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Short stature or shortening of the limbs can be the result of a variety of genetic variants. Achondroplasia is the most common cause of disproportionate short stature and is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR3). Short stature homeobox (SHOX) deficiency is caused by loss or defects of the SHOX gene or its enhancer region. It is associated with a spectrum of phenotypes ranging from normal stature to Léri-Weill dyschondrosteosis characterized by mesomelia and short stature or the more severe Langer mesomelic dysplasia in case of biallelic SHOX deficiency. Little is known about the interactions and phenotypic consequences of achondroplasia in combination with SHOX deficiency, as the literature on this subject is scarce, and no genetically confirmed clinical reports exist. We present the clinical findings in an infant girl with concurrent achondroplasia and SHOX deficiency. We conclude that the clinical findings in infancy are phenotypically compatible with achondroplasia, with no features of the SHOX deficiency evident. This may change over time, as some features of SHOX deficiency only become evident later in life., Competing Interests: Disclosure of conflict of interest None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Identifying hydatidiform moles (HMs) is crucial due to the risk of gestational trophoblastic neoplasia. When a HM is suspected on clinical findings, surgical termination is recommended. However, in a substantial fraction of the cases, the conceptus is actually a non-molar miscarriage. If distinction between molar and non-molar gestations could be obtained before termination, surgical intervention could be minimized., Methods: Circulating gestational trophoblasts (cGTs) were isolated from blood from 15 consecutive women suspected of molar pregnancies in gestational week 6-13. The trophoblasts were individually sorted using fluorescence activated cell sorting. STR analysis targeting 24 loci was performed on DNA isolated from maternal and paternal leukocytes, chorionic villi, cGTs, and cfDNA., Results: With a gestational age above 10 weeks, cGTs were isolated in 87% of the cases. Two androgenetic HMs, three triploid diandric HMs, and six conceptuses with diploid biparental genome were diagnosed using cGTs. The STR profiles in cGTs were identical to the profiles in DNA from chorionic villi. Eight of the 15 women suspected to have a HM prior to termination had a conceptus with a diploid biparental genome, and thus most likely a non-molar miscarriage., Discussion: Genetic analysis of cGTs is superior to identify HMs, compared to analysis of cfDNA, as it is not hampered by the presence of maternal DNA. cGTs provide information about the full genome in single cells, facilitating estimation of ploidy. This may be a step towards differentiating HMs from non-HMs before termination., Competing Interests: Declaration of competing interest KR, LH, RS, and PS are all employed in ARCEDI Biotech, a Danish biotech company involved in the development of cell-based non-invasive prenatal testing. The study was designed using the trophoblastic cell enrichment, detection and genetic analysis developed in ARCEDI Biotech., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Termination of a wanted pregnancy due to fetal anomaly may generate complex feelings of grief and loss. The aim of this study was to explore the different ways that women/couples articulated their relation to the fetus/child following a termination of pregnancy due to a prenatal diagnosis of Down syndrome., Method: Qualitative interview study with 21 women/couples who had recently terminated a wanted pregnancy. Data were analyzed using thematic analysis., Results: The analysis identified how some women detached themselves from the fetus/child following the diagnosis by mentally separating from the fetus/child, by acting as if they were not pregnant (e.g., by drinking wine), or by deliberately using the term 'fetus' to designate the fetus/child as a biological entity. The analysis also identified accounts of attachment such as singing a lullaby to the fetus/child or using the term 'our child' or 'my baby'. However, accounts of detachment and attachment often intermingled and changed over time. Following the termination, many women/couples felt ambiguous about the sonogram as a symbol of the potential child. Overall, the analysis showed that the relation to and the meaning of the fetus/child was ambiguous and open to reinterpretation., Conclusion: The main contribution of this study is the identification of how articulations of attachment and detachment are not mutually exclusive but coexist and may change over time. Furthermore, we argue that detachment does not equal indifference. Thus, healthcare professionals must support the couple in finding a terminology and a narrative that are meaningful for them., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Pycnodysostosis is a rare autosomal recessive osteosclerotic