Publications by authors named "Irene Netchine"

81 Publications

Silver Russell syndrome in a preterm girl with 8q12.1 deletion encompassing PLAG1.

Clin Dysmorphol 2021 Oct;30(4):194-196

Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint Antoine, APHP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France.

Silver Russell syndrome (SRS) is a congenital disorder characterized by intrauterine growth retardation (IUGR), feeding difficulties and postnatal growth retardation. In a small number of cases, PLAG1 variants have been described (OMIM #618907). PLAG1 haploinsufficiency decreases Insulin-like growth factor 2 expression and produces a Silver Russell syndrome-like phenotype. Here, we describe the phenotype and molecular features of a 26 months girl with clinical features of SRS, and a de novo 2.1 Mb deletion encompassing PLAG1 is reported in association with clinical features suggestive of SRS.
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http://dx.doi.org/10.1097/MCD.0000000000000375DOI Listing
October 2021

Screening of patients born small for gestational age with the Silver-Russell syndrome phenotype for DLK1 variants.

Eur J Hum Genet 2021 Jul 19. Epub 2021 Jul 19.

Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint Antoine, APHP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France.

Silver-Russell syndrome (SRS) is a rare imprinting disorder associated with prenatal and postnatal growth retardation. Loss of methylation (LOM) on chromosome 11p15 is observed in 40 to 60% of patients and maternal uniparental disomy (mUPD) for chromosome 7 (upd(7)mat) in ~5 to 10%. Patients with LOM or mUPD 14q32 can present clinically as SRS. Delta like non-canonical Notch ligand 1 (DLK1) is one of the imprinted genes expressed from chromosome 14q32. Dlk1-null mice display fetal growth restriction (FGR) but no genetic defects of DLK1 have been described in human patients born small for gestational age (SGA). We screened a cohort of SGA patients with a SRS phenotype for DLK1 variants using a next-generation sequencing (NGS) approach to search for new molecular defects responsible for SRS. Patients born SGA with a clinical suspicion of SRS and normal methylation by molecular testing at the 11p15 or 14q32 loci and upd(7)mat were screened for DLK1 variants using targeted NGS. Among 132 patients, only two rare variants of DLK1 were identified (NM_003836.6:c.103 G > C (p.(Gly35Arg) and NM_003836.6: c.194 A > G p.(His65Arg)). Both variants were inherited from the mother of the patients, which does not favor a role in pathogenicity, as the mono-allelic expression of DLK1 is from the paternal-inherited allele. We did not identify any pathogenic variants in DLK1 in a large cohort of SGA patients with a SRS phenotype. DLK1 variants are not a common cause of SGA.
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http://dx.doi.org/10.1038/s41431-021-00927-5DOI Listing
July 2021

New Horizons in Short Children Born Small for Gestational Age.

Front Pediatr 2021 13;9:655931. Epub 2021 May 13.

Department of Pediatrics, Institute for Research, Hospitalization and Health Care (IRCCS) Children's Hospital Giannina Gaslini, Genova, Italy.

Children born small for gestational age (SGA) comprise a heterogeneous group due to the varied nature of the cause. Approximately 85-90% have catch-up growth within the first 4 postnatal years, while the remainder remain short. In later life, children born SGA have an increased risk to develop metabolic abnormalities, including visceral adiposity, insulin resistance, and cardiovascular problems, and may have impaired pubertal onset and growth. The third "360° European Meeting on Growth and Endocrine Disorders" in Rome, Italy, in February 2018, funded by Merck KGaA, Germany, included a session that examined aspects of short children born SGA, with three presentations followed by a discussion period, on which this report is based. Children born SGA who remain short are eligible for GH treatment, which is an approved indication. GH treatment increases linear growth and can also improve some metabolic abnormalities. After stopping GH at near-adult height, metabolic parameters normalize, but pharmacological effects on lean body mass and fat mass are lost; continued monitoring of body composition and metabolic changes may be necessary. Guidelines have been published on diagnosis and management of children with Silver-Russell syndrome, who comprise a specific group of those born SGA; these children rarely have catch-up growth and GH treatment initiation as early as possible is recommended. Early and moderate pubertal growth spurt can occur in children born SGA, including those with Silver-Russell syndrome, and reduce adult height. Treatments that delay puberty, specifically metformin and gonadotropin releasing hormone analogs in combination with GH, have been proposed, but are used off-label, currently lack replication of data, and require further studies of efficacy and safety.
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http://dx.doi.org/10.3389/fped.2021.655931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155308PMC
May 2021

Growth Restriction and Genomic Imprinting-Overlapping Phenotypes Support the Concept of an Imprinting Network.

