Maternal Aunt Research Articles

Kin investment biases of aunts and uncles: associations with phenotypic resemblance and sociodemographic characteristics.

Higher investment in maternal than paternal aunts and uncles is explained by the "paternity uncertainty hypothesis". Regardless of laterality, however, aunts show a greater degree of investment than uncles, which is attributed to sex-specific reproductive strategies. Resemblance cues can be used as indicators of genetic relatedness. The central hypothesis of the current study was that perceived phenotypic resemblance between aunts/uncles and niblings would be associated with aunts' and uncles' investment. The association was predicted to be stronger with respect to patrilateral than matrilateral aunts and uncles and stronger with respect to patrilateral aunts than patrilateral uncles. 243 Iranians aged between 15 and 50 participated in a retrospective analysis and filled out a 52-item questionnaire focusing on the solicitude, emotional closeness, and contact frequency between aunts/uncles and their nephews/nieces. In addition, the participants had to rate their phenotypic resemblance with their aunts and uncles. Aunts' and uncles' solicitude, emotional closeness, and contact frequency were differentially expressed according to sex and laterality. Maternal aunts showed the significantly highest emotional closeness, contact frequency, and investment, while the opposite was true for paternal uncles. Moreover, investment was correlated with phenotypic resemblance. Such association was stronger for patrilateral than matrilateral aunts and uncles, and concerning solicitude it was stronger for patrilateral aunts than patrilateral uncles. The resemblance-based kin recognition mechanism among aunts and uncles was self- rather than family-referent. In conclusion, phenotypic similarity can be used as a cue to genetic kinship and is correlated with the investment of aunts and uncles. However, such associations also depend on the degree of genetic relatedness and the differential kin investment provided by each sex.

Severe Epilepsy in an Individual With a TSC2 R905Q Variant Prompting Late Diagnosis in Affected Family Members

BackgroundTuberous sclerosis complex (TSC) is a multisystemic disorder caused by inactivating variants in the mTOR pathway inhibitor genes TSC1 and TSC2. Individuals with TSC are predisposed to benign tumors in multiple organs as well as TSC-associated neuropsychiatric disorders (TAND) and epilepsy. Pathogenic variants in TSC2 are typically associated with a more severe phenotype compared with TSC1; the TSC2 R905Q variant has been shown to be an exception, where patients have been reported to present with unusually mild TSC features that may be undetected. MethodsWe studied the TSC phenotype of a 13-year-old individual and three family members with a TSC2 c.2714G>A (R905Q) pathogenic variant. ResultsPatient 1 presented with severe medically refractory epilepsy without tubers or subependymal nodules and only mild dermatologic features of TSC missed on virtual examinations. Her mother and maternal aunt (Patients 2 and 3–diagnosed after age 50 years) presented with a mild phenotype, with dermatologic features and TAND. Her maternal uncle (Patient 4–diagnosed at age 47 years) displayed the most severe phenotype, presenting with intellectual disability, medically refractory epilepsy, obsessive-compulsive disorder, post-traumatic stress disorder, and psychosis. ConclusionsThis study expands the possible phenotypic spectrum of TSC2 R905Q variant, demonstrating an association with severe epilepsy without associated neuroradiological stigmata. This presentation highlights the possibility of occult focal cortical dysplasia in TSC and emphasizes the importance of genetic testing in individuals with severe epilepsy. Moreover, a late adult diagnosis was subsequently made in other family members allowing for appropriate TSC surveillance to occur.

Female Infertility and Neurodevelopmental Disorders in Children: associations and evidence for familial confounding in Denmark.

