Height and body mass index in molecularly confirmed Silver-Russell syndrome and the long-term effects of growth hormone treatment.

OBJECTIVE: Silver-Russell syndrome (SRS) causes short stature. Growth hormone (GH) treatment aims to increase adult height. However, data are limited on the long-term outcomes of GH in patients with molecularly confirmed SRS. This study evaluated height, body mass index (BMI) and GH treatment in molecularly confirmed SRS. DESIGN: An observational study with retrospective data collection. PATIENTS: Individuals with molecularly confirmed SRS aged ≥13 years. MEASUREMENTS: Data were collected on height, height gain (change in height standard deviation score [SDS] from childhood to final or near-final height), BMI and gain in BMI (from childhood to adulthood) and previous GH treatment. RESULTS: Seventy-one individuals (40 female) were included. The median age was 22.0 years (range 13.2-69.7). The molecular diagnoses: H19/IGF2:IG-DMR LOM in 80.3% (57/71); upd(7)mat in 16.9% (12/71) and IGF2 mutation in 2.8% (2/71). GH treatment occurred in 77.5% (55/71). Total height gain was greater in GH-treated individuals (median 1.53 SDS vs. 0.53 SDS, p = .007), who were shorter at treatment initiation (-3.46 SDS vs. -2.91 SDS, p = .04) but reached comparable heights to GH-untreated individuals (-2.22 SDS vs. -2.74 SDS, p = .7). In GH-treated individuals, BMI SDS was lower at the most recent assessment (median -1.10 vs. 1.66, p = .002) with lower BMI gain (2.01 vs. 3.58, p = .006) despite similar early BMI SDS to GH-untreated individuals (median -2.65 vs. -2.78, p = .3). CONCLUSIONS: These results support the use of GH in SRS for increasing height SDS. GH treatment was associated with lower adult BMI which may reflect improved metabolic health even following discontinuation of therapy.

Increasing knowledge in IGF1R defects: lessons from 35 new patients.

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 IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R 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 IGF1R 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 IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R 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.

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

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 IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C. 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.

New clinical and molecular insights into Silver-Russell syndrome.

PURPOSE OF REVIEW: The purpose of review is to summarize new outcomes for the clinical characterization, molecular strategies, and therapeutic management of Silver-Russell syndrome (SRS). RECENT FINDINGS: Various teams have described the clinical characteristics of SRS patients by genotype. A clinical score for the definition of SRS and for orienting molecular investigations has emerged. Insulin-like growth factor 2 (a major fetal growth factor) has been implicated in the pathophysiology of SRS, as the principle molecular mechanism underlying the disease is loss of methylation of the 11p15 region, including the imprinted insulin-like growth factor 2 gene. Maternal uniparental disomy of chromosome 7 and recently identified rare molecular defects have also been reported in patients with SRS. However, 40% of patients still have no molecular diagnosis. SUMMARY: The definition of SRS has remained clinical since the first description of this condition, despite the identification of various molecular causes. The clinical issues faced by these patients are similar to those faced by other patients born small for gestational age (SGA), but patients with SRS require specific multidisciplinary management of their nutrition, growth, and metabolism, as they usually present an extreme form of SGA. Molecular analyses can confirm SRS, and are of particular importance for genetic counseling and prenatal testing.

Premature pubarche before one year of age: distinguishing between mini-puberty variants and precocious puberty.

BACKGROUND: The aim of this study was to facilitate the distinction between the benign "mini-puberty of early infancy" and precocious puberty (PP). MATERIAL AND METHODS: We compared 59 patients (21 boys and 38 girls) seen for pubic hair development before one year of age diagnosed as mini-puberty to 13 patients (2 boys) in whom pubertal development before one year revealed a PP. RESULTS: The boys with mini-puberty presented with pubic hair development and prepubertal testicular volume, with low plasma testosterone concentrations. Their gonadotropin responses to gonadotropin releasing hormone (GnRH) test showed predominant luteinising hormone increase in 9/13. The girls presented with pubic hair development that was accompanied by breast development in 47% of cases, with low plasma estradiol concentrations. Their gonadotropin responses showed predominant follicle-stimulating hormone increase in the 17 evaluated. The patients with PP had organic central PP (5 hypothalamic hamartoma) or idiopathic central PP (n=6), or peripheral PP (one ovarian tumor and one congenital adrenal hyperplasia). The diagnosis was challenging only in 3 girls with idiopathic central PP presenting with prepubertal plasma estradiol concentrations and responses to GnRH test. CONCLUSIONS: The diagnosis of PP was easily determined based on the clinical presentation and the pubertal concentrations of testosterone in boys or of estradiol in girls, as was the diagnosis of central or peripheral origin of PP based on gonadotropin response to the GnRH test. Once PP is excluded, these patients need careful follow-up and physician consultation is needed if clinical pubertal signs progress.

