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A male purebred Barbados Blackbelly, twin to another male, was born with obvious external congenital abnormalities. Male twinwas normal. Abnormal lamb had a short torso and spinal column. At 1 week, the lamb was presented with dyspnea and lethargy,and euthanasia was elected. Lamb was submitted for full necropsy and for additional diagnostics. After postmortem, in additionto histopathology, radiographs and computed tomographs were obtained. Lamb had congenital vertebral and occipital malformations,meningitis, hypospadias, and renal malformation. To authors’ knowledge, hypospadias and vertebral malformation inthe Barbados Blackbelly breed has not been reported. Apparently, Barbados Blackbelly breed harbors closely related genetics, thusvigilant monitoring for genetic malformations is suggested.

Desde distintos enfoques, en diez capítulos, este libro presenta investigaciones de actua-lidad sobre el sistema de seguridad social colombiano y expone situaciones de impacto socioeconómico con alcance global, tal como es el caso de la población migrante. Los autores brindan miradas críticas y posiciones filosóficas y pragmáticas frente a la Ley 100 y los problemas relacionados con la seguridad social en sus 30 años de vigencia. Cada uno de los autores examina algunos de los temas más relevantes desde el derecho comparado, la jurisprudencia, el ordenamiento jurídico en general y con estadísticas, para brindar propuestas que aspiran a engrosar la doctrina nacional sobre este tema.

Early diagnosis of Turner syndrome enhances care, but in routine practice, even within larger referral centers, diagnosis is delayed. Our study examines the utility of an electronic health record algorithm in identifying patients at high risk for Turner syndrome. Six percent of those identified had missed diagnoses of Turner syndrome.

Introduction: Short stature is one of the most common reasons for referral to a pediatric endocrinologist and can result from many etiologies. However, many patients with short stature do not receive a definitive diagnosis. Objective: To ascertain whether integrating targeted bioinformatics searches of electronic health records (EHRs) combined with genomic studies could identify patients with previously undiagnosed rare genetic etiologies of short stature. We focused on a specific rare phenotypic subgroup: patients with short stature and elevated IGF-I levels. Methods: We performed a cross-sectional cohort study at three large academic pediatric healthcare networks. Eligible subjects included children with heights below –2 SD, IGF-I levels >90th percentile, and no known etiology for short stature. We performed a search of the EHRs to identify eligible patients. Patients were then recruited for phenotyping followed by exome sequencing and in vitro assays of IGF1R function. Results: A total of 234 patients were identified by the bioinformatics algorithm with 39 deemed eligible after manual review (17%). Of those, 9 were successfully recruited. A genetic etiology was identified in 3 of the 9 patients including 2 novel variants in IGF1R and a de novo variant in CHD2. In vitro studies supported the pathogenicity of the IGF1R variants. Conclusions: This study provides proof of principle that patients with rare phenotypic subgroups can be identified based on discrete data elements in the EHRs. Although limitations exist to fully automating this approach, these searches may help find patients with previously unidentified rare genetic disorders.

The article aims to analyze if the linkages between migration policies and labor related measures for returnees in Colombia since the approval of the Law of Return, 2012. In order to do so, the authors use a documentary analysis methodology derived from a desk review of labor market information, employment and migration policies. This process considers aspects related to the design of differentiated programs for the returnee population and the existence or development of monitoring mechanisms. The article considers the context of emigration and return in Colombia, the labor profile of Colombian migrants in host countries, as well as the recent dynamics of the labor market in Colombia, discussing some structural factors such as unemployment and informality and the need to consider these aspects in the interventions created for the socioeconomic integration of returnees. The authors list and analyze the main activities on issues of employability and entrepreneurship as presented by the Ministries of Foreign Affairs and Labor in their management reports to demonstrate the existence and extent of inter-institutional coordination mechanisms. The article concludes with the need to collect and disseminate information on the evidence of the labor insertion of returnees in order to collect and propose technical inputs from different actors that could be included in the programs or policies aimed at doing so.

