Follow-up report of fundus findings of tuberous sclerosis-associated retinal astrocytoma of two siblings.

A late adolescent with tuberous sclerosis (TS) presented with reduced vision in one eye to our tertiary care university hospital 4 years ago. Fundus examination revealed multiple retinal astrocytic hamartomas (RAHs) in both eyes. His younger sibling, who also had TS, was found to have RAH on retinal screening. The swept-source optical coherence tomography (SS-OCT) findings were typical of RAH. We further noted that some of the RAH lesions showed segmental whitening of the outer walls of the arterioles, which traversed through them. The segmental whitening may suggest the enveloping of normal retinal vessels by the tumour. En-face and B-scan SS-OCT angiography of patients with TS showed vascularity within the tumour. The vessels within the tumour appeared to be in continuity with the retinal vasculature. Both siblings were reviewed annually. At the end of 4 years, there was no change in visual acuity, tumour size, number, vascularity and behaviour.

The relationship between gamma-band neural oscillations and language skills in youth with Autism Spectrum Disorder and their first-degree relatives.

BACKGROUND: Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairments and some of these autism-specific language difficulties are also present in their non-autistic first-degree relatives. One of the possible neural mechanisms associated with variability in language functioning is alterations in cortical gamma-band oscillations, hypothesized to be related to neural excitation and inhibition balance. METHODS: We used a high-density 128-channel electroencephalography (EEG) to register brain response to speech stimuli in a large sex-balanced sample of participants: 125 youth with ASD, 121 typically developing (TD) youth, and 40 unaffected siblings (US) of youth with ASD. Language skills were assessed with Clinical Evaluation of Language Fundamentals. RESULTS: First, during speech processing, we identified significantly elevated gamma power in ASD participants compared to TD controls. Second, across all youth, higher gamma power was associated with lower language skills. Finally, the US group demonstrated an intermediate profile in both language and gamma power, with nonverbal IQ mediating the relationship between gamma power and language skills. LIMITATIONS: We only focused on one of the possible neural contributors to variability in language functioning. Also, the US group consisted of a smaller number of participants in comparison to the ASD or TD groups. Finally, due to the timing issue in EEG system we have provided only non-phase-locked analysis. CONCLUSIONS: Autistic youth showed elevated gamma power, suggesting higher excitation in the brain in response to speech stimuli and elevated gamma power was related to lower language skills. The US group showed an intermediate pattern of gamma activity, suggesting that the broader autism phenotype extends to neural profiles.

Case of Hallervorden-Spatz Syndrome: A Tale of Twin Sisters.

Hallervorden-Spatz syndrome, now known as pantothenate kinase-associated neurodegeneration (PKAN), is a rare autosomal recessive disorder that is characterized by cerebral iron deposition and leads to progressive extrapyramidal dysfunction and dementia. Most commonly seen in the first two decades of a person's life, it is a differential for patients presenting with atypical progressive extrapyramidal disorder and cognitive impairment. It is characterized by progressive degeneration of the basal ganglia, globus pallidus, and the reticular part of the substantia nigra due to iron accumulation. The characteristic MRI brain pattern of the disease shows the eye-of-the-tiger sign. We report cases of early onset PKAN in two sisters of the same family, in which diagnosis was based on clinical features, lab parameters, and MRI imaging findings. This report aims to differentiate PKAN from other static and progressive neurological illnesses.

The feeding siblings questionnaire (FSQ): Development of a self-report tool for parents with children aged 2-5 years.

Over the last decade, there have been repeated calls to expand the operationalisation of food parenting practices. The conceptualisation and measurement of these practices has been based primarily on research with parent-child dyads. One unexplored dimension of food parenting pertains to the evaluation of practices specific to feeding siblings. This study describes the development and validation of the Feeding Siblings Questionnaire (FSQ) - a tool designed to measure practices in which siblings are positioned as mediators in parents' attempts to prompt or persuade a child to eat. Item development was guided by a conceptual model derived from mixed-methods research and refined through expert reviews and cognitive interviews. These interviews were conducted in two phases, where parents responded to the questionnaire primarily to test i) the readability and relevance of each item, and ii) its overall feasibility. The instrument was completed by 330 parents (96.1% mothers) in Australia with two children aged 2-5 years, and repeated by 133 parents (40.3%) two weeks later. Exploratory factor analysis was performed on baseline data. Internal consistency and test re-test reliability of the subsequent subscales were examined. Construct validity was assessed through comparisons with existing measures of food parenting practices and child eating behaviours. The final FSQ scale included 22 items, reflecting five food parenting practices: sibling competitiveness, active sibling influence, threatening unequal division of food, sibling role modelling, and vicarious operant conditioning. Internal consistency and test re-test reliability estimates were high, and there was some evidence of convergent construct validity. While its factor structure should be confirmed in a different sample, the FSQ offers a novel tool for assessing, monitoring, and evaluating feeding interactions beyond those confined to the parent-child dyad.