Genes (Basel) 2021 04 17;12(4). Epub 2021 Apr 17.

Medical Faculty, AP-HP, Armand Trousseau Hospital-Functional Endocrine Research Unit, INSERM, Research Centre Saint-Antoine, Sorbonne University, 75012 Paris, France.

Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach.
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http://dx.doi.org/10.3390/genes12040585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073901PMC
April 2021

Insights from the genetic characterization of central precocious puberty associated with multiple anomalies.

Hum Reprod 2021 01;36(2):506-518

Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics, LIM42, Department of Endocrinology and Metabolism, Clinicas Hospital, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.

Study Question: Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control?

Summary Answer: In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control.

What Is Known Already: A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder.

Study Design, Size, Duration: This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions.

Participants/materials, Setting, Methods: A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities.

Main Results And The Role Of Chance: Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams-Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS.

Limitations, Reasons For Caution: The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet.

Wider Implications Of The Findings: The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing.

Study Funding/competing Interest(s): This work was supported by grant number 2018/03198-0 (to A.P.M.C.) and grant number 2013/08028-1 (to A.C.V.K) from the São Paulo Research Foundation (FAPESP), and grant number 403525/2016-0 (to A.C.L.) and grant number 302849/2015-7 (to A.C.L.) and grant number 141625/2016-3 (to A.C.V.K) from the National Council for Scientific and Technological Development (CNPq). The authors have nothing to disclose.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa306DOI Listing
January 2021

Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN).

Orphanet J Rare Dis 2020 06 8;15(1):144. Epub 2020 Jun 8.

Department of Paediatrics and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany.

Background: With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex.

Main Body: This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate.

Conclusions: The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and -modifying mutation, their informational value, and cost-effectiveness. The future assessment of data from different omic approaches should be embedded in interdisciplinary discussions using all available clinical and molecular data.
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http://dx.doi.org/10.1186/s13023-020-01420-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278165PMC
June 2020

Sleep disordered breathing in Silver-Russell syndrome patients: a new outcome.

Sleep Med 2019 12 15;64:23-29. Epub 2019 Jun 15.

Sorbonne Université, INSERM, UMR_S 938 Centre de Recherche Saint Antoine, APHP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France.

Objective: Imprinting disorders (ID), such as Prader-Willi syndrome (PWS), are associated with sleep-disordered breathing (SDB). No data are available for Silver-Russell syndrome (SRS), another ID that shares clinical features with PWS, although many patients describe excessive daytime sleepiness, disturbed sleep, and snoring. The aim of this study was to characterize sleep in children with SRS and to evaluate the impact of recombinant growth hormone (rGH) therapy.

Methods: We performed a retrospective analysis of sleep recordings in 40 patients with molecularly proven SRS (methylation anomaly in 11p15 [n = 32] or maternal uniparental disomy of chromosome 7 [n = 16]). Sleep recordings were either by means of polygraphy or polysomnography (PSG) (n = 16). A total of 34 patients received rGH therapy.

Results: We collected 61 sleep recordings. The mean apnea-hypopnea index (AHI) was 3.4 events/h (0-12.4), with a mean central AHI of 0.5 events/h (0-2.4). SDB was identified in 73.8% (n = 45) of the recordings and was severe in 4.9%. SDB was present in 86.4% of patients before rGH therapy and was severe in 13.6%. AHI worsened for 5 of 12 patients with sleep recordings before and after rGH therapy initiation, reaching mild impairment. The mean rGH dose was 32.3 μg/kg/(12.9-51.4), with a mean insulin-like growth factor 1 plasma level of 1.7 SDS (-1.9 to 6.6).

Conclusion: Most patients with SRS present with SDB with an obstructive profile, possibly explained by narrowing of the airways and lymphoid organ hypertrophy. We recommend systematic ear-nose-throat evaluation of SRS patients and PSG if there are clinical anomalies, preferably before initiating rGH therapy, to monitor and adapt the management of patients with SDB.
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http://dx.doi.org/10.1016/j.sleep.2019.05.020DOI Listing
December 2019

Increasing knowledge in defects: lessons from 35 new patients.

J Med Genet 2020 03 5;57(3):160-168. Epub 2019 Oct 5.

Sorbonne Université, UFR Médecine, Paris, France.

Background: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.

Methods: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.

Results: We detected 21 defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of . Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.

Conclusion: We report eight new pathogenic variants of and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.
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http://dx.doi.org/10.1136/jmedgenet-2019-106328DOI Listing
March 2020

Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.

Horm Res Paediatr 2019 12;92(1):1-14. Epub 2019 Sep 12.

University Children´s Hospital, Tübingen, Germany.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
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http://dx.doi.org/10.1159/000502231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979443PMC
April 2020

Intellectual functioning in Silver-Russell syndrome: First study in adults.

Appl Neuropsychol Adult 2021 Jul-Aug;28(4):391-402. Epub 2019 Aug 8.

Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, CHU de Rennes, Rennes, France.

Silver-Russell syndrome (SRS) is a rare genetic disorder (estimated incidence 1/30,000 to 100,000 live births). So far, only a few studies have focused on the cognitive profile of individuals with SRS, and these were conducted some time ago, concentrated on pediatric cohorts, and included patients who had been diagnosed using a variety of clinical diagnostic systems. There has yet to be any research on the intellectual functioning of adults with SRS. This study sought to establish the intelligence, strengths and weaknesses within intellectual profile of adults with SRS, compared with normative data. Ten individuals with 11p15 epimutation aged 18-39 years completed the Wechsler Adult Intelligence Scale-Fourth Edition. Measures of interest included participants' intelligence (Full Scale Intelligence Quotient [FSIQ]) and four domains of cognitive functioning: verbal comprehension, perceptual reasoning, working memory and processing speed. Discrepancy scores were calculated, and descriptive statistical and linear correlations were used to investigate factors associated with IQ outcome. Clinical and medical information such as rehabilitation, and perceived difficulties in daily life were collected by interviews and questionnaires. Results showed that the mean FSIQ score was in the average range ( = 95.40,  = 18.55) and they performed best on verbal comprehension. Frequent daily difficulties were reported by patients and/or their families: learning disabilities and low self-esteem were perceived by 60% of adults. Early intervention and multidisciplinary care from childhood to adulthood are important in SRS for care potential medical, cognitive and psychosocial problems. This is the first study to document the intellectual functioning of adults with SRS.
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http://dx.doi.org/10.1080/23279095.2019.1644643DOI Listing
August 2019

Roles of Type 1 Insulin-Like Growth Factor (IGF) Receptor and IGF-II in Growth Regulation: Evidence From a Patient Carrying Both an 11p Paternal Duplication and 15q Deletion.

Front Endocrinol (Lausanne) 2019 30;10:263. Epub 2019 Apr 30.

Sorbonne Université, INSERM, Centre de Recherche Saint Antoine, APHP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France.

We report an original association of complex genetic defects in a patient carrying both an 11p paternal duplication, resulting in the double expression of , as reported in Beckwith-Wiedemann syndrome, and a 15q terminal deletion, including the (), resulting in haploinsufficiency for this gene. The patient was born with measurements appropriate for her gestational age but experienced growth retardation in early childhood, allowing a better comprehension of the IGF system in the pathophysiology of growth. It is possible that IGF-II plays a key role in fetal growth, independently of IGF1R signaling, and that its role is less important in post-natal growth, leaving IGF-I and growth hormone as the main actors.
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http://dx.doi.org/10.3389/fendo.2019.00263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503735PMC
April 2019

Normal Growth despite Combined Pituitary Hormone Deficiency.

Horm Res Paediatr 2019 25;92(2):133-142. Epub 2019 Apr 25.

Explorations Fonctionnelles et génétique endocriniennes, Hôpital Armand-Trousseau, AP-HP, Paris, France,

Background: The paradox of normal growth despite a lack of growth hormone (GH) is an unexplained phenomenon described in some pathological (sellar, suprasellar, and hypothalamic disorders) and overgrowth syndromes. It has been suggested that the paradoxical growth is due to other GH variants, GH-like moieties, prolactin, insulin, insulin-like growth factors (IGFs), and unidentified serum factors or growth mechanisms. The objective of this study was to determine the mechanism underlying this normal growth without GH.

Case Description: We describe here growth, hormonal, and genetic analyses for an adolescent boy with panhypopituitarism who achieved an adult height above his genetic potential.

Results: Normal growth was observed despite low serum GH, IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) concentrations, but the IGF-II/IGFBP-3 molar ratio was slightly high. Panhypopituitarism was associated with a heterozygous missense mutation of HESX1, with variable penetrance in heterozygous relatives. Exome analysis detected heterozygous missense mutations of various genes involved in intracellular signaling pathways. The growth-promoting activity of the patient's serum was unable to induce AKT phosphorylation in the MCF-7 cell line.

Conclusion: The high IGF-II/IGFBP-3 molar ratio was not the cause of the sustained high growth velocity, due to the low affinity of IGF-II for IGF type 1 receptor. The key finding was the HESX1 mutation, as similar cases have been described before, suggesting a common mechanism for growth without GH. However, the variable penetrance of this variant in heterozygous relatives suggests that modifier genes or mechanisms involving combinations with mutations of other genes involved in intracellular signaling pathways might be responsible.
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http://dx.doi.org/10.1159/000499318DOI Listing
May 2020

Overgrowth syndromes - clinical and molecular aspects and tumour risk.

Nat Rev Endocrinol 2019 05;15(5):299-311

Sorbonne Université, INSERM UMR_S938, Centre de Recherche Saint Antoine, AP-HP Hôpital Trousseau, Paris, France.

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.
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http://dx.doi.org/10.1038/s41574-019-0180-zDOI Listing
May 2019

Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes.

Genet Res (Camb) 2019 03 4;101:e3. Epub 2019 Mar 4.

Institute of Human Genetics, University Hospital, Technical University of Aachen,Aachen,Germany.

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients. The authors from different reference centres for BWS and SRS have identified single patients with unexpected and even contradictory molecular findings in respect to the clinical diagnosis. These patients clinically do not fit the characteristic phenotypes of SRS or BWS, but illustrate their clinical heterogeneity. Thus, comprehensive molecular testing is essential for accurate diagnosis and appropriate management, to avoid premature clinical diagnosis and anxiety for the families.
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http://dx.doi.org/10.1017/S001667231900003XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044970PMC
March 2019

Transcriptional profiling at the domain explains clinical overlap between imprinting disorders.

Sci Adv 2019 02 20;5(2):eaau9425. Epub 2019 Feb 20.

Sorbonne Université, INSERM, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France.

Imprinting disorders (IDs) often affect growth in humans, leading to diseases with overlapping features, regardless of the genomic region affected. IDs related to hypomethylation of the human 14q32.2 region and its domain are associated with Temple syndrome (TS14). TS14 is a rare type of growth retardation, the clinical signs of which overlap considerably with those of Silver-Russell syndrome (SRS), another ID related to down-regulation at 11p15.5 region. We show that 14q32.2 hypomethylation affects expression, not only for genes at this locus but also for other imprinted genes, and especially lowers levels at 11p15.5. Furthermore, expression of nonimprinted genes is also affected, some of which are also deregulated in SRS patients. These findings highlight the epigenetic regulation of gene expression at the domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.
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http://dx.doi.org/10.1126/sciadv.aau9425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382400PMC
February 2019

Corpus Callosum Abnormalities and Short Femurs in Beckwith-Wiedemann Syndrome: A Report of Two Fetal Cases.

Fetal Pediatr Pathol 2018 Dec 31;37(6):411-417. Epub 2018 Dec 31.

a Unité d'Embryofœtopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP , Paris , France.

Introduction: Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth syndrome. Clinical features are highly variable, including occasional posterior fossa malformations but no femoral shortening.

Case Report: We report two fetuses with BWS associated with short femurs and corpus callosum hypoplasia. Case 2 was growth restricted. BWS was confirmed by molecular studies showing a loss of methylation at ICR2 at 11p15 chromosomic region in case 1 and a gain of methylation at ICR1 and a loss of methylation at ICR2 locus in case 2.

Conclusion: Although the phenotype and the genotype of BWS is now well-known, the presence of corpus callosum abnormalities and short femurs expand the phenotypic spectrum of the disorder.
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http://dx.doi.org/10.1080/15513815.2018.1520942DOI Listing
December 2018

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

Am J Hum Genet 2018 12 29;103(6):1038-1044. Epub 2018 Nov 29.