BACKGROUND: Turner syndrome (TS) results from a complete or partial loss of the second X chromosome and affects 25-50 per 100,000 females. TS is common in females with unexplained short stature, but the diagnosis is often not made until late childhood (8-9 years) if classic features are not present or recognized in infancy. This results in delayed medical intervention and screening for comorbid conditions. The aim of our study was to determine if an electronic health record (EHR) notification model improves the timing and rate of detection of TS. METHODS/RESULTS: A search of the EHR was performed to identify a cohort of females with idiopathic short stature (ISS) who were seen in the endocrine clinic from 2012-2017. Selection criteria included a height ≤ -2 SD, BMI > 5%-ile, absence of chronic illness, and presence of mid-parental height (MPH) data, which yielded 216 patients. Given that a height deflection from MPH %-ile is one of the better predictors of TS1, we focused on those ≥ 1 SD below MPH %-ile. Of these 189 patients, 72 (38%) hadn’t received prior genetic testing. This group formed our study population and microarray analysis was performed on available samples to assess for undiagnosed TS or other chromosomal abnormalities. A total of 39 patient samples were prospectively recruited or obtained from an IRB approved biobank (including 5 TS controls). Microarray data was generated for 37 samples, as 2 had an insufficient quantity of DNA, and data was manually analyzed by a cytogeneticist. We identified two cases of undiagnosed TS (6%) and one with a different chromosomal abnormality (3%). One of these patients returned to endocrine clinic prior to microarray analysis and had a karyotype of 45,X/46,XY. The two other chromosomal abnormalities were picked up by microarray. One had mosaic monosomy X (45,X/46,XX). The other had a 2.7 Mb deletion from chromosome 1 (1q25.3->1q31.1) and a 2.1 Mb duplication from 22q11.21, which has been associated with short stature. CONCLUSIONS: The EHR algorithm was effective at identifying patients at risk for TS that merit genetic testing. Of the ISS females ≥ 1 SD below their MPH %-ile, 38% never had a karyotype done and on further investigation two new cases of TS (6%) and one other chromosomal abnormality (3%) were found. Although not all patients had DNA available for microarray analysis, if we assume that all other cases were negative, the rate of undiagnosed TS would still approach 3%. Extrapolating this data to a larger scale suggests that the diagnosis of TS may be delayed for many females with ISS, even after evaluation in endocrine clinics. We recommend the implementation of additional tools in the clinic workflow, such as EHR alerts based on specific growth parameters, to increase clinical suspicion and testing for TS. REFERENCES: 1. Grote, FK, et al (2008). Developing evidence-based guidelines for referral for short stature.Archives of Disease in Childhood,93(3), 212-217.

Background: Short stature is a common reason for referral to a pediatric endocrinologist. Despite adequate evaluation, a pathological diagnosis is not identified in the vast majority of patients. It is often difficult to determine which of these many patients have an undiagnosed genetic cause. The electronic health record (EHR) improves our ability to identify cohorts of patients with a specific phenotype of interest, and it has become a valued tool for the augmentation of clinical characterization to drive discovery of phenotype-genotype associations. The aim of our study was to assess the feasibility of using dense phenotypic information from the EHR to systematically identify a distinct cohort of patients with short stature who have a high probability of harboring a monogenic etiology for their short stature. Methods/Results: As an initial proof of principle, we chose to focus on patients with Insulin-like growth factor I (IGF-I) resistance. We performed a targeted bioinformatics search of the EHR at three leading pediatric endocrine departments (Boston Children’s Hospital (BCH), Children’s Hospital of Philadelphia (CHOP) and Cincinnati Children’s Hospital Medical Center (CCHMC)). Inclusion criteria were height below -2 SD (for age and sex) and an IGF-I level above the 90thpercentile. Patients with known underlying genetic conditions, other chronic illnesses, or precocious puberty were excluded. All eligible patients were approached by mail or telephone to participate in the study. Whole exome sequencing (WES) was performed on DNA extracted from whole blood or saliva samples from ten patients and their immediate family members. The targeted bioinformatics search identified a total of 234 patients (104 at CCHMC, 64 at CHOP and 62 in BCH). Of these, 39 patients were eligible for recruitment and 10 were successfully recruited for genetic testing. WES identified two novel pathogenic variants in IGF1R including a novel missense variant (p.Val1013Phe) and a maternally inherited single amino acid deletion (p.Thr28del) in two patients. In addition, a third patient was found to have a novel missense variant in CHD2 (p.Val540Phe). Functional analyses confirmed the pathogenicity of the p.Val1013Phe variant, and are ongoing for the other two variants. Conclusion: This novel approach combining bioinformatics and modern genetics successfully led to the identification of a genetic etiology in 3 of 10 patients, giving a yield of 30% including identification of two patients with novel pathogenic mutations in IGFIR. Notably, these patients were otherwise missed clinically as having a genetic condition. Similar algorithms can be designed to identify diverse cohorts of patients likely to have genetic conditions. This approach can be integrated into the EHR to generate best practice advisories to advance our ability to diagnose rare genetic conditions and improve patient care.

