The median (IQR) fat mass % (FM%) SDS was 2.53 (2.26; 2.90) and lean body mass (LBM) SDS -2.03 (-3.22; -1.28). There were no significant differences in clinical characteristics between patients with a UPD(14)mat and a methylation defect. Our patients share a distinct phenotype consisting of IUGR, SGA birth, precocious puberty, hypotonia, tube feeding after birth, psycho-behavioral problems and abnormal body composition with a high FM% and low LBM. Whilst similarities with Prader-Willi syndrome (PWS) and Silver-Russell syndrome (SRS) exist, TS14 is a discernible syndrome, deserving a tailored clinical approach. Testing for TS14 should be considered in patients with a PWS or SRS phenotype in infancy if PWS/SRS testing is negative.

Usefulness of the MS-MLPA technique in the diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome.

Epigenetic and genomic imprinting alterations of the 11p15.5 region cause excessive or deficient growth, which result in Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS), respectively. To evaluate the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methylation analysis technique in the diagnosis of BWS and SRS. 11p15.5 methylation and variants were evaluated in patients with clinical diagnosis of BWS and SRS using the MS-MLPA technique in peripheral blood DNA. Paternal uniparental disomy and loss of maternal IC2 methylation were identified in two patients with BWS who had omphalocele and macroglossia, respectively. Paternal IC1hypomethylation was recorded in two patients with SRS of classic phenotype. Adequate genotype-phenotype correlation was observed with the methylation defects that were identified, which confirms the usefulness of MLPA as a first-line study in patients diagnosed with BWS and SRS.

Congenital growth disorder: Silver Russell syndrome - A case report

Silver Russell syndrome is a congenital growth disorder with features of craniofacial dysmorphia and asymmetrical limbs. This case highlights failure to thrive (height and weight are less than -2SD), hemi-hypertrophy of the left side of the body and dysmorphic facial profile in a 13 year old boy. The parents have been counselled regarding etiology of the disease and the child is being treated with growth hormone therapy.

Craniofacial Malformations as Fundamental Diagnostic Tools in Syndromic Entities.

Background: A long list of syndromic entities can be diagnosed immediately through scrutinizing the clinical phenotype of the craniofacial features. The latter should be assisted via proper radiological interpretations. Patients and Methods: Different children aged from 1 month to 12 years were referred to our departments seeking orthopedic advice. Primarily, all received variable false diagnoses in other institutes. Two unrelated boys of one month and 12 months were falsely diagnosed as having positional plagiocephaly associated with contractures of idiopathic origin. Two unrelated boys of 14 months and 2 years were diagnosed with pseudo-hydrocephalus and non-specific syndrome, and were referred to explore their skeletal development. Two unrelated girls of 4 years old and 12 years old presented with multiple contractures were referred because of progressive scoliosis. A 4-year-old girl was referred with a false provisional diagnosis of facial diplegia. All children underwent detailed clinical, radiological and tomographic phenotypic characterizations and genetic testing, respectively. Results: Idaho syndrome (craniosynostosis associated with multiple dislocations) was the final diagnosis in the two unrelated boys with plagiocephaly and multiple contractures. Two children falsely diagnosed with pseudo-hydrocephalus and non-specific syndrome, were diagnosed with Silver–Russell syndrome (RSS). Contractural arachnodactyly Beals (CAB) was confirmed as the definitive diagnosis in the two unrelated girls with progressive scoliosis and multiple contractures. Parry–Romberg syndrome (PRS) associated with congenital lumbar kyphosis was the final diagnosis of the girl with the diagnosis of facial diplegia. Hypomethylation of ICR1 was confirmed in the RSS patients. Whole exome sequencing (WES) revealed a heterozygous mutation in the PRS patients. WES and array-CGH showed that no relevant variants or copy number variations (CNV) were identified in the CAB patients. Conclusions: On the one hand, newborn children can manifest diverse forms of abnormal craniofacial features, which are usually associated with either major or minor dysmorphic stigmata. A cleft lip/ palate is a major craniofacial malformation, and frontal bossing or a disproportionate craniofacial contour can be falsely considered as a transient plagiocephaly, which is spontaneously resolved by time. On the other hand, many physicians fall into the problem of deeming a countless number of diseases, such as contractures, as an idiopathic or non-specific syndrome. The latter stems from limited clinical experience. Therefore, failing to establish between the onset of the deformity and other inexplicit abnormal features that the patient or their immediate families or relatives carry is the final outcome. In this study, we used, for the first time, a reconstruction CT scan to further delineate the congenital disruption of the craniofacial anatomy and the other skeletal malformation complex.

