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.

Pubertal origin of growth retardation in inborn errors of protein metabolism: A longitudinal cohort study.

OBJECTIVES: Inherited amino-acid metabolism disorders (IAAMDs) require lifelong protein-restricted diet. We aimed to investigate: 1/ whether IAAMDs was associated with growth, pubertal, bone mineral apparent density (BMAD) or body composition impairments; 2/ associations linking height, amino-acid mixture (AAM), plasma amino-acids and IGF1 concentrations. DESIGN: Retrospective longitudinal study of 213 patients with neonatal-onset urea cycle disorders (UCD,n = 77), organic aciduria (OA,n = 89), maple syrup urine disease (MSUD,n = 34), or tyrosinaemia type 1 (n = 13). METHODS: We collected growth parameters, pubertal status, BMAD, body composition, protein-intake, and IGF1 throughout growth. RESULTS: Overall final height (n = 69) was below target height (TH): -0.9(1.4) vs. -0.1(0.9) SD, p < 0.001. Final height was ≤ TH-2SD in 12 (21%) patients. Height ≤ - 2SD was more frequent during puberty than during early-infancy and pre-puberty: 23.5% vs. 6.9%, p = 0.002; and vs. 10.7%, p < 0.001. Pubertal delay was frequent (26.7%). Height (SD) was positively associated with isoleucine concentration: ß, 0.008; 95%CI, 0.003 to 0.012; p = 0.001. In the pubertal subgroup, height (SD) was lower in patients with vs. without AAM supplementation: -1.22 (1.40) vs. -0.63 (1.46) (p = 0.02). In OA, height and median (IQR) isoleucine and valine concentrations(µmol/L) during puberty were lower in patients with vs. without AAM supplementation: -1.75 (1.30) vs. -0.33 (1.55) SD, p < 0.001; and 40 (23) vs. 60 (25) (p = 0.02) and 138 (92) vs. 191 (63) (p = 0.01), respectively. No correlation was found with IGF1. Lean-mass index was lower than fat-mass index: -2.03 (1.15) vs. -0.44 (0.89), p < 0.001. CONCLUSIONS: In IAAMDs, growth retardation worsened during puberty which was delayed in all disease subgroups. Height seems linked to the disease, AAM composition and lower isoleucine concentration, independently of the GH-IGF1 pathway. We recommend close monitoring of diet during puberty.

The experience of diagnosis announcement in rare endocrine diseases: A survey of the French FIRENDO network.

CONTEXT: Diagnosis announcement of a chronic disease is a crucial moment for patients as well as for their families and an important step in the management of severe conditions such as rare endocrine diseases. Little is known of how diagnosis is communicated to patients and families. The FIRENDO network was created by the third French Plan for Rare Diseases, to promote autonomy, care and research on rare endocrine diseases. OBJECTIVES: The aim of this study was to characterize, for the first time, the experience and needs of patients and/or their parents around the announcement of diagnosis to ensure optimal quality of care. METHODS: A quantitative self-administered survey on diagnosis announcement procedures in rare endocrine diseases was launched in April 2017 by the ad hoc FIRENDO thematic working group in collaboration with its 11 partnering patient associations and support groups. The questionnaire was designed and revised by patient support group representatives, adult and pediatric endocrinologists, psychologists and biologists, all expert in rare endocrine diseases. It was made available on the FIRENDO network website and distributed mainly by email with electronic links on their respective websites to members of all affiliated patient support groups. RESULTS: Questionnaires were filled out by 391 patients and 223 parents (median age of patients: 39 years). The following conditions were associated with at least 30 answers: Addison's disease, classical forms of congenital adrenal hyperplasia (CAH), Russell-Silver syndrome, Cushing's syndrome, acromegaly and craniopharyngioma. Overall, some announcement modalities were judged favorably by patients: physician's empathy, availability and use of clear terms, and presence of family at the time of announcement. However, a lack of psychological care and information documents was reported, as well as some inadequate procedures such as postal mail announcements. CONCLUSION: This work suggests that better knowledge of the patient's experience is useful for improving the diagnosis announcement of rare endocrine disorders. The main recommendations derived from the survey were the need for several announcement visits, information on patient support groups and reference centers, imperatively avoiding impersonal announcement, and the usefulness of a written accompanying document.