skeletal dysplasia caused by variants in the cathepsin K gene (CTSK). Clinical features include short stature, bone fragility, characteristic facial features and acro-osteolysis of the distal phalanges. Usually, patients suffer from multiple bone fractures. The purpose of this study was to describe the Danish population of pycnodysostosis patients with respect to genotype, phenotype and the prevalence of complications. We collected medical history, performed clinical examination, collected blood- and urine samples, performed dual-energy x-ray absorptiometry scan (DXA) and high-resolution peripheral quantitative computed tomography scan (HRpQCT) and obtained clinical photos. Information about complications, bone mineral density and bone markers in the blood were collected and analysed., Results: Ten patients with a median age of 32 years ranging from five to 51 years participated. The pycnodysostosis phenotype varied with respect to the number of bone fractures and degree of complications. DXA and HRpQCT showed high bone mineral density. A tendency of growth hormone treatment escalating growth and increasing final height was seen. A marker of bone resorption measured in blood was within normal range in nine patients and elevated in one patient. A novel pathogenic variant in CSTK causing pycnodysostosis was detected in two related patients. Moreover information about the patients' own health perception was reported. An example being they rated their mental health to be good despite multiple bone fractures., Conclusion: This study provides information about genotypes and phenotypes in a Danish pycnodysostosis population. It reports new data about the complications such as bone fractures and it elucidates the levels of bone turnover markers as well as the density of the bones in one of the biggest cohort of pycnodysostosis patients ever published. An individualised approach to treatment in this patient group is necessary as the phenotype including complications varies between patients. Additional studies are needed to further understand genotype-phenotype correlations., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: To develop a first trimester prediction model for gestational diabetes mellitus (GDM) using obesity, placental, and inflammatory biomarkers., Methods: We used a first trimester dataset of the ASPRE study to evaluate clinical and biochemical biomarkers. All biomarkers levels (except insulin) were transformed to gestational week-specific medians (MoMs), adjusted for maternal body mass index (BMI), maternal age, and parity. The MoM values of each biomarker in the GDM and normal groups were compared and used for the development of a prediction model assessed by area under the curve (AUC)., Results: The study included 185 normal and 20 GDM cases. In the GDM group, compared to the normal group BMI and insulin (P = 0.003) were higher (both P < 0.003). The MoM values of uterine artery pulsatility index (UtA-PI) and soluble (s)CD163 were higher (both P < 0.01) while pregnancy associated plasma protein A (PAPP-A), placental protein 13 (PP13), and tumor-necrosis factor alpha (TNFα) were lower (all P < 0.005). There was no significant difference between the groups in placental growth factor, interleukin 6, leptin, peptide YY, or soluble mannose receptor (sMR/CD206). In screening for GDM in obese women the combination of high BMI, insulin, sCD163, and TNFα yielded an AUC of 0.95, with detection rate of 89% at 10% false positive rate (FPR). In non-obese women, the combination of sCD163, TNFα, PP13 and PAPP-A yielded an AUC of 0.94 with detection rate of 83% at 10% FPR., Conclusion: A new model for first trimester prediction of the risk to develop GDM was developed that warrants further validation., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Placental mosaicism for a subset of a chromosome, a structural chromosomal aberration, is thought to be a very rare finding in chorionic villus samples. Here, we present clinical and laboratory data on five cases with such mosaicism for structural chromosomal aberrations., Methods: During a period of 6 months, chromosomal microarray was carried out on DNA extracted from 100 uncultured chorion villous samples from high-risk pregnancies., Results: In five of 100 consecutively collected samples (5/100), mosaicism for a structural chromosomal aberration was detected. The mosaic aberration was subsequently detected in fetal tissue in three of the five cases., Conclusion: Chromosomal microarray can detect placental mosaicism for structural chromosomal aberrations. This kind of mosaicism may be more frequent than previously anticipated, and the fetal involvement seems difficult to predict. These findings highlight the complexity of mosaicism for structural chromosomal aberrations in prenatal samples in the chromosomal microarray era., Competing Interests: Declaration of competing interest No conflict of interest to be declared for any of the authors., (Copyright © 2019. Published by Elsevier Masson SAS.)