Sorbonne Université, INSERM, UMR_S 938, APHP, Hospital Trousseau, 75012 Paris, France.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288413PMC
December 2018

Methylome profiling of healthy and central precocious puberty girls.

Clin Epigenetics 2018 11 22;10(1):146. Epub 2018 Nov 22.

Division of Endocrinology & Metabolism, Development Endocrinology Unit, Laboratory of Hormones and Molecular Genetics/LIM42, Clinical Hospital, Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, SP, Brazil.

Background: Recent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal.

Results: Analyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP.

Conclusion: Methylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty.
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http://dx.doi.org/10.1186/s13148-018-0581-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251202PMC
November 2018

Diagnosis and management of postnatal fetal growth restriction.

Best Pract Res Clin Endocrinol Metab 2018 08 5;32(4):523-534. Epub 2018 Apr 5.

Sorbonne Université, INSERM, UMR_S 938 Centre de Recherche Saint Antoine, APHP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, F-75012, Paris, France. Electronic address:

Fetal growth restriction (FGR) can result from multiple causes, such as genetic, epigenetic, environment, hormonal regulation, or vascular troubles and their potential interaction. The physiopathology of FGR is not yet fully elucidated, but the insulin-like growth factor system is known to play a central role. Specific clinical features can lead to the identification of genetic syndromes in some patients. FGR leads to multiple global health concerns, from the perinatal period, with higher morbidity/mortality, through infancy, with neurodevelopmental, growth, and metabolic issues, to the onset of puberty and later in life, with subfertility and elevated risks of cardiovascular and kidney diseases. Adequate follow-up and therapeutics should be offered to these patients. We first review the main molecular etiologies leading to FGR and their specificities. We then highlight the main issues that FGR can raise later in life before concluding with the proposed management of these children.
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http://dx.doi.org/10.1016/j.beem.2018.03.013DOI Listing
August 2018

Chromosome 14q32.2 Imprinted Region Disruption as an Alternative Molecular Diagnosis of Silver-Russell Syndrome.

J Clin Endocrinol Metab 2018 07;103(7):2436-2446

Sorbonne Université, INSERM, UMR_S 938 Centre de Recherche Saint Antoine, Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France.

Context: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap.

Objective: To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS.

Patients: We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis.

Results: Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation.

Conclusions: Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.
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http://dx.doi.org/10.1210/jc.2017-02152DOI Listing
July 2018

Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature.

Hum Mutat 2018 06 24;39(6):790-805. Epub 2018 Apr 24.

Service de Génétique, CHU de Tours, Hôpital Bretonneau, Tours, France.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).
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http://dx.doi.org/10.1002/humu.23428DOI Listing
June 2018

Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.

Endocr Connect 2018 Mar 26;7(3):R126-R134. Epub 2018 Feb 26.

Aarhus University HospitalAarhus, Denmark

Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly.

Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry.

Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs.

Consensus Process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process.

Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.
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http://dx.doi.org/10.1530/EC-18-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868631PMC
March 2018

Human 3beta-hydroxysteroid dehydrogenase deficiency associated with normal spermatic numeration despite a severe enzyme deficit.

Endocr Connect 2018 Mar 2;7(3):395-402. Epub 2018 Feb 2.

Service d'Endocrinologie et Médecine de la ReproductionCentre de Référence des Maladies Endocrines Rares de la Croissance, Hôpital Saint Antoine, Groupe Hospitalier Universitaire Est, AP-HP, Paris, France.

Human 3 beta-hydroxysteroid dehydrogenase deficiency (3b-HSD) is a very rare form of congenital adrenal hyperplasia resulting from gene mutations. The estimated prevalence is less than 1/1,000,000 at birth. It leads to steroidogenesis impairment in both adrenals and gonads. Few data are available concerning adult testicular function in such patients. We had the opportunity to study gonadal axis and testicular function in a 46,XY adult patient, carrying a mutation. He presented at birth a neonatal salt-wasting syndrome. He had a micropenis, a perineal hypospadias and two intrascrotal testes. gene sequencing revealed 687del27 homozygous mutation. The patient achieved normal puberty at the age of 15 years. Transition from the paediatric department occurred at the age of 19 years. His hormonal profile under hydrocortisone and fludrocortisone treatments revealed normal serum levels of 17OH-pregnenolone, as well as SDHEA, ACTH, total testosterone, inhibin B and AMH. Pelvic ultrasound identified two scrotal testes of 21 mL each, without any testicular adrenal rest tumours. His adult spermatic characteristics were normal, according to WHO 2010 criteria, with a sperm concentration of 57.6 million/mL ( > 15), 21% of typical forms ( > 4%). Sperm vitality was subnormal (41%;  > 58%). This patient, in contrast to previous reports, presents subnormal sperm parameters and therefore potential male fertility in a 24-years-old patient with severe 3b-HSD deficiency. This case should improve counselling about fertility of male patients carrying mutation.
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http://dx.doi.org/10.1530/EC-17-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827574PMC
March 2018