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.

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

BACKGROUND: Imprinting 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. RESULTS: We 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. CONCLUSIONS: Based 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.

Comprehensive genetic testing approaches as the basis for personalized management of growth disturbances: current status and perspectives.

The implementation of high-throughput and deep sequencing methods in routine genetic diagnostics has significantly improved the diagnostic yield in patient cohorts with growth disturbances and becomes increasingly important as the prerequisite of personalized medicine. They provide considerable chances to identify even rare and unexpected situations; nevertheless, we must be aware of their limitations. A simple genetic test in the beginning of a testing cascade might also help to identify the genetic cause of specific growth disorders. However, the clinical picture of genetically caused growth disturbance phenotypes can vary widely, and there is a broad clinical overlap between different growth disturbance disorders. As a consequence, the clinical diagnosis and therewith connected the decision on the appropriate genetic test is often a challenge. In fact, the clinician asking for genetic testing has to weigh different aspects in this decision process, including appropriateness (single gene test, stepwise procedure, comprehensive testing), turnaround time as the basis for rapid intervention, and economic considerations. Therefore, a frequent question in that context is 'what to test when'. In this review, we aim to review genetic testing strategies and their strengths and limitations and to raise awareness for the future implementation of interdisciplinary genome medicine in diagnoses, treatment, and counselling of growth disturbances.

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.

Analysis of a pitfall in congenital adrenal hyperplasia newborn screening: evidence of maternal use of corticoids detected on dried blood spot.

Neonatal screening for congenital adrenal hyperplasia (CAH) faces many specific challenges. It must be done using a performant analytical approach that combines sensitivity and specificity to capture the potential causes of mortality during the first week of life, such as salt wasting and glucocorticoid deficiency. Here, we confirm that maternal inhaled corticosteroid intake during pregnancy is a possible cause of missed CAH diagnosis. Thanks to liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, we were able to quantify endogenous steroid metabolites and also detect the presence of exogenous steroids in the dried blood spot of a newborn. Adding LC-MS/MS analysis as second-tier test, especially one that includes both 17-hydroxyprogesterone and 21-deoxycortisol measurements, would probably improve CAH diagnosis. In familial neonatal screening one could also look for maternal corticosteroid therapies that are hidden to prevent false-negative tests.

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.

A proof of concept of a machine learning algorithm to predict late-onset 21-hydroxylase deficiency in children with premature pubic hair.

In children with premature pubarche (PP), late onset 21-hydroxylase deficiency (21-OHD), also known as non-classical congenital adrenal hyperplasia (NCCAH), can be routinely ruled out by an adrenocorticotropic hormone (ACTH) test. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), a quantitative assay of the circulating steroidome can be obtained from a single blood sample. We hypothesized that, by applying multivariate machine learning (ML) models to basal steroid profiles and clinical parameters of 97 patients, we could distinguish children with PP from those with NCCAH, without the need for ACTH testing. Every child presenting with PP at the Trousseau Pediatric Endocrinology Unit between 2016 and 2018 had a basal and stimulated steroidome. Patients with central precocious puberty were excluded. The first set of patients (year 1, training set, n = 58), including 8 children with NCCAH verified by ACTH test and genetic analysis, was used to train the model. Subsequently, a validation set of an additional set of patients (year 2, n = 39 with 5 NCCAH) was obtained to validate our model. We designed a score based on an ML approach (orthogonal partial least squares discriminant analysis). A metabolic footprint was assigned for each patient using clinical data, bone age, and adrenal steroid levels recorded by LC-MS/MS. Supervised multivariate analysis of the training set (year 1) and validation set (year 2) was used to validate our score. Based on selected variables, the prediction score was accurate (100%) at differentiating premature pubarche from late onset 21-OHD patients. The most significant variables were 21-deoxycorticosterone, 17-hydroxyprogesterone, and 21-deoxycortisol steroids. We proposed a new test that has excellent sensitivity and specificity for the diagnosis of NCCAH, due to an ML approach.

Low Maternal DLK1 Levels at 26 Weeks Is Associated With Small for Gestational Age at Birth.