Objectives: Termination rates when Down syndrome (DS) is diagnosed prenatally are high in most countries. Thus, the present study aimed to explore how parents of prenatally diagnosed children with DS experienced the diagnostic process and their decision to continue the pregnancy., Methods: Data from a semi-structured, qualitative interview study with eight mothers and five fathers of prenatally diagnosed children with DS born between 2008 and 2017 were analyzed using thematic analysis., Findings: Several couples emphasized how they had not hoped for a child with DS, but following the diagnosis they strongly felt that this was the child that they "were given." The couples stressed that DS was not the worst that could happen. All couples sought experiential knowledge outside the hospital setting to explore the potential for living a fulfilling life with DS. Five couples had positive recollections of the delivery of the DS result. Three couples had negative recollections, mainly because the intention to terminate had been taken for granted. After the decision to continue pregnancy was made, their interaction with health-care professionals was generally experienced as positive and supporting. However, some couples still felt vulnerable because they were aware that their decision was uncommon., Conclusions: Health-care professionals must be careful to speak in unprejudiced ways throughout the diagnostic process and present both termination and continuation of pregnancy as equally legitimate options. Nevertheless, the couples may still experience doubt and feel vulnerable following their decision to continue the pregnancy., Competing Interests: Declaration of Competing Interest None, (Copyright © 2019 Elsevier B.V. All rights reserved.)

We present five Danish individuals with Hajdu-Cheney syndrome (HJCYS) (OMIM #102500), a rare multisystem skeletal disorder with distinctive facies, generalised osteoporosis and progressive focal bone destruction. In four cases positive genetic screening of exon 34 of NOTCH2 supported the clinical diagnosis; in one of these cases, mosaicism was demonstrated, which, to our knowledge, has not previously been reported. In one case no genetic testing was performed since the phenotype was definite, and the diagnosis in the mother was genetically confirmed. The age of the patients differs widely from ten to 57 years, allowing a natural history description of the phenotype associated with this ultra-rare condition. The evolution of the condition is most apparent in the incremental bone loss leading to osteoporosis and the acro-osteolysis, both of which contribute significantly to disease burden., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Introduction: MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients., Materials and Methods: In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing., Results: All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations., Conclusions: Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: We sought to examine associations among serum relaxin levels, cervical length, and spontaneous preterm birth (sPTB)., Study Design: We conducted a case-control study within a cohort of 1080 singleton pregnant women. In all, 38 women (3.5%) delivered spontaneously preterm (< 37 completed weeks of gestation). Relaxin was measured in serum in gestational weeks 12 and 19, cervical length only in week 19. Associations to sPTB were evaluated by logistic regression analysis and receiver operating characteristic curves., Results: Cervical length and relaxin in week 19, but not week 12 were associated to sPTB. There were no correlations between cervical length and relaxin level in week 12 (controls: Spearman rho: -0.07, P = .45; cases: Spearman rho: -0.07, P = .72) or week 19 (controls: Spearman rho: -0.03, P = .77; cases: Spearman rho: 0.04, P = .84)., Conclusion: There were no correlation between relaxin concentrations and the cervical length, indicating that relaxin is probably not the cause of preterm shortening of the cervix.

The interests in monitoring inflammation by immunoassay determination of blood inflammatory markers call for information on the stability of these markers in relation to the handling of blood samples. The increasing use of stored biobank samples for such ventures that may have been collected and stored for other purposes, justifies the study hereof. Blood samples were stored for 0, 4, 24, and 48 h at 4 degrees C, room temperature (RT), and at 35 degrees C, respectively, before they were separated into serum or plasma and frozen. Dried blood spot samples (DBSS) were stored for 0, 1, 2, 3, 7, and 30 days at the same temperatures. 27 inflammatory markers in serum and plasma and 25 markers in DBSS were measured by a previously validated multiplex sandwich immunoassay using Luminex xMAP technology. The measurable concentrations of several cytokines in serum and plasma were significantly increased when blood samples were stored for a period of time before the centrifugation, for certain cytokines more than 1000 fold compared to serum and plasma isolated and frozen immediately after venepuncture. The concentrations in serum generally increased more than in plasma. The measurable concentrations of inflammatory markers also changed in DBSS stored under various conditions compared to controls frozen immediately after preparation, but to a much lesser degree than in plasma or serum. The study demonstrates that trustworthy measurement of several inflammatory markers relies on handling of whole blood samples at low temperatures and rapid isolation of plasma and serum. Effects of different handling procedures for all markers studied are given. DBSS proved to be a robust and convenient way to handle samples for immunoassay analysis of inflammatory markers in whole blood.