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Nat Rev Endocrinol 2018 04 29;14(4):229-249. Epub 2018 Jan 29.

South West Thames Regional Genetics Service and St George's University of London and Institute of Cancer Research, London, SW17 0RE, UK.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
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http://dx.doi.org/10.1038/nrendo.2017.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022848PMC
April 2018

The Importance of Collaboration in Advancing Understanding of Rare Disorders: US/EU Joint Initiative on Silver-Russell Syndrome.

Pediatr Endocrinol Rev 2017 Nov;15(Suppl 1):98-101

Icahn School of Medicine at Mount Sinai, Department of Pediatrics, 1 Gustave L. Levy Pl, New York, New York 10029, USA.

Patient-support organizations can facilitate a significant change in the way rare disorders are approached. Besides connecting families with each other and directing patients to experienced medical specialists, these groups, by collaborating with government initiatives like COST, can effect the direction and funding of rare disease research. By concentrating the rare disease patient population and funneling them to specific centers of excellence, these organizations help build specialists' experience and their study populations. It requires a basic spirit of collaboration, driven parent leaders, a well-organized support platform, sources of funding, supportive clinical and research professionals and finally an effective method of collecting and disseminating information. Silver-Russell Syndrome is an excellent example of a rare disorder that has become better recognized, understood and treated because patient-support organizations, using the internet as a critical tool, have worked together with clinical care/research specialists and public funding agencies to build collaboration.
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http://dx.doi.org/10.17458/per.vol15.2017.snh.importancecollaborationadvancingDOI Listing
November 2017

Structural and sequence variants in patients with Silver-Russell syndrome or similar features-Curation of a disease database.

Hum Mutat 2018 03 11;39(3):345-364. Epub 2018 Jan 11.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Silver-Russell syndrome (SRS) is a clinically and molecularly heterogeneous disorder involving prenatal and postnatal growth retardation, and the term SRS-like is broadly used to describe individuals with clinical features resembling SRS. The main molecular subgroups are loss of methylation of the distal imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 (50%) and maternal uniparental disomy of chromosome 7 (5%-10%). Through a comprehensive literature search, we identified 91 patients/families with various structural and small sequence variants, which were suggested as additional molecular defects leading to SRS/SRS-like phenotypes. However, the molecular and phenotypic data of these patients were not standardized and therefore not comparable, rendering difficulties in phenotype-genotype comparisons. To overcome this challenge, we curated a disease database including (epi)genetic phenotypic data of these patients. The clinical features are scored according to the Netchine-Harbison clinical scoring system (NH-CSS), which has recently been accepted as standard by consensus. The structural and sequence variations are reviewed and where necessary redescribed according to recent recommendations. Our study provides a framework for both research and diagnostic purposes through facilitating a standardized comparison of (epi)genotypes with phenotypes of patients with structural/sequence variants.
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http://dx.doi.org/10.1002/humu.23382DOI Listing
March 2018

Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences.

J Med Genet 2018 03 9;55(3):205-213. Epub 2017 Dec 9.

AP-HP, Hôpitaux Universitaires Paris Est, Hôpital des Enfants Armand Trousseau, Service d'Explorations Fonctionnelles Endocriniennes, Paris, France.

Background: The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.

Objectives: To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.

Methods: From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.

Results: Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of , rather than , in the control of growth. Furthermore, it highlights the role of within the centromeric domain and suggests that the expected overexpression of from the paternal allele (in partial paternal duplications, excluding ) does not affect the expression of .

Conclusions: The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.
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http://dx.doi.org/10.1136/jmedgenet-2017-104919DOI Listing
March 2018
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