Grand Research Articles

SAT165 A Novel Mutation In The HNF4α Gene (C.691C>T, P.arg231trp) Likely To Be Pathogenic For Maturity Onset Diabetes Of The Young Type 1 Presenting With Hyperinsulinemic Hypoglycemia In An Infant

Abstract Disclosure: A. Rodriguez: None. S. Sastry: None. W. Chemaitilly: None. N. Gurtunca: None. Background: Maturity Onset Diabetes of the Young type 1 (MODY 1) is a monogenic form of diabetes mellitus caused by a defective HNF4α gene, resulting in reduced insulin secretion and diabetes in early adolescence and young adulthood. MODY 1 is also known to be associated with increased insulin secretion during fetal, neonatal and childhood periods with consequences that range from fetal macrosomia to persistent hyperinsulinism. Traditionally, HNF4α gene mutations represents 5% of all cases of diazoxide-responsive hyperinsulinism. Clinical Case: A 1 month old male born full term and large for gestational age (birth weight of 4920g) following an uncomplicated pregnancy and delivery developed hypoglycemia soon after birth and required hospital admission on day of life 2 with a serum glucose of 30 mg/dL and an insulin level of 5 uIU/mL. A fasting challenge showed hypoglycemia at 9 hours with a serum glucose of 47 mg/dL and an insulin level of 10.3 uIU/mL confirming hyperinsulinemic hypoglycemia. He was started on diazoxide to which he responded well and was placed on a continuous glucose monitor (CGM). He was originally started on diazoxide 8mg/kg/day that later was decreased to 6.6mg/kg/day due to blood glucoses in the 200’s. He passed the fasting study 5 days after starting diazoxide and went home with the CGM with subsequent dose titration made with guidance from remote data sharing. A neonatal hypoglycemia panel was sent and showed a novel mutation, c.691C>T, p.ARG231Trp in the HNF4α gene classified as a variant of uncertain significance. Computer modeling software suggested that this gene might disrupts the gene structure and function. This variant is present in population databases at a 0.0009% frequency and this missense change has been observed in individuals with clinical features of maturity onset diabetes of the young. Patient’s father carries the same mutation and paternal grandmother carries a diagnosis of type 2 diabetes mellitus. Conclusion: This is a novel mutation that should be considered pathogenic based on this patient’s neonatal presentation and previous literature. This case also presents possible uses of CGM in infants with diazoxide responsive congenital hyperinsulinism in order to decrease burden from monitoring and streamline communication with the medical team Presentation: Saturday, June 17, 2023

FRI249 New Onset Heart Failure In A Patient With Rapidly Progressive Adrenocortical Carcinoma

Abstract Disclosure: J. Peeples: None. S. Shu: None. K.G. Romo: None. J. Tereul: None. B.B. Grissett: None. Background: Adrenocortical carcinomas (ACC) are rare, relatively large (>4cm), lipid-rich, and often aggressive tumors. They may be functional, which typically presents as Cushing’s syndrome and/or virilization, or non-functional, which typically presents as an abdominal mass or incidental finding. They occur in two peak incidences: at the first decade of life and between 40-50 years of age. Over half of adult patients with ACC present with an advanced tumor stage. This case describes a young man with new onset heart failure and adrenal mass with metastases who was found to have biopsy-confirmed ACC. Clinical Case: A 20-year-old man with a history of cigarette smoking and marijuana use, but otherwise in prior good health, presented as a transfer for new onset heart failure in the setting of hypertensive emergency (SBP 260s), and CT findings of left adrenal mass, with multiple lung and liver masses. He noted 2 months of rapidly progressive weight gain, easy fatigability, dyspnea on exertion, and leg swelling. Exam revealed central adiposity with abdominal striae, bilateral clavicular and cervical fat pad, and bilateral lower extremity swelling. Investigations revealed hypercortisolism and ventricular ejection fraction 20-25%. Liver mass biopsy revealed metastatic ACC. Family history was significant for multiple members with early onset hypertension and congestive heart failure, including the death of maternal grandmother at age 40. The patient was initially managed in the ICU with an etomidate drip for adrenal suppression. Cortisol levels appropriately decreased to goal. Additionally, he started IV dexamethasone while inpatient. He was discharged once euvolemic on PO furosemide and follow-up was scheduled with cardiology, oncology, and endocrinology. At discharge, he transitioned to PO hydrocortisone (HC) and was placed on trimethoprim/sulfamethoxazole for PJP prophylaxis, doxazosin, and ketoconazole. He also started mitotane for his cancer treatment, with HC to prevent adrenal insufficiency while on mitotane. Subsequently, he started and failed carboplatin plus etoposide palliative chemotherapy with a continued increase in adrenal mass size. Now, he is on second line pembrolizumab with an ECOG score of 2. Conclusion: ACC is a rare and often aggressive tumor that should be considered in the setting of hypercortisolism and cushingoid features. This is particularly important for patients with a relatively unremarkable history and new onset heart failure with dyspnea on exertion. In these cases, mitotane can be used for hypercortisolism associated with ACC. Unfortunately, these tumors are usually diagnosed when they have already progressed to a late stage, and the prognosis for ACC is poor. Presentation: Friday, June 16, 2023