Perinatal features of children with Silver-Russell syndrome due to 11p15 loss of methylation.

Background: A diagnosis of Silver-Russell syndrome (SRS), a rare imprinting disorder responsible for foetal growth restriction, is considered for patients presenting at least four criteria of the Netchine-Harbison clinical scoring system (NH-CSS). Certain items of the NH-CSS are not assessable until the age of 2 years. The objective was to determine perinatal characteristics of children with SRS to allow an early diagnosis. Methods: We retrospectively compared the perinatal characteristics of children with SRS (n = 17) with those of newborns small for gestational age (SGA) due to placental insufficiency (PI) (n = 21). Results: Children with SRS showed earlier and more severely altered foetal biometry than SGA newborns due to PI. Twenty-three percent of patients with SRS showed uterine artery Doppler anomalies. SRS children were significantly smaller at birth (birth length <-3 SDS in 77% of cases in the SRS group vs. 15% in the PI group, p = 0.0001). Conclusion: The diagnosis of SRS must be evoked in the neonatal period for SGA newborns with a growth delay present from the second trimester of pregnancy, a birth length <-3 SDS and a relative macrocephaly. Doppler anomalies, classically used to orient the cause of SGA towards PI, did not rule out the diagnosis of SRS.

Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis.

BACKGROUND: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. METHODS: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. RESULTS: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. CONCLUSIONS: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.

Imprinting disorders.

Imprinting disorders (ImpDis) are congenital conditions that are characterized by disturbances of genomic imprinting. The most common individual ImpDis are Prader-Willi syndrome, Angelman syndrome and Beckwith-Wiedemann syndrome. Individual ImpDis have similar clinical features, such as growth disturbances and developmental delay, but the disorders are heterogeneous and the key clinical manifestations are often non-specific, rendering diagnosis difficult. Four types of genomic and imprinting defect (ImpDef) affecting differentially methylated regions (DMRs) can cause ImpDis. These defects affect the monoallelic and parent-of-origin-specific expression of imprinted genes. The regulation within DMRs as well as their functional consequences are mainly unknown, but functional cross-talk between imprinted genes and functional pathways has been identified, giving insight into the pathophysiology of ImpDefs. Treatment of ImpDis is symptomatic. Targeted therapies are lacking owing to the rarity of these disorders; however, personalized treatments are in development. Understanding the underlying mechanisms of ImpDis, and improving diagnosis and treatment of these disorders, requires a multidisciplinary approach with input from patient representatives.

IGF2: Development, Genetic and Epigenetic Abnormalities.

In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of IGF2 expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired IGF2 gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver-Russell and Beckwith-Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of IGF2-linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering IGF2 expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of IGF2 defects in these patients.

Dental pulp stem cells as a promising model to study imprinting diseases.

Parental imprinting is an epigenetic process leading to monoallelic expression of certain genes depending on their parental origin. Imprinting diseases are characterized by growth and metabolic issues starting from birth to adulthood. They are mainly due to methylation defects in imprinting control region that drive the abnormal expression of imprinted genes. We currently lack relevant animal or cellular models to unravel the pathophysiology of growth failure in these diseases. We aimed to characterize the methylation of imprinting regions in dental pulp stem cells and during their differentiation in osteogenic cells (involved in growth regulation) to assess the interest of this cells in modeling imprinting diseases. We collected dental pulp stem cells from five controls and four patients (three with Silver-Russell syndrome and one with Beckwith-Wiedemann syndrome). Methylation analysis of imprinting control regions involved in these syndromes showed a normal profile in controls and the imprinting defect in patients. These results were maintained in dental pulp stem cells cultured under osteogenic conditions. Furthermore, we confirmed the same pattern in six other loci involved in imprinting diseases in humans. We also confirmed monoallelic expression of H19 (an imprinted gene) in controls and its biallelic expression in one patient. Extensive imprinting control regions methylation analysis shows the strong potential of dental pulp stem cells in modeling imprinting diseases, in which imprinting regions are preserved in culture and during osteogenic differentiation. This will allow to perform in vitro functional and therapeutic tests in cells derived from dental pulp stem cells and generate other cell-types.

Impact of claudin-10 deficiency on amelogenesis: Lesson from a HELIX tooth.

In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin-10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron-based X-ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations.

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

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.

Demographic Characteristics, Risk Factors, and Presenting Features of Children with Symptomatic Nutritional Rickets: A French Series.

AIM: To describe the demographic characteristics, risk factors, and presenting features of children with symptomatic nutritional rickets in France. METHODS: This is a retrospective study of 38 children diagnosed with nutritional rickets from 1998 to 2019. RESULTS: We observed a higher frequency of rickets in males (74 vs. 26%), in young children (median age at diagnosis: 23 months; 82% were younger than 5 years), and in children with a non-Caucasian ethnic background (89%). Most children were exclusively breastfed (78%) without adequate vitamin D supplementation (89%). The most common presentations were bowed legs (63%), hypocalcemic seizures (21%), and growth retardation (11%). Approximately half (62%) of the children were hypocalcemic. The children presenting with hypocalcemic seizures were significantly younger (0.8 vs. 2.2 years; p = 0.041) and had lower total serum calcium levels (1.44 vs. 2.17 mmol/L; p < 0.0001), higher phosphatemia (1.43 vs. 1.23 mmol/L; p = 0.020), and lower 25-hydroxy vitamin D levels (3 vs. 7 ng/mL; p = 0.020) but similar parathyroid hormone levels (357 vs. 289 ng/mL; p = 0.940) compared to rickets cases who did not experience hypocalcemic seizures. A dilated cardiomyopathy was detected in 14% of the children who had undergone echocardiography. CONCLUSION: Nutritional rickets remains endemic in the pediatric population and its most severe forms can have life-threatening sequelae. Health practitioners need to be cognizant of these facts to raise awareness and screen high-risk populations.

Overgrowth syndromes - clinical and molecular aspects and tumour risk.

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.

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

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.

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.

We report an original association of complex genetic defects in a patient carrying both an 11p paternal duplication, resulting in the double expression of insulin-like growth factor 2 (IGF2), as reported in Beckwith-Wiedemann syndrome, and a 15q terminal deletion, including the type 1 IGF receptor gene (IGF1R), 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.

Transcriptional profiling at the DLK1/MEG3 domain explains clinical overlap between imprinting disorders.

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 DLK1/MEG3 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 IGF2 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 IGF2 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 DLK1/MEG3 domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.

Diagnosis and management of postnatal fetal growth restriction.

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.

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

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.

Imprinted disorders and growth.

Fetal growth is a complex process. Its restriction is associated with morbidity and long-term metabolic consequences. Imprinted genes have a critical role in mammalian fetal growth. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders with opposite fetal growth disturbance. SRS is leading to severe fetal and postnatal growth retardation with severe feeding difficulties during early childhood and long-term metabolic consequences and BWS is an overgrowth syndrome with an enhanced risk of tumors during childhood. Epigenetic (abnormal methylation at the imprinting center regions) or genetic (mutations, duplications, uniparental disomy [UPD]) including defects of imprinted genes on chromosome 11 (BWS and SRS), 7 (SRS) and more recently 14 (SRS) have been identified in these two syndromes. In humans, the 11p15 region contains genes important for the regulation of fetal and postnatal growth. This region includes two imprinted domains: the IGF2/H19 domain regulated by imprinting center region 1 (ICR1 or H19/IGF2:IG-DMR) and the CDKN1C/KCNQ1OT1 domain regulated by ICR2 (or KCNQ1OT1: TSS DMR).