Existing research suggests the impact of infertility on the risk of neurodevelopmental disorders in children, however, studies to date have failed to separate the impact of male and female infertility, often blurring the lines with proxies that encompass all forms of infertility. Moreover, while both health conditions co-occurring with infertility and genetic factors operating upstream have been suggested to influence the association between infertility and child outcomes, their roles and potential impact on observed associations remain unclear. The objectives of this study are to investigate the relationship between female infertility and autism in the child, differentiating it from the effects of male and the couple infertility; consider the role of various maternal and birth factors in the association; and examine the effects of shared familial confounders on the association. Danish population-based cohort study, including all singleton live births in Denmark 1998-2015, their parents and parents' siblings. The cohort was followed up until December 31, 2016. The exposure was a history of female infertility in the mother and the mother's sister. We examined four definitions of female infertility based on the ICD-10 codes derived from the Danish National Patient Register - any female infertility; specified female infertility; female exclusive infertility; and female or male infertility. The outcome was diagnosis of autism spectrum disorder (ASD) in the Danish Psychiatric Central Research Register or the national patient register. A multivariable Cox regression model was used to estimate the associations between female infertility and autism, accounting for child's sex, year of birth, maternal age, education level, chronic comorbidities, and pregnancy and birth complications. The effects of shared familial factors on the association were analyzed using exposure information from the child's maternal aunt. The cohort included 1,131,899 mother-child pairs, among which 18,374 children with ASD diagnosis. History of female infertility in the mother (all definitions) was significantly associated with autism in the child, with the association remaining robust after adjustment for covariates (HRadj=1.14 (95% CI, 1.03-1.26) for specified infertility). The diagnosis of infertility in a child's maternal aunt was also significantly linked to the child's autism risk, even after adjustment for maternal infertility (HRadj=1.10 (95% CI, 1.00-1.20). in This population-based birth cohort study, we found a slightly higher risk of autism in children born to mothers with a history of infertility, with the association remaining consistent across various definitions of female infertility and robust to adjustments for demographic, child, and maternal factors. The study suggests for the first time that shared familial factors, possibly both genetic and non-genetic, could be influencing both female infertility and the risk of autism in children, indicating a need for further investigation into these familial effects.

Prompt Cytopathological Diagnosis of Multiple Xanthomatous Skin Nodules in an Adolescent Girl Opening the Doors to Detection of Familial Hypercholesterolemia

Background Xanthomas are papulo-nodular, yellow, soft, painless, dermal-based non-neoplastic cutaneous lesions that comprise of localized aggregates of lipid-laden histiocytes. Case report A thirteen-year-old adolescent girl presented with multiple, large, bilateral, nodules present over elbows, posterior aspect of heel, and knees for five years. Fine needle aspiration cytology was performed, and the smears showed numerous foamy histiocytes, a few benign spindle cells, and foreign-body giant cells against a lipidaceous background. Her maternal aunt and grandmother also had xanthelasma palpebrarum. Serum lipid levels were advised and were markedly deranged in all three of them. Based on the corroborative clinical, biochemical, and cytopathological findings, a final diagnosis of familial hypercholesterolemia (FH) was rendered. Conclusion The present case sheds light on the importance of prompt cytopathological diagnosis of xanthomatous lesions, especially in children and adolescents, as it can help prevent morbidity and mortality due to associated premature adverse cardiovascular and cerebrovascular events if left undiagnosed.

A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis.

Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband's motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.

Phenotypic and genetic analysis of a Chinese pedigree affected with type 1 Otopalatodigital syndrome

To analyze the clinical phenotype and genetic basis of a Chinese pedigree affected with Otopalatodigital syndrome type 1 (OPD1). A pedigree which was evaluated at the Department of Endocrinology, General Hospital of the Central Theater Command on December 3, 2020 was selected as the study subject. Clinical phenotype and genetic features of the proband were analyzed. Whole exome sequencing was employed to screen for genetic variants in the proband, and Sanger sequencing was used to verify the candidate variants in the proband's mother, uncle, maternal aunt, and paternal aunt. Pathogenicity analysis was also conducted for the candidate variants. The proband, a 16-year-old male, had shown distinctive facial features including mildly prominent eyebrows, down-slanting palpebral fissures, hypertelorism, and depressed nasal bridge. Additionally, he had clubbing of bilateral thumbs and big toes, and central type diabetes insipidus. Genetic sequencing revealed that he has harbored a heterozygous c.586C>T (p.R196W) missense variant of the FLNA gene (NM_001110556.2), which was also carried by his mother and uncle. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), this variant was classified as likely pathogenic (PM1+PM2_Supporting+PP2+PP3+PS4 Supporting). The heterozygous c.586C>T (p.R196W) variant of the FLNA gene probably underlay the pathogenesis in this OPD1 family. The central type diabetes insipidus in the proband may represent a newly discovered phenotype of OPD1. Above finding has contributed crucial information for the comprehensive understanding of the clinical manifestations and pathogenic mechanisms of OPD1.

Abstract PO5-20-11: Synchronous Breast Cancer and Pheochromocytoma: A Case Series

Abstract Background: Pheochromocytomas are rare, although literature suggests a rising incidence due to the widespread use of sensitive imaging modalities. Synchronous presentation of breast cancer with a pheochromocytoma is exceedingly rare with only one case documented in the literature. We present two cases of malignancy in the breast in which pheochromocytomas were incidentally detected during workup and management with vastly different presentations. Case Presentation: Two patients presented with breast cancer and were secondarily diagnosed with pheochromocytoma. Patient 1 is a 48-year-old postmenopausal female with a history of intraductal papilloma four years prior, who presented with right breast nipple discharge. Diagnostic mammogram showed a right breast mass and biopsy confirmed an intraductal papilloma with intermediate-grade DCIS, ER+/PR-. She had no family history of cancer or PGL/PPC. During a scheduled lumpectomy, she developed hypoxia, hypotension, and flash pulmonary edema requiring intubation and ECMO with prolonged ICU stay and long recovery with tracheostomy for four months. Contrast-enhanced CT of her abdomen showed a 9 cm right adrenal mass. Serum and urine metanephrines were markedly elevated, and it was determined that she had an adrenal crisis secondary to undiagnosed pheochromocytoma. She completed treatment for DCIS with lumpectomy and radiation and is currently on adjuvant anastrozole. She additionally had an adrenalectomy for pheochromocytoma, which was found to be stage PASS 2. Subsequent genetic testing confirmed the absence of germline mutations associated with hereditary PGL/PPC or breast cancer. Patient 2 is a 57-year-old female presenting with a history of left breast mass she first noted a year ago, with newly found nipple retraction and skin changes. Biopsy showed invasive ductal carcinoma of the breast, G3, Stage IIIA, pT3N2aM0, ER 95%/PR-/Her2- (IHC 0). Staging PET scan showed a 3.4 cm hypermetabolic left adrenal mass in addition to the breast mass and left axillary adenopathy. Serum and urine metanephrines were elevated, and pheochromocytoma was diagnosed. Family history was positive only for pancreatic cancer in a maternal aunt. Comprehensive genotype testing was negative for hereditary breast cancer and PGL/PCC syndromes. She was concomitantly treated with a radical mastectomy for breast cancer and a left adrenalectomy and tolerated the procedure well as she received perioperative alpha-adrenergic blockade with doxazosin. She has received chemotherapy and radiation for breast cancer treatment and is currently on adjuvant anastrozole. The adrenal mass was confirmed to be a pheochromocytoma PASS 2-3. Discussion: We present two unique cases of breast cancer and pheochromocytomas discovered in tandem with variable clinical manifestations. It is extremely uncommon to have a presentation of primary breast malignancy concomitantly with pheochromocytoma, and we demonstrate two cases that occurred within months of one another at our facility. During the first case, metastatic workup was not indicated for DCIS. However, during the seemingly benign lumpectomy procedure, the patient experienced significant complications, leading to intense ICU management, intubation, and tracheostomy. In the second case, a metastatic workup was completed due to locally advanced breast cancer where the adrenal mass was detected and a pheochromocytoma was diagnosed prior to surgery. This allowed both cancers to be resected simultaneously and safely. This series demonstrates the importance of keeping pheochromocytomas in the differential during the workup of adrenal masses prior to surgical interventions. Additionally, they demonstrate how the usual workup and management of breast cancer does not take into account these rare but significant diagnoses, and that can result in fatal consequences. Citation Format: Nikita Dahake, Abhimanyu Tushir, Aruna Padmanabhan. Synchronous Breast Cancer and Pheochromocytoma: A Case Series [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-11.

Eccrine Spiradenoma

First described in 1956, spiradenomas are benign tumors that arise from the bulge of the hair follicle rather than the sweat gland. Epidemiologically, spiradenomas are rare, malignant ones are even rarer, with only around 120 documented cases worldwide. No racial association or sexual predilection for spiradenomas has been reported. Most spiradenomas occur between the ages of 15 and 35. As for malignant spiradenomas, they tend to develop after the age of 50, with a median age of 60 years. Clinically, they are generally skin-colored nodules approximately 1 cm in diameter with a soft consistency, located on the scalp, neck, upper part of the trunk, breasts and rarely the armpits and vulva. While malignant spiradenomas tend to have slightly different characteristics from benign spiradenomas which can metastasize with an estimated rate of 19%. We report the case of a 45-year-old primiparous patient who had been postmenopausal for 5 years and had a maternal aunt who died of breast cancer who consulted for the discovery on self-palpation of a subcutaneous nodule near the left axillary area. The breast examination is unremarkable on D cup breasts with palpation of a subcutaneous nodule measuring 2.5 x 1.5 cm near the left axillary area. Echo mammography finds tissue and cystic lesions of the left breast classified ACR3 and a left axillary subcutaneous lesion measuring 24x13mm that is difficult to characterize. After biopsy of this lesion, the histological and immunohistochemical appearance returned in favor of a cutaneous adnexal tumor compatible with an ECCRINE SPIRADENOMA The extension assessment made by Thoracal abdomino pelvic CT had revealed non-specific pulmonary micronodules to be monitored The patient was sent to multidisciplinary team discussion with the decision to perform a left lumpectomy of the axillary lesion. The management of malignant spiradenomas is multidisciplinary with a surgeon, an oncologist and possibly a radiation oncologist.

Stage IV perihilar cholangiocarcinoma with loss of expression of MSH2 and MSH6: hereditary cancer syndrome?

We present the case of a 69-year-old male diagnosed with stage IV perihilar cholangiocarcinoma with loss of expression of MSH2 and MSH6 proteins, but somatic wild type MSH2 and MSH6 genes with Oncomine Comprehensive Assay (OCA) genomic sequencing panel. In his cancer family history, there was a maternal aunt with sigmoid colon adenocarcinoma also missing MSH2 and MSH6 protein expression. Subsequently, we will discuss whether or not we are facing a hereditary cancer syndrome.

Incendiary: Fire setting behaviors in youth

A 12‐year‐old boy presented for psychiatric assessment with a chief complaint of “fire setting.” The patient was reluctant to speak, however, his caregiver stated that he had set a fire in the basement of his home while the rest of the family were asleep. They were alerted due to the smoke alarm going off and were able to hurriedly contain the situation. The patient had a history of physical and emotional abuse from parents and was residing with his legal guardian, his maternal aunt.

Targeted long-read sequencing identified a causal structural variant in X-linked nephrogenic diabetes insipidus.

X-linked nephrogenic diabetes insipidus (NDI) is a rare genetic renal disease caused by pathogenic variants in the AVPR2 gene. Single nucleotide variants and small insertions/deletions in AVPR2 are reliably detected by routine clinical sequencing. Nevertheless, structural variants involving AVPR2 are challenging to identify accurately by conventional genetic testing. Here, we report a novel deletion of AVPR2 in a Czech family identified for the first time by targeted long-read sequencing (T-LRS). A male proband with X-linked NDI underwent clinical sequencing of the AVPR2 gene that failed and thus indicated possible whole-gene deletion. Therefore, PCR mapping and subsequent targeted long-read sequencing (T-LRS) using a Pacific Biosciences sequencer were applied to search for the suspected deletion. To validate the deletion breakpoints and prove variant segregation in the family with X-linked NDI, Sanger sequencing of the deletion junction was performed. Quantitative real-time PCR was further carried out to confirm the carrier status of heterozygous females. By T-LRS, a novel 7.5 kb deletion of AVPR2 causing X-linked NDI in the proband was precisely identified. Sanger sequencing of the deletion junction confirmed the variant breakpoints and detected the deletion in the probands´ mother, maternal aunt, and maternal cousin with X-linked NDI. The carrier status in heterozygous females was further validated by quantitative real-time PCR. Identifying the 7.5 kb deletion gave a precise molecular diagnosis for the proband, enabled genetic counselling and genetic testing for the family, and further expanded the spectrum of structural variants causing X-linked NDI. Our results also show that T-LRS has significant potential for accurately identifying putative structural variants.

Wu Type GRIA3 Mutation Associated X-Linked Syndromic Intellectual Developmental Disorder: A Case Report

Background: A Wu type X-linked syndromic intellectual developmental disorder is caused by mutations in the GRIA3 gene This disorder is characterised by autistic features, hyporeflexia, intellectual disability and facial dysmorphism. Case report: The patient, a 4 year old male child, came with chief complaints of runny nose and tooth ache for 5 days. There was a past history of frequent falls, myoclonic jerks, tongue fibrillation, shudder attacks and delayed developmental milestones. The child at presention did not have myoclonic jerks or frequent falls. Family history is significant for maternal aunt presenting with similar complaints. On examination, protruding tongue, depressed nasal bridge, high arched palate, short fingers, right eye divergent squint, cafe-au-lait spot on the right knee, deep tendon reflexes- sluggish on both upper and lower limbs, power of 3/5 and hypotonia was observed in all four limbs with plantar- extensor bilaterally. Conclusion: On DNA testing, a missense mutation of GRIA 3 gene was noted. He was treated on a multidisciplinary approach and was admitted in a special school where occupational therapy, speech therapy, behavioural therapy and physiotherapy was given.

CONSANGUINITY AS A SIGNIFICANT RISK FACTOR FOR DIABETES MELLITUS: A SYSTEMATIC REVIEW

Objectives:This systematic review aims to study the recent updates regarding the association between consanguinity and DM. Methods:PubMed, SCOPUS, Web of Science, and Science Direct were systematically searched for relevant literature. Rayyan QRCI was employed throughout this comprehensive process. Results& interpretation: Our results included ten studies with a total of 8878 patients, and 4565 (51.4%) were males. Eight studies included patients with T2D, and two included T1D. The prevalence of consanguinity ranged from 21.9% to 95% in T2D and 70.8% in T1D.PreoperThe development of T2D was significantly influenced by consanguinity, consanguineous marriages, and maternal diabetes, particularly in developing Arab countries where the prevalence of T2D in families is very high. Significant risk variables for T2D in MetS patients were consanguineous marriages, maternal aunts, maternal grandpas, and the presence of MetS in the parents family. A family history of autoimmune disease in children or paternal consanguinity is not strongly associated with the complexity of T1D.

CONSANGUINITY AS A SIGNIFICANT RISK FACTOR FOR DIABETES MELLITUS: A SYSTEMATIC REVIEW

Objectives:This systematic review aims to study the recent updates regarding the association between consanguinity and DM. Methods:PubMed, SCOPUS, Web of Science, and Science Direct were systematically searched for relevant literature. Rayyan QRCI was employed throughout this comprehensive process. Results& interpretation: Our results included ten studies with a total of 8878 patients, and 4565 (51.4%) were males. Eight studies included patients with T2D, and two included T1D. The prevalence of consanguinity ranged from 21.9% to 95% in T2D and 70.8% in T1D.PreoperThe development of T2D was significantly influenced by consanguinity, consanguineous marriages, and maternal diabetes, particularly in developing Arab countries where the prevalence of T2D in families is very high. Significant risk variables for T2D in MetS patients were consanguineous marriages, maternal aunts, maternal grandpas, and the presence of MetS in the parents family. A family history of autoimmune disease in children or paternal consanguinity is not strongly associated with the complexity of T1D.

Male androphilia, fraternal birth order, and female fecundity in Samoa: A 10-y retrospective.

Two separate but related literatures have examined familial correlates of male androphilia (i.e., sexual attraction and arousal to masculine adult males). The fraternal birth order effect (FBOE) is a widely established finding that each biological older brother a male has increased the probability of androphilia 20-35% above baseline rates. Other family demographic variables, such as reproduction by mothers, maternal aunts, and grandmothers, have been used to test evolutionary hypotheses that sexually antagonistic genes lead to androphilia among males, lowering or eliminating reproduction, which is offset by greater reproductive output among their female relatives. These proposed female fecundity effects (FFEs), and the FBOE, have historically been treated as separate yet complementary ways to understand the development and evolution of male androphilia. However, this approach ignores a vital confound within the data. The high overall reproductive output indicative of an FFE results in similar statistical patterns as the FBOE, wherein women with high reproductive output subsequently produce later-born androphilic sons. Thus, examination of the FBOE requires analytic approaches capable of controlling for the FFE, and vice-versa. Here, we present data simultaneously examining the FBOE and FFE for male androphilia in a large dataset collected in Samoa across 10 y of fieldwork, which only shows evidence of the FBOE.

Non-Activating Integrin β3(R734C) Mutation Associated with Macrothrombocytopenia and Impaired Platelet Function

Introduction We and others identified several mutations in ITGA2B or ITGB3 associated with congenital macrothrombocytopenia. These mutations are located around transmembrane domains of αIIb or β3, and basically induce constitutive activation of αIIbβ3. Recently, we identified a mutation, β3(R734C), which is located in cytoplasmic tail of β3 without inducing αIIbβ3 activation in a Japanese family with macrothrombocytopenia. We analyzed the effect of the mutation on platelet production and function using knock-in (KI) mice. Cases and Transfection assay The proband was a 14-year-old Japanese girl, who showed macrothrombocytopenia with 60-90 x 10 9/L platelet counts and mild bleeding tendency. Her mother, her maternal aunt and a cousin also showed macrothrombocytopenia. The expression of αIIbβ3 on their platelets was decreased to ~50% of healthy control. GPVI expression was decreased, whereas GPIb expression was increased probably due to the increase in platelet size. Genetic analysis revealed that all affected subjects were heterozygous of β3(R734C) mutation. No PAC-1 binding was observed to the platelets of the affected subjects or αIIbβ3(R734C)-transfected 293T cells, indicating that the mutation does not cause αIIbβ3 activation. Methods and Results of mouse studies We generated β3(R734C) KI mouse (C57BL6/J background) by CRISPR/Cas9-mediated genome editing. The β3(R734C) KI mice were viable with no apparent bleeding tendency. Platelet counts of heterozygous (Hetero), and homozygous (Homo) KI mice were decreased relative to those of wild-type (WT) mice [WT: 1095 ± 52 (x10 9/L), Hetero: 834 ± 93**, Homo: 445 ± 30** (mean±SD, **P<0.01 compared with WT, n=6 respectively)], with an increase in platelet size, indicating that β3(R734C) leads to macrothrombocytopenia. Moreover, the expression of αIIbβ3 and GPVI in platelets was decrease in KI mice like human subjects. Platelet aggregations were impaired in KI mice. JON/A binding was not detected on non-stimulated platelets and agonist-induced P-selectin and JON/A binding were impaired in homo KI mice, particularly in PAR4-AP stimulation. Platelet spreading on fibrinogen (Fgn) was impaired in KI mice with or without ADP and thrombin stimulation. Next, we analyzed megakaryocytes (Mgk) derived from bone marrow after 5 days incubation with murine thrombopoietin. Interestingly, the expression of αIIbβ3 in Mgk of KI mice was compatible with WT and the rate of filopodia and/or lamellipodia formation of Fgn-adhered Mgk was decreased in KI mice [WT: 78(%), Homo: 32(%) (P<0.01)]. RhoA activation was assessed by ELISA and it was significantly decreased in Fgn-adhered Mgk of KI mice [WT: 0.33±0.039, Homo: 0.16±0.029 (mean OD 490nm Δblank±SD, P<0.01)]. Finally, we observed impaired proplatelet formation of fetal liver derived-Mgk in KI mice [WT: 26.2±2.7(%), Homo: 15.2±1.9(%) (P<0.01)] with abnormal morphology (Figure 1). These results suggest that impaired αIIbβ3 outside-in signaling and cytoskeletal remodeling in KI mice lead to macrothrombocytopenia. Conclusions We revealed that a non-activating β3(R734C) is a causal mutation of macrothrombocytopenia in human and mouse. This mutation leads to impaired inside-out and outside-in signaling of αIIbβ3, which results in abnormal platelet production with impaired cytoskeletal reorganization. Our results also suggest that abnormal signaling induced by β3(R734C) causes reduced expression of GPVI, which has not been reported in other αIIbβ3-related macrothrombocytopenia.

Li-Fraumeni Syndrome: The Two Faces of a Coin in Myeloid Malignancies

Background Li-Fraumeni Syndrome (LFS) is a rare, autosomal dominant genetic disorder caused by germline mutations in the TP53 tumor suppressor gene. It is characterized by a predisposition to a wide range of cancers, including hematological malignancies. Hematological malignancies account for approximately 3-4% of all LFS-related cancers of which are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Myelodysplastic syndromes (MDS) and lymphomas. Method and Results We retrospectively analyzed our clinical data for patients with hematological malignances from the period of Jan 2016-Jan 2022 at the national center for cancer care and research (NCCCR), the only tertiary hematology center in the country. We report on two cases with Li Fraumeni syndrome with acute leukemia and their variable spectrum of the disease manifestations and prognosis. Case 1: 16 years old male known case of rheumatic heart disease presented with double malignancy; left mandible osteosarcoma and lymphoblastic leukemia/ lymphoma concurrently in 2020. For his Leukemia he received BFM*2009 protocol and after remission he underwent surgical resection and received radiotherapy for the osteosarcoma. Patient has family history of breast cancer in his maternal aunt and his paternal great aunt. Germline Genetic testing from buccal swab revealed a pathogenic variant in TP53 gene confirming Li Fraumeni syndrome which is most likely De novo as it was not detected in both parents and his 3 siblings. In 2022 patient presented with pancytopenia and therapy related AML/MDS with complex Karyotype. He was started on salvage therapy and was planned for allogenic stem cell transplant (SCT) from his HLA matched brother, however, unfortunately, patient didn't achieve complete remission thus could not receive the SCT and he passed away one year later in 2023. Case 2: 60-year-old female known case of hypertension who was diagnosed with right breast cancer in 2011 for which she underwent surgery, chemotherapy, and radiotherapy. A year later, patient was diagnosed with left upper lobe squamous cell lung carcinoma, and underwent left upper lobectomy, chemotherapy and radiotherapy. Patient was in remission for 6 years, until 2018 when she presented with pancytopenia and therapy related AML with complex monosomic Karyotype. Due to patient's age and comorbidities, she was unfit for intensive therapy, thus she received hypomethylation agent (Azacitidine) till disease progression and was referred to genetic counseling. Patient has a family history of unknown cancer in her paternal half-sister at the age of 77 and an unknown cancer in her paternal cousin. Genetic testing reveled a mosaic pathogenic variant in TP53 gene present in 17% of the 1137 next generation sequencing reads. Shortly later, patient passed away without confirmatory fibroblast testing. Conclusion: Genetic testing indications for Li-Fraumeni syndrome present challenges as patients with full mutationin TP53 often but not always present with the full spectrum of the disease, whereas patients with mosaic profilepresent with a later onset of the disease and might not be identified early. In both scenarios, patients can be miss-identified and exposed to radiotherapy thus testing criteria warrants further evaluation. Acute Leukemia in Li-Fraumeni syndrome is associated with poor prognosis and usually presents in the context of therapy related myeloid malignancies . Identification of patients with Li-Fraumeni syndrome early on is crucial to avoid exposures to radiotherapy whenever possible thus reducing the risk of subsequent malignancies and the tragic outcomes of the disease. There are unmet clinical needs in Li-Fraumeni syndrome diagnostic and therapeutic approaches which needs further attention.