Objective: Preterm birth rate in the United States is higher in blacks than whites. It has been hypothesized that a differential inflammatory response may explain this disparity. The objective of this study is to examine the inflammatory cytokine, tumor necrosis factor (TNF)-alpha and soluble TNF receptor concentrations (sTNFR1 and sTNFR2) in the amniotic fluid of black and white women at delivery., Study Design: Amniotic fluid samples were collected during active labor from 158 cases (preterm births, gestational age 22(0/7) weeks to 36(0/7) weeks, 52 black and 106 white) and 175 controls (term births, gestational age 37(0/7) weeks to 42(0/7) weeks, 87 black and 88 white) at Centennial Women's Hospital, Nashville, TN. Amniotic fluid TNF-alpha, sTNFR1, and sTNFR2 concentrations and the molar ratios of TNF-alpha to its receptors were compared between cases and controls within each racial group., Results: Median TNF-alpha concentration was associated with preterm birth when whites and blacks were analyzed together, with cases having higher values (191.5 pg/mL) than controls (68.9 pg/mL; P < .001). There were no significant associations with sTNFR1 or sTNFR2 concentrations between cases (2409.4 and 2934.3 pg/mL, respectively) and controls (2759.9 and 3084.1 pg/mL, respectively) when the racial groups were analyzed together (P = .08, P = .4, respectively). Black cases associated with higher TNF-alpha concentrations (1287.0 pg/mL in cases and 67.3 pg/mL in controls; P < .001). In whites there was no association between TNF-alpha and preterm birth (P = .3). The molar ratio of TNF-alpha/total sTNFR (R1 plus R2) associated with higher TNF-alpha in black cases, compared with black controls (P < .001). There was no significant association between white cases and controls for ligand receptor ratios (P = .3)., Conclusion: The TNF-alpha/sTNFR profile in pregnancy differs between racial groups, suggesting a difference in bioavailability of TNF-alpha. The larger molar ratio of TNF-alpha/sTNFR in black cases may be indicative of a TNF-alpha mediated pathological process of preterm birth in blacks but not in whites.

Objective: The purpose of this study was to evaluate the relationship between serum concentrations of relaxin and soluble CD163 with cervical length and preterm delivery in women with previous spontaneous preterm delivery., Study Design: Sixty-one of 69 pregnant women with a previous spontaneous preterm had serum relaxin and soluble CD163 measured at week 16 (range, 12-25 weeks). End points were cervical length and gestational age at delivery., Results: Of the 61 women, 26% had >1 previous spontaneous preterm delivery; 84% were black; 87% were unmarried; 13% were smokers, and 39% were delivered before 37 weeks of gestation. Neither relaxin (median, 368 ng/L; range, 83-1493 ng/L) nor soluble CD163 (2.4 mg/L; range, 0.86-6.85 mg/L) correlated with cervical length or gestational age at delivery. Black women had higher relaxin levels (436 vs 205 ng/L; P = .002), but soluble CD163 levels were similar among racial groups., Conclusion: Relaxin and soluble CD163 measured at 16 weeks of gestation are not clinically useful predictors of short cervical length or preterm delivery in women with a previous spontaneous preterm delivery.

Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-alpha (TNF-alpha), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-alpha, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model., Study Design: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-alpha (6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (cases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB., Results: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at -7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs -3448 of TNF-alpha, -7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre- to low-risk genotypes is 3.50 (95% CI 2.52-4.87, P < .001)., Conclusion: This is the first report to document a multilocus interaction in sPTB that predicts 65.2% of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB.