Familial Disorder Research Articles

The Complexity of Familial Inheritance in Pectus Excavatum: A Ten-Family Exome Sequencing Analysis

Background/Objectives: Pectus excavatum (PEx) is considered, at least partially, a familial disorder. A variety of inheritance patterns, associations with genetic syndromes, and pathogenic variants have been reported. However, the etiology of this condition is still not completely understood, and no known genes have been identified as definitive contributors. Methods: Family members with a confirmed PEx diagnosis (one proband and two first-degree relatives) and non-affected members were recruited into this study. Exome sequencing was performed on all affected familial PEx cases to systematically screen for candidate genes that are likely to be causative for PEx, and on non-affected family members for variant segregation analysis. Results: Ten families, with three affected members each, participated, providing thirty familial PEx cases. Different inheritance patterns were represented across the ten pedigrees, with possible incomplete penetrance. Genetic variants in REST (essential for neuronal development and associated with pectus deformities in prior studies), SMAD4 (variants can predispose individuals to thoracic aortic diseases), and COL5A (associated with Ehlers–Danlos syndrome and Fibromuscular dysplasia) were initially identified as potentially linked to the development of pectus deformities and segregated with the phenotype. No variants were shared across families in the studied population. Conclusions: Germline exome sequencing of families with multiple individuals affected by PEx in our study identified potential gene candidates linked to PEx. These candidates are private to individual families and no strong candidates shared across multiple families were identified. These findings suggest that the inheritance of PEx may not be strongly related to a shared single genetic variant in known genes. Given the accumulating evidence for the genetic basis of familial PEx, further studies, including polygenic analyses, as well as assessment of the non-coding genome and possible epigenetic markers are warranted.

Molecular Modeling and In Vitro Functional Analysis of the RGS12 PDZ Domain Variant Associated with High-Penetrance Familial Bipolar Disorder.

Bipolar disorder's etiology involves genetics, environmental factors, and gene-environment interactions, underlying its heterogeneous nature and treatment complexity. In 2020, Forstner and colleagues catalogued 378 sequence variants co-segregating with familial bipolar disorder. A notable candidate was an R59Q missense mutation in the PDZ (PSD-95/Dlg1/ZO-1) domain of RGS12. We previously demonstrated that RGS12 loss removes negative regulation on the kappa opioid receptor, disrupting basal ganglia dopamine homeostasis and dampening responses to dopamine-eliciting psychostimulants. Here, we investigated the R59Q variation in the context of potential PDZ domain functional alterations. We first validated a new target for the wildtype RGS12 PDZ domain-the SAPAP3 C-terminus-by molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation. While initial molecular dynamics (MD) studies predicted negligible effects of the R59Q variation on ligand binding, SPR showed a significant reduction in binding affinity for the three peptide targets tested. AlphaFold2-generated models predicted a modest reduction in protein-peptide interactions, which is consistent with the reduced binding affinity observed by SPR, suggesting that the substituted glutamine side chain may weaken the affinity of RGS12 for its in vivo binding targets, likely through allosteric changes. This difference may adversely affect the CNS signaling related to dynorphin and dopamine in individuals with this R59Q variation, potentially impacting bipolar disorder pathophysiology.

First description of leucism in the deep-sea angular rough shark (Oxynotus centrina) and the first documented pigment disorder in family Oxynotidae Gill, 1912.

The capture of a rare, critically endangered adult angular rough shark, Oxynotus centrina (Linnaeus, 1758), with abnormal coloration is reported in this paper. The shark exhibited a partial reduction in pigmentation, resulting in an overall pale appearance with white-greyish patches. Since the retinal pigmentation appeared normal, the shark was considered leucistic. This represents the first documented case of leucism in this species and the first colour disorder reported in the family Oxynotidae Gill, 1912. Despite the atypical appearance, the physical health of the shark seemed unaffected, supporting the notion that pigment disorders in deep-sea sharks do not inherently impair survival and growth. Full morphometric characteristics are presented and compared with those of a normal individual of the same sex caught in the same area, showing no differences.

The importance of genetic variant cleaners: From patient to wet lab and back to clinical practice.

Laureano J. Kamiya and colleagues have identified two novel missense variants (Gly168Arg and Gly168Glu) in the RUNX1 gene. These variants, identified in two unrelated families with familial platelet disorder with a predisposition to acute myeloid leukaemia (FPD/AML) phenotype, were initially classified as variants of uncertain significance (VUS). However, functional studies of RUNX1 target genes enabled their reclassification as likely pathogenic. The findings highlight Gly168 as a new mutation hotspot in RUNX1, providing important insights for genetic counselling and leukaemia monitoring. The study emphasizes the necessity for continuous updates to diagnostic guidelines and data sharing among laboratories to improve the classification and interpretation of genetic variants. Commentary on: Kamiya etal. Two novel families with RUNX1 variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML diagnosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19776.

7331 A Rare Case Of Familial Hypoparathyroidism

Abstract Disclosure: N. Sekhon: None. K.Z. Win: None. Background: Autosomal dominant hypoparathyroidism disorders are very rare and mostly asymptomatic. We present an interesting case of autosomal hypoparathyroidism with a new variant of gene defect on genetic analysis. Case: A 66-year-old female was referred to the endocrinology clinic for familial hypoparathyroidism and calcium oxalate nephrolithiasis. She had onset of seizures at age 16. She was diagnosed with hypocalcemia and hypoparathyroidism at age 30 when she had her first episode of nephrolithiasis. She had recurrent nephrolithiasis and lithotripsies, ultimately developing chronic kidney impairment that was at stage 3b at the time of evaluation. Renal Ultrasound revealed bilateral nephrolithiasis, and nephrocalcinosis. There was a history of hypoparathyroidism in her father, paternal uncle, and son. Her medications included calcium carbonate-vitamin D3 600-400 mg-unit oral 2 tablets daily and calcitriol 0.5 mcg daily. The pertinent physical examination finding was a short stature with height 4’11” and calluses in fingers. Her recent serum chemistry showed calcium 8.8 mg/dL (reference range 8.3 - 10.6 mg/dL), PTH < 6.3 pg/mL (reference range 18.4 - 80.1 pg/ mL), and phosphorus 3.3 mg/dL (reference range 2.4 - 5.5 mg/dL). 24 hr urine calcium was 96 mg (reference range 50-300 mg/24h). She was treated with hydrochlorothiazide for nephrolithiasis but was discontinued due to hypokalemia. We performed genetic testing that resulted positive for CASR NM_001178065.1 with heterozygosity and damaging missense predictions inherited as autosomal dominant or recessive. Discussion: The calcium-sensing receptor (CaSR) has an important role in calcium homeostasis by regulating parathyroid hormone (PTH) secretion and urinary calcium excretion. Familial hypoparathyroidism disorders are divided into Autosomal dominant hypocalcemia (ADH) type 1 and Autosomal dominant hypocalcemia (ADH) type 2. ADH1 is caused by an activating mutation of calcium-sensing receptor (CASR). The estimated prevalence of ADH1 ranges from 1 per 70,000 to 3.9 per 100,000. It is characterized by mild to moderate hypocalcemia, hyperphosphatemia, hypercalciuria, and inappropriately low but detectable PTH levels. It can be associated with Bartter syndrome Type 5. ADH2 is due to mutations in the alpha subunit of the G protein G11 (Gα11). Our patient had classic symptoms of hypocalcemia including short stature, seizures, kidney stones and its sequelae. Her 24-hour urine analysis showed inappropriately normal urine calcium with low normal serum calcium, undetectable serum PTH, and normal phosphorus. Our patient’s genetic analysis revealed a heterozygous defect in gene CASR with DNA variants c.2564G>A with damaging missense predictions. There is no such variant reported or listed in the ClinVar database. To our knowledge, this is the first such case of an autosomal dominant hypoparathyroidism with this gene defect. Presentation: 6/1/2024

9234 A Case of Gigantism Due to An AIP Gene Mutation: Implications for Genetic Counseling and Preimplantation Genetic Diagnosis

Abstract Disclosure: M. Serebro: None. M. Yacobi Bach: None. N. Even Zohar: None. A. Reches: None. Y. Greenman: None. From the age of 17 the patient experienced accelerated growth, facial changes, and enlargement of hands and feet. Despite having a sister already diagnosed with acromegaly, the patient did not undergo endocrine evaluation until the age of 25, when he was diagnosed with gigantism. Magnetic resonance imaging (MRI) revealed the presence of a macroadenoma with suprasellar extension reaching the optic chiasm. The patient underwent transsphenoidal surgery and excision of a sparsely granulated somatotroph adenoma that was Pit1 positive and exhibited weak immunostaining for growth hormone (GH). Insulin-like growth factor 1 (IGF1) levels normalized after surgery, and a fasting GH level was 0.6 ng/ml. Given the family history and the early onset of the disease, genetic counseling was recommended. Genetic testing revealed a heterozygote likely pathogenic variant in the AIP gene (c.713G>A). This finding prompted the recommendation for genetic testing of all first-degree relatives. The patient and his wife, who desired to have children, were referred to obstetrics and gynecology for pregestational diagnosis. Family segregation testing indicated that the patient's mother also carried the same AIP variant. Preimplantation genetic diagnosis (PGD) was conducted, revealing that 11 out of 20 embryos were carriers of the AIP variant. The non-carrier embryos were selected for implantation, and pregnancy was achieved. Efforts to inform first-degree relatives about the importance of genetic testing were undertaken, and one sister was tested and found to be healthy. Other siblings have not yet been tested. The patient's mother, identified as an AIP variant carrier, underwent endocrine laboratory tests that showed GH, IGF1, and prolactin levels within the normal range. Brain MRI did not reveal a pituitary lesion.This case highlights the significance of genetic counseling and testing in patients with familial endocrine disorders, the potential implications of a molecular diagnosis of a pathogenic AIP variant, and the challenges faced in reproductive decision-making for affected individuals and their families. Presentation: 6/3/2024

6891 Exclusive Normetanephrine Secreting Pheochromocytoma In A Young Male

Abstract Disclosure: E. Askar: None. H. Moran: None. IntroductionPheochromocytomas and paragangliomas arise from chromaffin cells and produce excessive catecholamines. Hypertension is their primary clinical symptom. they differ in their catecholamine secretory phenotype; paragangliomas typically secrete norepinephrine, while pheochromocytomas typically secrete epinephrine. Here, we present a case 21-year-old male with pheochromocytoma with elevated norepinephrine but normal epinephrine levels.Case presentationA 21 -year-old male with no past medical history presented with episodes of palpitations, sweating, and elevated blood pressure. He also reported abdominal pain. On admission, his blood pressure was 143/92 mmHg, pulse was 71/min, respiration was 16/min, and oxygen saturation was 100% in room air. The rest of physical exam was not significant. His electrolyte panel was normal. Computed tomography (CT) abdomen and pelvis with contrast was performed and showed a right adrenal mass measuring 4.9 x 4.0 x 6.5 cm which is predominantly hypoattenuating (approximately 30 Hounsfield units) with thick nodular rim of enhancement. Hormonal workup showed normal serum testosterone, DHEA-S, AM cortisol, ACTH, aldosterone, plasma metanephrine, and urine metanephrine, but profoundly high plasma normetanephrine 3641.6 (0.0-210.1) pg/mL. His 24-hour urinary normetanephrine was elevated at 14874 (80-440) ug/24hr, confirming a pheochromocytoma. The high norepinephrine level in the setting of normal epinephrine raised suspicion for Von Hippel Lindau (VHL). He was started on alpha and beta blockage and had laparoscopic removal of the right adrenal gland. The pathology report confirmed the diagnosis of pheochromocytoma confined to right adrenal. The patient was then referred for genetic testing. Conclusion: Pheochromocytoma can be a part of familial disorders, although being sporadic in nature most of the time. As demonstrated in our case, the hallmark of pheochromocytoma associated with VHL is nearly exclusive normetanephrine secretion and a high ratio of normetanephrine to metanephrine. Confirmation and testing of genes aid in proper monitoring and follow-up. The preferred course of treatment is radical resection. Presentation: 6/2/2024

Hierarchical Genomic Analysis of Susceptibility to Schizophrenia in Sudanese multi-case families

Background Schizophrenia, with its diverse and complex presentation, is a prime candidate for genetic investigation. Its heritability in both familial and sporadic cases, clinical overlap with other psychiatric conditions, and individual variations in response to treatment contribute to its complexity. Numerous genes and associated biochemical pathways show significant differences at the population, familial, and individual levels. Additionally, schizophrenia may represent an evolutionary trade-off for human brain development, creativity, and intellectual performance. Material and Methods This case pseudo-control study analyzed the whole genomes/exomes of seven Sudanese families with multiple siblings affected by schizophrenia. We examined shared variants among family members, including both cases and controls, and unique variants shared between patients but not controls. These variants were filtered based on their impact on protein function, expression levels, allele frequencies, ACMG classification for rare variants, and disease associations. Networks were created to identify central genes and common biological pathways. Results and Discussion The examination of this complex disorder in Sudanese families revealed numerous variants, both common and rare, showing differences between families and between our population and those reported in the literature. This highlights the challenge of accounting for the known heritability of the disease. Our hierarchical approach demonstrates that schizophrenia’s etiology involves the cumulative effect of various interacting variants in an ascending order of influence. Common variants are shared among all samples, while rare variants are shared among two or three families, most of which are associated with schizophrenia. In conclusion The significance lies not merely in the number of detected variants but in understanding their interactive roles, step by step, to reveal the complete picture of the disease’s phenotype.

The predictive role of Systemic Inflammation Response Index (SIRI), Neutrophil-Lymphocyte Ratio (NLR), and Platelet-Lymphocyte Ratio (PLR) in the prognosis of acute coronary syndrome in a tertiary care hospital

Background& Objective: Acute coronary syndrome (ACS) is a major cause of mortality globally, with significant morbidity and economic impact. This study aimed to correlate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammatory response index (SIRI) values in ACS patients with their prognosis via the GRACE scoring criteria and to propose the SIRI as a superior inflammatory marker for predicting ACS prognosis. MethodsEthical approval was obtained for a retrospective cross-sectional study, which included patients from the outpatient department and Tamilnadu Accident Emergency Initiative Ward at Government Medical College, Omandurar Government Estate, who were diagnosed with ACS according to American College of Cardiology guidelines from January 2022 to December 2023. We excluded patients with familial hypercholesterolemia, platelet disorders, infections, inflammatory conditions, or incomplete health records. Data on demographics, clinical findings, blood counts, ECGs, cardiac enzymes, echocardiography, serum creatinine, and vital signs were collected and analyzed to calculate the NLR, PLR, SIRI, and GRACE scores. Statistical analyses included Kolmogorov‒Smirnov and Anderson‒Darling tests, Spearman correlation, Kruskal‒Wallis one-way ANOVA, GLM modeling, k-fold cross-validation, and receiver operating characteristic (ROC) curve analysis. ResultsAfter applying the exclusion criteria, 247 ACS patients were included in the analysis. Significant associations were found between the NLR and the PLR, SIRI, and GRACE scores. The SIRI demonstrated the strongest association, whereas the PLR had the weakest association. All three variables significantly influenced prognostic risk, as determined by the GRACE score. GLM models highlighted the predictive significance of the NLR, PLR, and SIRI in estimating GRACE scores, with the SIRI showing potential superiority. K-fold cross-validation confirmed the superior predictive accuracy and ability of the SIRI to explain a larger proportion of variance in GRACE scores than the NLR and PLR. ConclusionsThe SIRI emerges as a promising prognostic marker for ACS, outperforming the NLR and PLR. Its ease of calculation from routine hemogram tests underscores its potential clinical utility for risk stratification in ACS management. Further validation and integration into existing risk assessment models could enhance prognosis assessment in ACS patients.

Adverse reactions of immune checkpoint inhibitors combined with Proton pump inhibitors: a pharmacovigilance analysis of drug-drug interactions

BackgroundCombining immune checkpoint and proton pump inhibitors is widely used in cancer treatment. However, the drug-drug interactions of these substances are currently unknown. This study aimed to explore drug-drug interactions associated with concomitant immune checkpoint and proton pump inhibitors.MethodsData were obtained from the US Food and Drug Administration Adverse Event Reporting System from 2014 to 2023. Disproportionality analysis was used for data mining by calculating the reporting odds ratios (RORs) with 95% confidence intervals (95%Cls). The adjusted RORs (RORadj) were then analysed using logistic regression analysis, considering age, sex, and reporting year. Drug-drug interactions occur when a combination treatment enhances the frequency of an event. Further confirmation of the robustness of the findings was achieved using additive and multiplicative models, which are the two statistical methodologies for signal detection of DDIs using spontaneous reporting system.ResultsThe total number of reports on immune checkpoint combined with proton pump inhibitors was 4,276. Median patient age was 66 years (interquartile range [IQR]: 60–74 years). Significant interaction signals were observed for congenital, familial and genetic disorders (RORadj = 2.66, 95%CI, 1.38–5.14, additive models = 0.7322, multiplicative models = 3.5142), hepatobiliary disorders (RORcrude = 6.64, 95%CI, 5.82–7.58, RORadj = 7.10, 95%CI, 6.16–8.18, additive models = 2.0525, multiplicative models = 1.1622), metabolism and nutrition disorders (RORcrude = 3.27, 95%CI, 2.90–3.69, RORadj = 2.66, 95%CI, 2.30–3.08, additive models = 0.6194), and skin and subcutaneous tissue disorders (RORcrude = 1.41, 95%CI, 1.26–1.58, RORadj = 1.53, 95%CI, 1.34–1.75, additive models = 0.6927, multiplicative models = 5.3599). Subset data analysis showed that programmed death-1 combined with proton pump inhibitors was associated with congenital, familial, and genetic disorders; hepatobiliary disorders; and skin and subcutaneous tissue disorders. Programmed death ligand-1 combined with proton pump inhibitors was associated with adverse reactions of metabolism and nutrition disorders. Cytotoxic T-lymphocyte antigen-4 combined with proton pump inhibitors was associated with congenital, familial, and genetic disorders, and skin and subcutaneous tissue disorders.ConclusionsBased on real-world data, four Standardized MedDRA Query System Organ Class toxicities were identified as drug-drug interactions associated with combining immune checkpoint and proton pump inhibitors. Clinicians should be cautious when administering these drugs concomitantly. Preclinical trials and robust clinical studies are required to explore the mechanisms and relationships underlying interactions, thus improving understanding of drug-drug interactions associated with this combination therapy.

On the edge of the image: Guiding the lenses to the individual service plan

This article seeks to unveil Brazilian Public Policies in the establishment of norms, which in practice act as mechanisms of violence and social exclusion, and are not welcoming to those who are socially marginalized. A qualitative analysis with documental bias revealed Education and Socioeducation actions through secondary source documents, namely, the Individual Service Plan (o Plano Individual de Atendimento − PIA). Four thematic markers were identified which deal with school, work, gender and family. The results revealed that the absence of a political-economic structure can generate family disorders which negatively impact school performance, concluding that the variables are related to the offending behavior of adolescents.

Noncanonical inheritance of phenotypic information by protein amyloids.

All known heritable phenotypic information in animals is transmitted by direct inheritance of nucleic acids, their covalent modifications or histone modifications that modulate expression of associated genomic regions. Nonetheless, numerous familial traits and disorders cannot be attributed to known heritable molecular factors. Here we identify amyloid-like protein structures that are stably inherited in wild-type animals and influence traits. Their perturbation by genetic, environmental or pharmacological treatments leads to developmental phenotypes that can be epigenetically passed onto progeny. Injection of amyloids isolated from different phenotypic backgrounds into naive animals recapitulates the associated phenotype in offspring. Genetic and proteomic analyses reveal that the 26S proteasome and its conserved regulators maintain heritable amyloids across generations, which enables proper germ cell sex differentiation. We propose that inheritance of a proteinaceous epigenetic memory coordinates developmental timing and patterning with the environment to confer adaptive fitness.

Effectiveness of cascade screening for elevated lipoprotein(a), an underdiagnosed family disorder.

Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent, genetic risk factor for cardiovascular disease. Though crucial for adequate risk assessment, detection of individuals at increased risk because of elevated Lp(a) is severely lacking in practice. In this light, several consensus statements have recommended familial cascade screening strategies to increase detection of elevated Lp(a). This review aims to synthesize findings from recent research into the effectiveness of cascade screening for elevated Lp(a). Cascade screening is an effective method for identifying individuals with elevated Lp(a) and is superior to opportunistic screening. Cascade screening identifies approximately one new case of elevated Lp(a) ≥ 125 nmol/L for every two first-degree relatives screened. The number needed to screen (NNS) ranged from 1.3 to 2.9, depending on Lp(a) threshold values and selected population. Cascade screening appears to be a promising strategy for identifying individuals with elevated Lp(a). However, several challenges persist regarding the implementation of this strategy in clinical practice. Deciding on threshold values for initiating cascade screening, considering the implications of ethnicity-related variability of Lp(a) levels, and further research into the clinical relevance of cascade screening are crucial steps. Understanding these factors will be essential for optimizing cascade screening protocols and enhancing its effectiveness in clinical practice. http://links.lww.com/COL/A31.

Effects of Probiotic Supplementation on Body Weight, Growth Performance, Immune Function, Intestinal Microbiota and Metabolites in Fallow Deer.

Intestinal diseases are one of the diseases that affect the growth and immunity of deer. Currently, more lactic acid bacteria (LAB) are available as feed additives to improve the intestinal ecological balance of ruminants in production practices. In this study, Enterococcus faecalis was supplemented in the feed of fallow deer for 170 d, and body weights, blood indices and immune levels of fallow deer were counted at 35, 65 and 170 d. The effects of Enterococcus faecalis on the intestinal microbiota and the metabolism of fallow deer were analysed using 16S rDNA and UPLC-MS/MS methods. The results showed that the addition of Enterococcus faecalis to the diet improved body weight and immune function and increased the aggregation of gut microbiota in fallow deer. The addition of Enterococcus faecalis altered the community structure of intestinal microorganisms in fallow deer and increased the number of beneficial bacteria. In addition, combined with metabolomics analysis, it was found that supplementation with Enterococcus faecalis significantly altered the metabolites of fallow deer, mainly regulating lipid metabolism, carbohydrate metabolism and phospholipid metabolism. In conclusion, this study presents, for the first time, evidence that the LAB strain Enterococcus faecalis can be used as a potential probiotic for deer and points to a new direction for the treatment of intestinal disorders in the deer family.

Association between the copy number variations of Methyl-CpG binding domain family and schizophrenia

Schizophrenia is recognized as one of the most severe psychiatric disorders, with its pathogenesis likely involving genetic, epigenetic, developmental, and environmental factors. Members of the Methyl-CpG Binding Domain (MBD) Family play a crucial role in the regulation of genomic DNA methylation, and studies have implicated the association between MBD family and neurodevelopmental disorders. Copy number variations (CNVs) are a significant genetic basis for human genomic variation, also playing a critical role in the genetic processes of schizophrenia. Therefore, we aimed to evaluate the susceptibility of MBD family CNVs to schizophrenia by exploring and validating them in two separate populations using CNVplex™ and qPCR methods, and to explore the relationship between MBD family CNVs and clinical phenotypes in the overall population using chi-square tests and Fisher’s exact tests. Results suggest that an increase in MBD1 gene copy number and a deficiency in MBD2 gene copy number may be associated with the risk of schizophrenia. The deficiency in MBD2 gene copy number may increase the risk of delusion of reference and delusion of persecutory in the overall sample, as well as in males. This research provides preliminary evidence supporting the association between MBD family CNVs and schizophrenia, highlighting the potential role of the MBD family in the pathogenesis of schizophrenia.

Anxiety in the family: A five-wave random-intercept cross-lagged panel analysis of dynamic reciprocal associations between father, mother, and child anxiety.

This five-wave longitudinal study examined the between- and within-family dynamic associations between father, mother, and child anxiety and the moderating effects of child gender in Chinese culture. Five hundred and twenty-two father-mother dyads of children (59% boys; Mage T1 = 8.34 years) completed measures of father, mother, and child anxiety at five time points, 6 months apart. Between-family associations suggested that children whose parents had more anxiety symptoms showed higher anxiety levels, and mothers or fathers whose partners had more anxiety symptoms showed higher anxiety levels. At the within-family level, after periods with higher child anxiety symptoms, mothers reported higher anxiety symptoms and vice versa. However, no reciprocal associations were found between father and child anxiety and between father and mother anxiety. Finally, the associations between father, mother, and child anxiety did not differ across boys and girls. Our findings highlight the importance of distinguishing among between-family and within-family associations and help to develop effective programs to prevent anxiety disorders in families.

Unilateral Renal Cystic Disease

Background: Unilateral renal cystic disease of kidney is a non familial and non progressive disorder, characterized by replacement of the renal parenchyma by a cluster of multiple cysts with a normal contralateral kidney. Case: A 2-day-old newborn baby came to the Urology Department of the Perinatology Department of Andalas University Hospital. The baby with prenatal ultrasound results showed unilateral hydronephrosis and multicystic kidneys. From the postnatal ultrasound, it was found: The right kidney was normal in shape and size; clear differentiation of the cortex and medulla; the pelvic calyx system was not dilated; No stones were seen; There were multiple cystic lesions with regular borders in the renal cortex, the largest cyst size was 5.5x4 cm. The left kidney was normal in shape and size; clear differentiation of the cortex and medulla; The pelvic calyx system was not dilated; No stones or sludge were seen. The impression of multiple renal cysts. The patient was followed up for renal function and cyst development. Conclusion : This case highlights the importance of early diagnosis and follow-up in infants with unilateral renal cystic lesions. Differentiating URCD from other cystic renal diseases is essential for appropriate management and counseling. Further studies are needed to elucidate the pathogenesis and long-term outcomes of URCD.

Antidepressant-associated diagnostic change from major depressive to bipolar disorder.

Anticipating diagnostic change from major depressive (MDD) to bipolar disorder (BD) can support better prognosis and treatment, especially of depression but is challenging and reported research results are inconsistent. We therefore assessed clinical characteristics associated with diagnostic change from MDD to BD with antidepressant treatments. We compared characteristics of 3212 initially MDD patients who became (hypo)manic during antidepressant treatment to those with stable MDD diagnoses as well as with cases of stable, spontaneous BD, using standard bivariate and multivariate statistics. Among MDD patients, 6.69% [CI: 5.85-7.61] changed to BD, mostly type II (BD2, 76.7%). BD-converters had higher rates of familial mood disorders (74.1% vs. 57.1%) or BD (33.7% vs. 21.0%) and 2.8-years younger onset than stable MDD patients. They also had more prior depressive recurrences/year, years-of-illness, mood-stabilizer treatment, divorces, fewer children, more suicide attempts and drug-abuse, and higher intake cyclothymia, YMRS and MDQ scores. Predictors independently associated with diagnostic conversion were: more familial BD, depressions/year, unemployment, cyclothymic temperament, suicidal ideation or acts, and fewer children. BD-converters vs. spontaneous BD cases had significantly more suicide attempts, BD2 diagnoses, and affected relatives. Converting to vs. spontaneous BD1 was associated with more ADHD, more suicidal ideation or behavior, MDI course, and younger onset; converting to vs. spontaneous BD2 had more episodes/year, unemployment, ADHD, substance abuse, suicidal ideation or attempts, and more relatives with BD. Few (6.69%) initially MDD subjects converted to BD, most (76.7%) to BD2. Independent predictive associations with diagnostic change included: familial BD, more depressions/year, unemployment, cyclothymic temperament, suicidal behavior and fewer children. Notably, several characteristics were stronger among those changing to BD during antidepressant treatment vs. others with spontaneous BD.

Nonfamilial cherubism in a 6-month-old infant: a case report

BackgroundCherubism is known as a very rare autosomal dominant familial disorder of childhood caused by a mutation in the SH3BP2 gene on 4p16.3. It has not yet been observed at birth and is usually diagnosed in children aged 2–7. Here, we present a non-hereditary case of cherubism at a very early age.Case presentationA 6-month-old girl presented with bilateral progressive jaw enlargement. On physical examination, bilateral asymmetrical jaw enlargement, predominantly on the left side, and some enlarged, non-tender, mobile submandibular lymph nodes were detected. No other abnormality was observed. Further investigations with radiology suggested cherubism and Burkitt’s lymphoma as differential diagnoses. Later on, histopathologic evaluations were suggestive of cherubism. No surgical interventions were indicated, and the child is on regular follow-ups.ConclusionNon-hereditary Cherubism, despite scarcity, can present in children below two years of age, even as early as the beginning of primary dentition. Accurate and swift diagnosis is essential to avert physical and psychological complications. Our case report shows the importance of keeping cherubism in mind as a differential diagnosis of bone disease, even in children under a year old, and the value of interdisciplinary collaboration in dealing with rare genetic disorders.

FLI1 is associated with regulation of DNA methylation and megakaryocytic differentiation in FPDMM caused by a RUNX1 transactivation domain mutation

Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It is characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematological malignancies. Although FPDMM is a precursor for diseases involving abnormal DNA methylation, the DNA methylation status in FPDMM remains unknown, largely due to a lack of animal models and challenges in obtaining patient-derived samples. Here, using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous RUNX1 mutations. These iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. The FPDMM-mimicking HPCs showed DNA methylation patterns distinct from those of wild-type HPCs, with hypermethylated regions showing the enrichment of ETS transcription factor (TF) motifs. We found that the expression of FLI1, an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a RUNX1 transactivation domain (TAD) mutation. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of FLI1 restored their megakaryocytic differentiation efficiency and hypermethylation status. These findings suggest that FLI1 plays a crucial role in regulating DNA methylation and correcting defective megakaryocytic differentiation in FPDMM-mimicking HPCs with a RUNX1 TAD mutation.