FRI047 Clinical Characteristics Of Patients With Morbid Obesity With Semaphorines (SEMA3D,E,G) And PLXNA3&4 Gene Variants

Abstract Disclosure: M. Berra: None. A. Khattab: None. S.B. Ten: None. A.S. Bhangoo: None. Aim of the study: To describe the clinical characteristics of patients with morbid obesity with SEMA3D,E,G and PLXNA3&4 gene variants. Introduction: Heterozygous variants of SEMA3s and their receptors PLXNA3 and 4 were described in cases of morbid obesity (Ref1). SEMA3 genes encodes a member of the semaphorin III family of secreted signaling proteins that are involved in axon guidance during neuronal development. SEMA3s signaling pathway is important for POMC neurons projections from the arcuate to the paraventricular nucleus. Methods: Patients with morbid obesity underwent genetic testing at the Prevention Genetics after obtaining consent. Results: Heterozygous gene variants were found in 8 cases, 3 males, 5 females, from 2 to 22 yrs., average BMI 33.3±8.6 kg/m2, 5 Hispanics, 2 Caucasians, 1 Asian. All cases presented with early morbid obesity from 2-4 yrs. of age, hyperphagia. Leptin was measured in 4 cases and was low for the degree of obesity (5.8-7.8 ng/ml). They had fatty liver, elevated triglycerides 168±33; had HDL 41.7±6.9 (data presented as avg±SDS).16 yrs. old female, BMI 31.2, PLXN3, c.1556G>A, p.Arg519His variant. Father had morbid obesity, treated with bariatric surgery lap band procedure.8 yrs. old girl, BMI 28.7, PLXN3, c.1733C>T, p.Ala578Val variant. Maternal aunt had bariatric surgery.22 yrs. old female, BMI 53, PLXNA4, c.1982C>T, p.Ser661Leu variant. She had impaired glucose tolerance, PCOS, a nodular goiter, impaired glucose tolerance, 2 sisters and a brother had bariatric surgery.16 yrs. old boy, BMI 35.5, SEMA3D, c.1048T>C, p.Ser350Pro variant. He had anxiety, panic attacks, depression. His PGF and paternal uncle has morbid obesity. 16 yrs. old girl, BMI 30.9, SEMA3G, c.2305>G variant. She had impaired fasting glucose, elevated prolactin and amenorrhea. Mother and MGM had morbid obesity. 2 year old male with BMI of 30.1, SEMA3E, c.1443A>T, p.Glu481Asp variant. Mother had morbid obesity.4 year old female with BMI of 23.7, SEMA3G, c.2086GA, p.Gly696Arg variant. She has autism, epilepsy and motor delay. Mother and maternal aunt had morbid obesity.11 year old male, BMI 33.6, PLXNA4, c.4896CA, p.Asp1632Glu variant. MGF had morbid obesity. Conclusion: Clinical phenotype of patients with heterozygous variants of Semaphorins and its receptors shows presence of severe obesity from a young age of 2-4 yrs. All had a very strong family history of morbid obesity. These children developed insulin resistance with elevated TG and fatty liver from a young age. Leptin levels in few were low for the degree of obesity. Ref1. van der Klaauw AA, Farooqi IS et.al. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. Cell. 2019 Feb 7;176(4):729-742.e18. doi: 10.1016/j.cell.2018.12.009. PMID: 30661757. Presentation: Friday, June 16, 2023

SAT580 Incidental Diagnosis Of Genetic Variant PTPN11 Noonan Syndrome With Multiple Lentigines, Sensorineural Hearing Loss And Rheumatoid Arthritis In Adult Female With Hashimoto’s Thyroiditis. Case Report