CASE DESCRIPTION A 2-year-old primiparous miniature Scottish Highland cow with an unknown breeding date was evaluated for suspected hydrops. CLINICAL FINDINGS Transabdominal and transrectal ultrasonographic examination identified a large amount of hypoechoic fluid within an enlarged uterus; the fetus could not be identified. Presence of a severely distended uterus and concerns regarding associated health risks to the cow led to the decision to induce labor. Although fluids were expelled, parturition did not progress further over the following 48 hours. Vaginal examination revealed a partially dilated cervix and an abnormally shaped fetus that was too large to pass vaginally. TREATMENT AND OUTCOME Supportive care was provided to the cow, and a stillborn bull calf was delivered by cesarean section. Grossly evident chondrodystrophic dwarfism with hydrocephalus, compatible with so-called bulldog calf malformations, was confirmed by diagnostic imaging and histopathologic evaluation. The cow recovered from surgery uneventfully and was discharged from the hospital the following day. Genetic analysis of DNA from hair roots collected from the sire and dam confirmed both were carriers of an aggrecan-1 gene mutation (bulldog dwarfism1) previously associated with dwarfism and bulldog calf malformations in Dexter cattle. CLINICAL RELEVANCE To our knowledge, this is the first reported case of bulldog calf malformations associated with an aggrecan-1 gene mutation in miniature Scottish Highland cattle, confirming that at least 1 genetic mutation associated with this condition is found in cattle breeds other than Dexter. The findings highlighted the clinical importance of testing for known genetic diseases in breeding cattle, particularly among miniature breeds.

The R183H mutation in the growth hormone gene (GH1) is a well-described genetic variant that causes autosomal dominant isolated growth hormone deficiency (IGHD) type II. Previous studies have demonstrated that individuals with this mutation have releasable growth hormone (GH) stores, but such release is severely impaired. Hess et al. reported variable height deficits (-4.5 to -1.0 SDS), variable IGF-I concentrations (-2.9 to -0.8 SDS), and low but detectable, or even normal stimulated peak GH in several patients with the R183H mutation. This article is protected by copyright. All rights reserved.

To compare the use of controlled intravaginal drug release (CIDR, EAZI-BREED™ CIDR® Sheep, USA, Zoetis) with the ram effect, a combination of CIDR and ram effect and the addition of P.G.600® to each of these scenarios on their contribution to inducing the onset of cyclicity and their ability to improve reproductive efficiency in a commercial sheep flock, a randomized clinical trial was conducted. Multiparous ewes (n = 283) were randomly assigned to one of six treatments prior to intact male introduction on day 0: only CIDR devices (day −5 to day 0) (n = 40), exposure to two vasectomized rams (d-14 to d0) (n = 55), CIDR (d-5 to d0) and an intramuscular injection of P.G.600® (d0) (n = 40), exposure to two vasectomized rams (d-14 to d0) and treated with CIDR devices (day −5 to day 0) (n = 40). exposure to vasectomized rams (d-14 to d0), CIDR (d-5 to d0) and an intramuscular injection ofP.G.600®, (d0) (n = 38), and a control group, without exposure to vasectomized rams, CIDRs or P.G.600® (n = 70). Ewes were exposed to intact males on day 0. Days to lambing from the earliest expected lambing date at 150 days post introduction of rams was compared between groups with survival analysis. The mean survival time was significantly shorter in all groups that used CIDR compared to the control group (P

CDKN1C is a cyclin-dependent kinase Inhibitor and negative regulator of cellular proliferation. Recently, gain-of-function mutations in the PCNA domain of CDKN1C have been reported as the genetic basis of various growth-retarded syndromes including IMAGe syndrome, Russell Silver syndrome as well as a novel undergrowth syndrome that additionally exhibited early adulthood onset diabetes. This review summarizes the key clinical features and the molecular advances that have contributed to our understanding of this complex phenotypic spectrum.