Grandparent alcohol use disorder and grandparent-grandchild relationships.

Involvement of grandparents in grandchildren's lives is important for grandchild well-being. Studies suggest that the quality of relationships between grandparents and their adult children may "spill over" to the quality of their relationships with their grandchildren. However, no research has tested whether grandparent alcohol use disorder (AUD) disrupts intergenerational relationships. This is important because grandchildren may not benefit from closeness with grandparents with AUD. In a sample of 295 parents and their children (N = 604) from a larger longitudinal study oversampled for familial AUD, this study tested whether grandparents (G1, "Generation 1") with AUD had poorer relationships with their adult children (G2 "Generation 2") in terms of greater stress and less support provided and less closeness with their grandchildren (G3, "Generation 3"). We also tested whether poorer G1-G2 relationship quality predicted less G1-G3 closeness. Finally, we tested whether effects of G1 AUD on G1-G3 closeness were explained by G1-G2 relationship quality. Separate models were estimated for maternal and paternal grandparents. We found evidence for three indirect effects. First, G1 maternal grandparent AUD predicted greater stress in the G1 grandmother-G2 mother relationship, which was associated with greater closeness between maternal grandmothers and grandchildren. This indirect effect was replicated in G1 paternal grandfathers and G2 fathers. Additionally, G1 paternal grandparent AUD was associated with lower levels of support provided from G1 grandfathers to G2 fathers, which predicted less closeness between paternal grandfathers and grandchildren. The results demonstrate complex intergenerational effects of AUD on family relationships and consistent with the hypothesized "spillover" effect of intergenerational relationships. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Types of Parenting Behavior of Grandchildren During Early Childhood by Paternal and Maternal Grandmother: The Q Methodological Approach

The Types of Parenting Behavior of Grandchildren During Early Childhood by Paternal and Maternal Grandmother: The Q Methodological Approach

A history of asthma may be associated with grandparents' exposures to stress and cigarette smoking.

Introduction: Within human epidemiological studies, associations have been demonstrated between grandparental exposures during childhood and grandchildren's outcomes. A few studies have assessed whether asthma has ancestral associations with exposure to cigarette smoking, but results have been mixed so far. Material and methods: In this study we used four generations: (F0 great-grandparents, F1 grandparents, F2 parents, F3 study children) of the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether there is evidence of associations between asthma in generations F2 or F3 and exposures to severe trauma in childhood and/or active cigarette smoking during the adolescence of grandmothers and grandfathers in generations F0 and F1 respectively, or of a history of a F0 or F1 grandmother smoking during pregnancy. Results: We have shown that: a) stress exemplified by the death of a F1 grandparent's parent during the grandparents' childhood was associated with increased risk of asthma in generation F3, especially if the grandparent involved was the paternal grandmother; b) if the grandparents of generations F0 or F1 smoked during adolescence (i.e. < 17 years), their grandchildren in generations F2 and F3 were more likely to have a history of asthma; c) paternal F1 grandmother's smoking in pregnancy was associated with her F3 grandchild's asthma at age 7; d) There were differences between the results for the grandsons and granddaughters of the paternal grandmother with exposure to smoking in adolescence and with smoking in pregnancy. e) The addition of all of the individual exposure variables to the different analyses often provided a considerable increase in goodness of fit compared with only adding demographic factors associated with asthma at P < 0.10 such as social class; this was particularly true when all four exposure variables were combined in one model, suggesting possible synergistic effects between them. Discussion: We have shown associations between all four types of exposure to the grandparents to be associated with asthma in the grandchildren, such that the results both depended on whether the male or female line was involved, and the sex of the grandchildren. It was notable that the paternal grandmother was particularly involved in many of the associations. We emphasize that these are exploratory analyses, that asthma diagnostic criteria likely changed over time and may not be consistent between generations, and that the results should be tested in other cohorts.