Abstract Disclosure: M.M. Eid: None. T. Zahra: None. J. Vargas-Jerez: None. Introduction: Hashimoto’s thyroiditis (HT, chronic lymphocytic thyroiditis, autoimmune thyroiditis) and Rheumatoid arthritis (RA) are autoimmune disorders, affect mainly females (1). Noonan syndrome with Multiple Lentigines (NSML, Leopard Syndrome) is a rare multigenetic autosomal dominant disorder. It includes cerebrovascular and cardiac anomalies, facial phenotype, hearing abnormality and developmental delay (2). Case: 41 yo, Female with history of HT since 2002 (high TSH, thyroid peroxidase antibody more than 1000 u/ml, low FT4 and FT3) on levothyroxine 150mcg/day. Recently moved to the USA from EL Salvador. Presented for initial evaluation. Denied smoking, alcohol, allergy. Maternal aunt with thyroid disease. Had menstrual irregularities, no previous attempt to conceive. Review of system: 5 months of pain, swelling and morning stiffness for 1 hour in hand joints, hearing difficulty for 2 years, painless brown skin spots for years, childhood learning difficulty and constipation. Physical examination body weight 139Ib, height 162cm, Stable vitals, diffuse lentigines. Head: board forehead, hypertelorism, high arched eye brows, micrognathia, low set ears. Heart: normal heart sounds, no murmur. No thyromegaly, nystagmus or vertigo. Hand: swelling of metacarpophalangeal and proximal interphalangeal joints. Laboratory work up TSH 8 normal 0.27 to 4.2 uIU/ml, FT4 0.8 normal 0.9-1.8 ng/dl, A1C 5.7, positive rheumatoid factor 199IU/ml, anti-CCP antibody > 250U, ANA 1/320, ESR 61ml/hr, negative anti-tissue transglutaminase antibody, normal liver and kidney function tests and complete blood count. Hand X-ray: decrease joint space and bone erosion. Thyroid US: normal size, vascularity, no nodule. Normal Echocardiogram, EKG and chest X ray. Internal auditory canal MRI: no masses or abnormal enhancement. DEXA Scan: osteopenia of femur and lumbar spine. She was diagnosed with seropositive RA, B/L sensorineural hearing loss (SNHL) more on right side. Genetic test revealed heterozygous pathogenic variant of PTPN11 gene consistent with NSML and negative for Neurofibromatosis type 1. Kept on prednisone and methotrexate, levothyroxine was increased 162mcg/day. Conclusion: Autoimmune disorders have a common pathogenesis including humoral and cell mediated immunity, autoimmune oxidative stress, UV radiation exposure, genetic linkage and biochemical changes. Diagnosis of one autoimmune disorder increases the possibility of other autoimmune disorders (1). NSML has a variable presentation. PTPN11-NSML is usually associated with SNHL and cardiac anomalies as pulmonary stenosis. It is infrequent to diagnose NSML with HT and structurally normal heart like our case(2).

Down’s Syndrome Presented with Transmission of Maternal Translocation of 2; 21 Chromosomes. A Case Report

Background: Down's syndrome is a genetic condition marked by distinctive physical characteristics and some degree of cognitive impairment. Down's syndrome is mostly caused by trisomy of chromosome 21, while chromosome translocations are also frequent. Objective: To evaluate a rare 2;21 translocation in the proband's family that was associated with Down syndrome. Methods: Chromosomal analysis was carried out using the G-banding technique and traditional peripheral lymphocyte culture. Case: The proband was a 9 months baby boy of non-consanguineous parents. The doctors clinically diagnosed him as having Down's syndrome with all typical features. The proband was found to have trisomy 21 associated with a 2;21 translocation inherited from his mother because his mother has the same type of translocation without any phenotypic features. Maternal age at the time of the study was 35 years and first pregnancy ended in stillbirth at 26th weeks of gestation, the proband was the second issue. His maternal aunt and cousin brother both had the same type of translocation. In chromosomal analysis, the proband's father and uncle had normal genotypic distribution. The current example was a Down's syndrome case with one normal 21 no chromosome and one Reciprocal translocation t (2;21). Conclusion: The present case of Down’s syndrome occurs due to reciprocal translocation (2;21) probably has arisen by familial transmission. Once an imbalanced translocation in the fetus/child has been found, the prenatal cytogenetic analysis is critical for the next pregnancies. Bangladesh Medical Res Counc Bull 2023; 49(2): 143-147