Comparable outcomes of allogeneic peripheral blood versus bone marrow hematopoietic stem cell transplantation from a sibling donor for pediatric patients.

Traditionally, bone marrow (BM) has been preferred as a source of stem cells (SCs) in pediatric hematopoietic SC transplantation (HSCT); however, the use of peripheral blood SCs (PBSC) has recently increased. With advancing graft-versus-host disease (GVHD) prophylaxis, whether the BM is still a better SC source than PB in sibling donor HSCT remains controversial. Here, we compared the results of BM transplantation (BMT) and PBSC transplantation (PBSCT) in pediatric patients with malignant or non-malignant diseases receiving sibling HSCT using a total of 7.5 mg/kg of anti-thymocyte globulin (ATG). We retrospectively reviewed children who received HSCT from a sibling donor between 2005 and 2020 at Seoul National University Children's Hospital. Of the 86 patients, 40 underwent BMT, and 46 underwent PBSCT. Fifty- six patients had malignant diseases, whereas thirty patients had non-malignant diseases. All conditioning regimens comprised ATG. Busulfan-based myeloablative conditioning regimens were administered to patients with malignant diseases and approximately half of those with non-malignant diseases. The remaining half of the patients with non-malignant diseases were administered cyclophosphamide-based reduced- intensity conditioning regimens. According to studies conducted at our center, all BM donors received G-CSF before harvest to achieve early engraftment. In all 86 patients (47 males and 39 females), the median age at the time of HSCT was 11.4 (range, 0.7 - 24.6) years. The median follow-up period was 57.9 (range, 0.9-228.6) months, and the corresponding values for those with BM and PBSC were 77 (range, 2.4-228.6) months and 48.7 (range, 0.9-213.2) months, respectively. Engraftment failure occurred in one patient with BM and no patient with PBSC. The cumulative incidence of acute GVHD with grades II-IV was higher in PBSC (BM 2.5%, PBSC 26.1%, p = 0.002), but there was no significant difference in those with grades III-IV acute GVHD (BM 0%, PBSC 6.5%, p = 0.3703) and extensive chronic GVHD (BM 2.5%, PBSC 11.6%, p = 0.1004). There were no significant differences in treatment-related mortality (TRM) (BM 14.2%, PBSC 6.8%, p = 0.453), 5-year event-free survival (EFS) (BM 71.5%, PBSC 76.2%, p = 0.874), and overall survival (OS) rates (BM 80.8%, PBSC 80.3%, p = 0.867) between BM and PBSC in the univariate analysis. In the multivariate analysis, which included all factors with p < 0.50 in the univariate analysis, there was no significant prognostic factor for EFS or OS. There was no significant difference in the relapse incidence between BM and PBSC among patients with malignant diseases (BM 14.2%, PBSC 6.8%, p = 0.453). Additionally, there were no significant differences in the TRM, 5-year EFS, and OS rates between malignant and non-malignant diseases nor between the busulfan-based myeloablative regimen and reduced-intensity chemotherapy using cyclophosphamide. In this study, we showed no significant differences in EFS, OS, TRM, and GVHD, except for acute GVHD grades II-IV, between BMT and PBSCT from sibling donors, using ATG (a total of 7.5 mg/kg). Therefore, PB collection, which is less invasive for donors and less labor-intensive for doctors, could also be considered an acceptable SC source for sibling donor HSCT in children.

Using emulated clinical trials to investigate the risk of being diagnosed with psychiatric ill health following the cancer diagnosis of a sibling.

BACKGROUND: The sibling bond is often the longest relationship in an individual's life, spanning both good and bad times. Focusing on the latter, we investigated whether a cancer diagnosis in one adult sibling is predictive of psychiatric illness in the other, and if any such effect differs according the 'sociodemographic closeness' between the siblings in terms of sex, age, education, marital status and residence. METHODS: We used hospital records to identify psychiatric diagnoses (2005-2019) in a Swedish total-population cohort born in 1953, and cancer diagnoses (2005-2017) in their full siblings. By means of emulated clinical trials, the cohort member's risk of a diagnosis within two years following a first exposure (or non-exposure) to a sibling's cancer was analyzed through Cox regression. RESULTS: Exposed cohort members had a higher risk of psychiatric diagnosis than unexposed (HR = 1.15; CI: 1.08-1.23), with men displaying a higher risk (1.19; CI: 1.09-1.31) than women (HR = 1.11; CI: 1.01-1.22). Sub-analyses of the exposed group showed that women with a cancer-stricken sister had a higher risk of adverse psychiatric outcomes (HR = 1.31; CI: 1.07-1.61) than women with a cancer-stricken brother. Furthermore, unmarried cohort members ran a higher risk, both when the cancer-stricken sibling was married (HR = 2.03; CI: 1.67-2.46) and unmarried (HR = 2.61; CI: 2.16-3.15), than in cases where both siblings were married. No corresponding difference were detected for 'closeness' in age, education and residence. CONCLUSIONS: In line with theories of linked lives, our findings suggest that negative events in one sibling's life tend to 'spill over' on the other sibling's wellbeing, at least during the 15-year-long period leading up to retirement age.

Automated Single-Sperm Selection Software (SiD) during ICSI: A Prospective Sibling Oocyte Evaluation.

The computer-assisted program SiD was developed to assess and select sperm in real time based on motility characteristics. To date, there are limited studies examining the correlation between AI-assisted sperm selection and ICSI outcomes. To address this limit, a total of 646 sibling MII oocytes were randomly divided into two groups as follows: the ICSI group (n = 320): ICSI performed with sperm selected by the embryologist and the ICSI-SiD group (n = 326): ICSI performed with sperm selected using SiD software. Our results show a non-significant trend towards improved outcomes in the ICSI-SiD group across various biological parameters, including fertilization, cleavage, day 3 embryo development, blastocyst development, and quality on day 5. Similarly, we observed a non-significant increase in these outcomes when comparing both groups with sperm selection performed by a junior embryologist. Embryo development was monitored using a timelapse system. Some fertilization events happen significantly earlier when SiD is used for ICSI, but no significant difference was observed in the ICSI-SiD group for other timepoints. We observed comparable cumulative early and clinical pregnancy rates after ICSI-SiD. This preliminary investigation illustrated that employing the automated sperm selection software SiD leads to comparable biological outcomes, suggesting its efficacy in sperm selection.

Severe Transfusion-Dependent Thalassemia in Compound Heterozygote Palestinian Siblings with Two α-Globin Gene Defects, Hb Taybe D HBA1: C.119_121delCCA Mutation and HBA2: C.*94A > G Mutation.

Alpha and Beta Thalassemia are autosomal recessive anemias that cause significant morbidity and mortality worldwide, especially in the Middle East and North Africa (MENA) region where carrier rates reach up to 50%. We report the case of two siblings of Palestinian origin born who presented to our tertiary healthcare center for the management of severe transfusion dependent hemolytic anemia. Before presentation to our center, the siblings were screened for a-thalassemia using the Alpha-globin StripAssay. They were found to carry the α2 polyA-1 [AATAAA > AATAAG] mutation in the heterozygous form, which was insufficient to make a diagnosis. No pathogenic variants were detected on Sanger sequencing of the HBB gene. Full sequencing of the a-gene revealed compound heterozygous variants (HBA1:c.119_121delCCA and the previously detected HBA2:c.*+94A > G Poly A [A->G]) with trans inheritance. This report highlights the impact of non-deletional mutations on α-globin chain stability. The compound heterozygosity of a rare α-globin chain pathogenic variant with a polyadenylation mutation in the probands leads to clinically severe a-thalassemia. Due to the high carrier status, the identification of rare mutations through routine screening techniques in our populations may be insufficient. Ongoing collaboration among hematologists, medical geneticists, and counselors is crucial for phenotypic-genotypic correlation and assessment of adequate genetic testing schemes.

[Analysis of efficacy and prognosis of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency].

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors. Methods: In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children's Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors. Results: Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% vs. (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis (HR=2.55, 95%CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant (HR=2.96, 95%CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions: Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.

A population-based estimation of maternal mortality in Lagos State, Nigeria using the indirect sisterhood method.

BACKGROUND: Pregnancy and delivery deaths represent a risk to women, particularly those living in low- and middle-income countries (LMICs). This population-based survey was conducted to provide estimates of the maternal mortality ratio (MMR) in Lagos Nigeria. METHODS: A community-based, cross-sectional study was conducted in mapped Wards and Enumeration Areas (EA) of all Local Government Areas (LGAs) in Lagos, among 9,986 women of reproductive age (15-49 years) from April to August 2022 using a 2-stage cluster sampling technique. A semi-structured, pre-tested questionnaire adapted from nationally representative surveys was administered using REDCap by trained field assistants for data collection on socio-demographics, reproductive health, fertility, and maternal mortality. Data were analysed using SPSS and MMR was estimated using the indirect sisterhood method. Ethical approval was obtained from the Lagos State University Teaching Hospital Health Research and Ethics Committee. RESULTS: Most of the respondents (28.7%) were aged 25-29 years. Out of 546 deceased sisters reported, 120 (22%) died from maternal causes. Sisters of the deceased aged 20-24 reported almost half of the deaths (46.7%) as due to maternal causes, while those aged 45-49 reported the highest number of deceased sisters who died from other causes (90.2%). The total fertility rate (TFR) was calculated as 3.807, the Lifetime Risk (LTR) of maternal death was 0.0196 or 1-in-51, and the MMR was 430 per 100,000 [95% CI: 360-510]. CONCLUSION: Our findings show that the maternal mortality rate for Lagos remains unacceptable and has not changed significantly over time in actual terms. There is need to develop and intensify community-based intervention strategies, programs for private hospitals, monitor MMR trends, identify and contextually address barriers at all levels of maternal care.

Familial chylomicronemia syndrome: case reports of siblings with deletions of the GPIHBP1 gene.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare monogenic form of severe hypertriglyceridemia, caused by mutations in genes involved in triglyceride metabolism. Herein, we report the case of a Korean family with familial chylomicronemia syndrome caused by compound heterozygous deletions of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). CASE PRESENTATION: A 4-year-old boy was referred for the evaluation of severe hypertriglyceridemia (3734 mg/dL) that was incidentally detected 4 months prior. His elder brother also demonstrated an elevated triglyceride level of 2133 mg/dL at the age of 9. Lipoprotein electrophoresis revealed the presence of chylomicrons, an increase in the proportion of pre-beta lipoproteins, and low serum lipoprotein lipase levels. The patient's parents and first elder brother had stable lipid profiles. For suspected FCS, genetic testing was performed using the next-generation sequencing-based analysis of 31 lipid metabolism-associated genes, which revealed no pathogenic variants. However, copy number variant screening using sequencing depth information suggested large heterozygous deletion encompassing all the coding exons of GPIHBP1. A real-time quantitative polymerase chain reaction was performed to validate the deletion site. The results showed that the siblings had two heterozygous copy number variants consisting of the whole gene and an exon 4 deletion, each inherited from their parents. During the follow-up period of 17 months, the patient did not develop pancreatitis, following dietary intervention. CONCLUSION: These siblings' case of familial chylomicronemia syndrome caused by rare GPIHBP1 deletions highlight the implementation of copy number variants-beyond next-generation sequencing-as an important consideration in diagnosis. Accurate genetic diagnosis is necessary to establish the etiology of severe hypertriglyceridemia, which increases the risk of pancreatitis.

The Detection of Environmental Influences on Academic Achievement Appears to Depend on the Analytic Approach.

One long-standing analytic approach in adoption studies is to examine correlations between features of adoptive homes and outcomes of adopted children (hereafter termed 'measured environment correlations') to illuminate environmental influences on those associations. Although results from such studies have almost uniformly suggested modest environmental influences on adopted children's academic achievement, other work has indicated that adopted children's achievement is routinely higher than that of their reared-apart family members, often substantially so. We sought to understand this discrepancy. We examined academic achievement and literacy-promotive features of the home in 424 yoked adoptive/biological families participating in the Early Growth and Development Study (EGDS; i.e., adopted children, adoptive mothers, birth mothers, and biological siblings of the adopted children remaining in the birth homes) using an exhaustive modeling approach. Results indicated that, as anticipated, adopted children scored up to a full standard deviation higher on standardized achievement tests relative to their birth mothers and reared-apart biological siblings. Moreover, these achievement differences were associated with differences in the literacy-promotive features of the adoptive and birth family homes, despite minimal measured environment correlations within adoptive families. A subsequent simulation study highlighted noise in measured environmental variables as an explanation for the decreased utility of measured environment correlations. We conclude that the field's heavy focus on measured environment correlations within adoptive families may have obscured detection of specific environmental effects on youth outcomes, and that future adoption studies should supplement their measured environment analyses with mean differences between reared-apart relatives.

Multilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders.

BACKGROUND: Multilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context. METHODS: We conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD). RESULTS: We found siblings with MPVs driven by long ROH regions in 8.5% of families (4/47). The patients with MPVs exhibited significantly higher FROH values (p-value = 1.4e-2) and larger total ROH length (p-value = 1.8e-2). Long ROH regions mainly contribute to this pattern; the siblings with MPVs have a larger total size of long ROH regions than their siblings in all families (p-value = 6.9e-3). Whereas the short ROH regions in the siblings with MPVs are lower in total size compared to their sibling pairs with single locus pathogenic variants (p-value = 0.029), and there are no statistically significant differences in medium ROH regions between sibling pairs (p-value = 0.52). CONCLUSION: This study sheds light on the significance of considering MPVs in families with affected sibling pairs and the role of ROH as an adjuvant tool in explaining clinical variability within families. Identifying individuals carrying MPVs may have implications for disease management, identification of possible disease risks to different family members, genetic counseling and exploring personalized treatment approaches.

Joint application of A-InDels and miniSTRs for forensic personal, full and half sibling identifications, and genetic differentiation analyses in two populations from China.

BACKGROUND: Previously, a novel multiplex system of 64 loci was constructed based on capillary electrophoresis platform, including 59 autosomal insertion/deletions (A-InDels), two Y-chromosome InDels, two mini short tandem repeats (miniSTRs), and an Amelogenin gene. The aim of this study is to evaluate the efficiencies of this multiplex system for individual identification, paternity testing and biogeographic ancestry inference in Chinese Hezhou Han (CHH) and Hubei Tujia (CTH) groups, providing valuable insights for forensic anthropology and population genetics research. RESULTS: The cumulative values of power of discrimination (CDP) and probability of exclusion (CPE) for the 59 A-InDels and two miniSTRs were 0.99999999999999999999999999754, 0.99999905; and 0.99999999999999999999999999998, 0.99999898 in CTH and CHH groups, respectively. When the likelihood ratio thresholds were set to 1 or 10, more than 95% of the full sibling pairs could be identified from unrelated individual pairs, and the false positive rates were less than 1.2% in both CTH and CHH groups. Biogeographic ancestry inference models based on 35 populations were constructed with three algorithms: random forest, adaptive boosting and extreme gradient boosting, and then 10-fold cross-validation analyses were applied to test these three models with the average accuracies of 86.59%, 84.22% and 87.80%, respectively. In addition, we also investigated the genetic relationships between the two studied groups with 33 reference populations using population statistical methods of FST, DA, phylogenetic tree, PCA, STRUCTURE and TreeMix analyses. The present results showed that compared to other continental populations, the CTH and CHH groups had closer genetic affinities to East Asian populations. CONCLUSIONS: This novel multiplex system has high CDP and CPE in CTH and CHH groups, which can be used as a powerful tool for individual identification and paternity testing. According to various genetic analysis methods, the genetic structures of CTH and CHH groups are relatively similar to the reference East Asian populations.

Associations between the number of siblings, parent-child relationship and positive youth development of adolescents in mainland China: A cross-sectional study.

BACKGROUND: Positive development plays an important role in youth when dealing with stressful circumstances. According to the resource dilution theory, adolescents with or without siblings may receive different levels of emotional and material resources from their parents. The purpose of this study is to examine the association between the positive development of adolescents in China today with their family characteristics such as the number of siblings. METHODS: A total of 2072 junior high and senior high school students (13 to 18 years old) in Chengdu, Sichuan, China, were investigated by cluster sampling. The Chinese Positive Youth Development scales (CPYDs) were used to measure positive youth development. The generalized linear model was used to explore the relationships among the number of siblings, parent-child relationships and positive youth development. RESULTS: Adolescents from only-child families had better performance on positive development (H = 21.87, P < 0.001) and better relationships with parents (H = 15.1, P < 0.05). The positive development of male and female adolescents does not significantly differ in families with different numbers of siblings. The generalized linear model showed that a positive parent-child relationship is positively correlated with adolescent positive development (P < 0.05). CONCLUSION: Positive youth development is not only associated with the number of siblings but also other modifiable familial factors. The positive relationship between parents and adolescents is of great practical value in daily life to improve youth development, and this might be the real lesson the resource dilution theory tells.

Comorbidities in women with polycystic ovary syndrome: a sibling study.

BACKGROUND: Polycystic ovary syndrome (PCOS) has previously been associated with several comorbidities that may have shared genetic, epigenetic, developmental or environmental origins. PCOS may be influenced by prenatal androgen excess, poor intrauterine or childhood environmental factors, childhood obesity and learned health risk behaviors. We analyzed the association between PCOS and several relevant comorbidities while adjusting for early-life biological and socioeconomic conditions, also investigating the extent to which the association is affected by familial risk factors. METHODS: This total-population register-based cohort study included 333,999 full sisters, born between 1962 and 1980. PCOS and comorbidity diagnoses were measured at age 17-45 years through national hospital register data from 1997 to 2011, and complemented with information on the study subjects´ early-life and social characteristics. In the main analysis, sister fixed effects (FE) models were used to control for all time-invariant factors that are shared among sisters, thereby testing whether the association between PCOS and examined comorbidities is influenced by unobserved familial environmental, social or genetic factors. RESULTS: Three thousand five hundred seventy women in the Sister sample were diagnosed with PCOS, of whom 14% had obesity, 8% had depression, 7% had anxiety and 4% experienced sleeping, sexual and eating disorders (SSE). Having PCOS increased the odds of obesity nearly 6-fold (adjusted OR (aOR): 5.9 [95% CI:5.4-6.5]). This association was attenuated in models accounting for unobserved characteristics shared between full sisters, but remained considerable in size (Sister FE: aOR: 4.5 [95% CI: 3.6-5.6]). For depression (Sister FE: aOR: 1.4 [95% CI: 1.2-1.8]) and anxiety (Sister FE: aOR: 1.5 [95% CI: 1.2-1.8), there was a small decrease in the aORs when controlling for factors shared between sisters. Being diagnosed with SSE disorders yielded a 2.4 aOR (95% CI:2.0-2.6) when controlling for a comprehensive set of individual-level confounders, which only decreased slightly when controlling for factors at the family level such as shared genes or parenting style. Accounting for differences between sisters in observed early-life circumstances influenced the estimated associations marginally. CONCLUSION: Having been diagnosed with PCOS is associated with a markedly increased risk of obesity and sleeping, sexual and eating disorders, also after accounting for factors shared between sisters and early-life conditions.

Two case reports of a novel missense mutation in the PNPLA6 gene in two siblings with chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar ataxia.

BACKGROUND: Boucher Neuhäuser Syndrome (BNS) is a rare disease with autosomal recessive inheritance defined by the classical triad; early-onset ataxia, hypogonadism and chorioretinal dystrophy. CASE PRESENTATION: We present two siblings diagnosed with BNS at midlife, identified with homozygous state of a novel PNPLA6 missense mutation. One healthy sibling and the mother were heterozygous carriers of the mutation. The proband presented with the classical triad and the other sibling presented with visual problems at first. The proband was referred to our department by a private Neurologist, in early adulthood, because of hypogonadism, cerebellar ataxia, axonal neuropathy, and chorioretinal dystrophy for further evaluation. The sibling was referred to our department for evaluation, at childhood, due to visual problems. Later, the patient displayed the triad of ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. The unusual medical history of the two siblings led to further examinations and eventually the diagnosis of the first BNS cases in Cyprus. WES-based ataxia in silico gene panel analysis revealed 15 genetic variants and further filtering analysis revealed the PNPLA6 c.3323G > A variant. Segregation analysis in the family with Sanger sequencing confirmed the PNPLA6 homozygous variant c.3323G > A, p.Arg1108Gln in exon 29. CONCLUSIONS: This highlights the importance of considering rare inherited causes of visual loss, spinocerebellar ataxia, or/and HH in a neurology clinic and the significant role of genetic sequencing in the diagnostic process.

Germline MYOF1::WNK4 and VPS25::MYOF1 Chimeras Generated by the Constitutional Translocation t(17;19)(q21;p13) in Two Siblings With Myelodysplastic Syndrome.

BACKGROUND/AIM: Constitutional chromosomal aberrations are rare in hematologic malignancies and their pathogenetic role is mostly poorly understood. We present a comprehensive molecular characterization of a novel constitutional chromosomal translocation found in two siblings - sisters - diagnosed with myelodysplastic syndrome (MDS). MATERIALS AND METHODS: Bone marrow and blood cells from the two patients were examined using G-banding, RNA sequencing, PCR, and Sanger sequencing. RESULTS: We identified a balanced t(17;19)(q21;p13) translocation in both siblings' bone marrow, blood cells, and phytohemagglutinin-stimulated lymphocytes. The translocation generated a MYO1F::WNK4 chimera on the der(19)t(17;19), encoding a chimeric serine/threonine kinase, and a VPS25::MYO1F on the der(17), potentially resulting in an aberrant VPS25 protein. CONCLUSION: The t(17;19)(q21;p13) translocation found in the two sisters probably predisposed them to myelodysplasia. How the MYO1F::WNK4 and/or VPS25::MYO1F chimeras, perhaps especially MYO1F::WNK4 that encodes a chimeric serine/threonine kinase, played a role in MDS pathogenesis, remains incompletely understood.

From classroom to life: Gender differences in the persistent effect of learning disabilities on adult depressive symptoms.

Despite the well-established link between adolescent learning disabilities (LD) and mental health, little is known about its long-term consequences. This study examines the relationship between adolescent LD and adult depressive symptoms, with a focus on gender differences and underlying mechanisms. Using a sibling sample from the National Longitudinal Study of Adolescent to Adult Health (N = 3,414), this study estimated sibling fixed effects models to account for unobserved family-level characteristics such as genes and early childhood family and social context. Sobel mediation analyses were conducted to examine social-psychological mechanisms, including the student-teacher relationship, the student-student relationship, and a sense of school belonging. LD in adolescence was positively associated with depressive symptoms in adulthood (b = 0.823, p < 0.05). This association remained robust when controlling for unobserved family-level confounders as well as educational attainment in adulthood. Gender-stratified models showed that only the association for women is statistically significant (b = 1.935, p < 0.05), and its magnitude is nearly three times that of the association for men. Sobel mediation tests indicate that a decline in a sense of school belonging mediates approximately 17% of the association between adolescent LD and adult depressive symptoms. This study's findings suggest that LD in adolescence is associated with an increase in depressive symptoms in adulthood, particularly in women, and a low sense of school belonging may be a potential mediator. Implementing interventions to improve the school integration of girls with LD could be an effective means of improving their long-term mental health.

Association of Very Low Birth Weight Infants With Parental and Sibling Mental Health Care Usage.

BACKGROUND AND OBJECTIVES: Parents and siblings of very low birth weight, premature infants are at risk for poor mental health outcomes with increased mental health care usage. Knowledge regarding mental health care use patterns could guide interventions. METHODS: This retrospective cohort study included US families with commercial insurance coverage from a single carrier. Neonates born at ≤30 weeks' gestational age or with a birth weight <1500 g were identified by insurance claim data between July 1, 2015, and June 30, 2016. Each case neonate family was matched with up to 4 control families. RESULTS: The study included 1209 case and 1884 control neonates (with 134 deaths among only the case neonates [11.1% of cases]); 2003 case and 3336 control parents (mean [SD] age, 34.6 [5.4] years; 2858 [53.5%] female); and 884 case and 1878 control siblings (mean [SD] age, 6.8 [5.5] years; 1375 [49.8%] female). Compared with controls, more case parents used mental health care over the first year after birth hospitalization discharge. Higher usage was observed for bereaved case parents soon after their child's death. A smaller proportion of bereaved case siblings received mental health care compared with controls. Although nonbereaved case parents returned toward the proportion of use observed in controls, nonbereaved case female siblings, bereaved case female and male siblings, and bereaved male parents experienced continued differences. CONCLUSIONS: Understanding and meeting the mental health care needs of parents and siblings of very low birth weight premature neonates can be guided by these findings, including elevated and prolonged needs of bereaved parents and siblings.