Detecting SGA (small for gestational age) during pregnancy improves the fetal and neonatal prognosis. To date, there is no valid antenatal biomarker of SGA used in clinical practice. Maternal circulating DLK1 (delta-like non-canonical notch ligand 1) levels have been shown to be significantly lower in pregnant women at 36 weeks of gestation (WG) who delivered a SGA newborn than in controls. Data in the literature are contradictory on the association between maternal circulating DLK1 levels and placental vascular dysfunction. The objective was to determine if maternal DLK1 levels in the second trimester of pregnancy are predictive of SGA, and to assess whether the measurement of DLK1 levels in maternal blood could be a means to distinguish SGA with placental vascular dysfunction from that due to other causes. We conducted a nested cased-control study within the EDEN mother-child cohort. 193 SGA (birth weight < 10th percentile) and 370 mother-child control (birth weight between the 25th and 75th percentile) matched pairs were identified in the EDEN cohort. Maternal circulating DLK1 levels at 26 WG were significantly lower for children born SGA than for controls (27.7 ± 8.7 ng/mL vs 30.4 ± 10.6 ng/mL, p = 0.001). Maternal blood DLK1 levels in the first quartile (DLK1 < 22.85 ng/mL) were associated with an odds ratio for SGA of 1.98 [1.15 - 3.37]. DLK1 was less predictive of SGA than ultrasound, with an area under the curve of 0.578. Maternal circulating DLK1 levels were not significantly different in cases of SGA with signs of placental vascular dysfunction (n = 63, 27.1 ± 9.2 ng/mL) than in those without placental dysfunction (n = 129, 28.0 ± 8.5 ng/mL, p = 0.53). The level of circulating DLK1 is reduced in the second trimester of pregnancy in cases of SGA at birth, independently of signs of placental vascular dysfunction. However, DLK1 alone cannot predict the risk of SGA.

Quality of life and mental health of adolescents and adults with Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by prenatal and postnatal growth retardation. Despite normal intellectual functioning, psychosocial and behavioral difficulties have been observed in this syndrome. However, few studies have dealt with these aspects, even though this could enhance the current understanding of the SRS and, more importantly, improve the management of potential psychosocial problems. Given the sparse literature, this cross-sectional study aimed to establish the psychosocial and behavioral profile of individuals with SRS. To this end, we assessed the quality of life (World Health Organization Quality of Life Questionnaire-Short Form), self-esteem (Coopersmith's Self-Esteem Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory), and behavioral and emotional problems (Child Behavior Checklist and Adult Behavior Checklist) in a sample of 19 adolescents and adults with SRS and 18 without SRS (controls). We also analyzed clinical features, molecular genetic diagnosis, and past or current treatments of participants with SRS. Based on prior studies, we expected to observe psychological and behavioral difficulties in our clinical population. We also expected these difficulties, shared by both adolescents and adults with SRS, to be associated with factors such as height, genetics, or treatment. Overall, our results showed that participants with SRS had similar performances to those of controls, despite high interindividual variability among the adults with SRS. For example, while adults with SRS had a similar mean total self-esteem score to control participants, 45% of the adults with SRS still had very low self-esteem. In addition, adolescents and adults with SRS did not necessarily have the same difficulties. Social and behavioral problems appeared to be more common in adolescents with upd(7)mat while in adults, difficulties were not associated with either height, weight, NH-CSS score, or GH treatment but did appear to be associated with GnRHa treatment. Indeed, low self-esteem was associated with GnRHa treatment. Overall, this study shows that early intervention and multidisciplinary care right up to adulthood, including psychological support, are needed for this population, regardless of the molecular abnormality responsible for SRS, to cope with potential psychosocial problems.

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.

Age at diagnosis in patients with chronic congenital endocrine conditions: a regional cohort study from a reference center for rare diseases.

BACKGROUND: For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as  it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late. OBJECTIVE: To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development. PATIENTS AND METHODS: This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening. RESULTS: Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD. CONCLUSION: The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.

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

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.

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.

New Horizons in Short Children Born Small for Gestational Age.

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.

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

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.

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

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 (M = 95.40, SD = 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.

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

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.