Maternal uniparental disomy of chromosome 7 underlying argininosuccinic aciduria and Silver-Russell syndrome

We describe a patient presenting with argininosuccinic aciduria and Silver-Russell syndrome (SRS). SRS was caused by maternal uniparental disomy of chromosome 7 (UPD(7)mat). UPD(7)mat also unmasked a maternally inherited splicing variant in ASL on chromosome 7, leading to the onset of argininosuccinic aciduria. The phenotype of the present case was more severe than that of a previous case, demonstrating a phenotypic variation in the combination of argininosuccinic aciduria and SRS.

Survey on experiences and attitudes of parents toward disclosing information to children with genetic syndromes and their siblings in Japan

Many parents face the dilemma of when, how, and what to disclose to their children regarding their genetic conditions. The purpose of this study was to learn about the experiences of parents regarding disclosing information to their children with genetic conditions. A questionnaire was sent to 378 parents of children and adolescents with the following genetic syndromes: 22q11.2 deletion syndrome, Beckwith–Wiedemann syndrome, Noonan syndrome, Russell–Silver syndrome, Kabuki syndrome, Williams syndrome, Prader–Willi syndrome, and Sotos syndrome. Findings were analyzed using descriptive statistics for multiple-choice questions. Of the parents surveyed, 158 (41.8%) responded to the questionnaires. The average age of children with genetic syndromes was 12 years. Sixty-seven parents had disclosed relevant information to their children, whereas 91 had not. Among them (who had disclosed information), out of 53 respondents who answered that their affected child had siblings, 50 had disclosed the genetic condition of the affected child to the siblings as well. Sixty-eight out of 91 respondents who had not told information to affected child were planning to disclose the information in the future. Many respondents who had disclosed information did not regret this. They felt good talking about genetic conditions, and had talked about genetic conditions with the affected children following disclosure. This study contributed to our understanding of the attitudes of parents towards disclosing information to children with genetic syndromes.

Pubertal timing in children with Silver Russell syndrome compared to those born small for gestational age.

ContextData on pubertal timing in Silver Russell syndrome (SRS) are limited.Design and methodsRetrospective observational study including twenty-three SRS patients [11p15 loss of methylation, (11p15 LOM, n=10) and maternal uniparental disomy of chromosome 7 (mUPD7, n=13)] and 21 small for gestational age (SGA). Clinical (thelarche in females; testis volume ≥ 4 ml in males; pubarche), BMI SD trend from the age of 5 to 9 years to the time of puberty, biochemical parameters of puberty onset [Luteinizing hormone (LH), 17-β-estradiol, testosterone], and bone age progression were evaluatedResultsPubertal onset and pubarche occurred significantly earlier in children with SRS than in SGA (p 0.03 and p 0.001, respectively) and clinical signs of puberty onset occurred earlier in mUPD7 than in 11p15LOM group (p 0.003). Five SRS children experienced central precocious puberty and LH, 17-β-estradiol, testosterone were detected earlier in SRS than in SGA (p 0.01; p 0.0001). Bone age delay in SRS children was followed by rapid advancement; the delta between bone age and chronological age in SRS group became significantly higher than in SGA group at the age of 9-11 years (p 0.007). 11p15LOM patients were underweight at the age of 5 years and showed a progressive normalization of BMI that was significantly higher than in mUPD7 (p 0.04) and SGA groups (p 0.03) at puberty onset.ConclusionTiming of puberty is affected in SRS and occurred earlier in mUPD7 compared to 11p15LOM. The impact of early puberty on adult height and metabolic status deserves long-term evaluation.