Characterization of Behavioral Phenotypes in Heterozygous DAT Rat Based on Pedigree.

Dopamine is an essential neurotransmitter whose key roles include movement control, pleasure and reward, attentional and cognitive skills, and regulation of the sleep/wake cycle. Reuptake is carried out by the dopamine transporter (DAT; DAT1 SLC6A3 gene). In order to study the effects of hyper-dopaminergia syndrome, the gene was silenced in rats. DAT-KO rats show stereotypical behavior, hyperactivity, a deficit in working memory, and an altered circadian cycle. In addition to KO rats, heterozygous (DAT-HET) rats show relative hypofunction of DAT; exact phenotypic effects are still unknown and may depend on whether the sire or the dam was KO. Our goal was to elucidate the potential importance of the parental origin of the healthy or silenced allele and its impact across generations, along with the potential variations in maternal care. We thus generated specular lines to study the effects of (grand) parental roles in inheriting the wild or mutated allele. MAT-HETs are the progeny of a KO sire and a WT dam; by breeding MAT-HET males and KO females, we obtained subjects with a DAT -/- epigenotype, named QULL, to reflect additional epigenetic DAT modulation when embryos develop within a hyper-dopaminergic KO uterus. We aimed to verify if any behavioral anomaly was introduced by a QULL (instead of KO) rat acting as a direct father or indirect maternal grandfather (or both). We thus followed epigenotypes obtained after three generations and observed actual effects on impaired maternal care of the offspring (based on pedigree). In particular, offspring of MAT-HET-dam × QULL-sire breeding showed a compulsive and obsessive phenotype. Although the experimental groups were all heterozygous, the impact of having a sire of epigenotype QULL (who developed in the uterus of a KO grand-dam) has emerged clearly. Along the generations, the effects of the DAT epigenotype on the obsessive/compulsive phenotype do vary as a function of the uterine impact on either allele in one's genealogical line.

SEMANTIC STRUCTURE OF BLOOD RELATIONSHIP TERMS (FATHER — OTA — PADRE) IN THE RUSSIAN, UZBEK AND SPANISH LANGUAGES

The article is devoted to a comparative-contrastive study of the structural and semantic features of the vertical line of blood relationship (consanguinity) terms отец (Russian), padre (Spanish), oтa (Uzb.), representing the national, cultural and linguistic specificity. Their study led to the conclusion that they are used both in direct and figurative meanings. The conducted analysis indicates some regularities of these terms: men in the descending line use them when referring to older men in age, to the spiritual father, and the women — to their husbands in the meaning of «father of my children». In the Uzbek language, oтa is used not only when referring to one’s own father, but also to one’s paternal grandfather; in Spanish — along with padre, its synonym progenitor «parent» is used to refer to the father.

O.2.1-10 Intergenerational leisure-time physical activity across three generations in Finland

Abstract Purpose Associations of leisure-time physical activity (LTPA) in three-generational families has not been well studied. This study aimed to examine these associations in a three-generational data including children, and their parents and grandparents. Methods Self-reported LTPA data, along with a range of family sociodemographic and health-related variables, were extracted from the ongoing Young Finns Study. The cohort consists of 2501 children aged 7–38 years, their parents, and grandparents in 2018. Structural equation modeling was fitted to estimate the associations of children’s LTPA with parents’ and grandparents’ LTPA in different age and sex groups. Results Interrelationships of parental and grandparental LTPA with children’s LTPA varied by age and sex groups. For children aged 7–12 years, mothers’ LTPA was associated with higher LTPA in both boys (r = 0.22, p = 0.017) and girls (r = 0.34, p &amp;lt; 0.001), while fathers’ LTPA was associated with higher LTPA in boys (r = 0.25, p = 0.01). High LTPA level in maternal grandfathers and grandmothers was associated with higher LTPA in grandgirls (r = 0.29, p = 0.024 and r = 0.23, p = 0.039). For adolescents aged 13–18 years, only fathers’ LTPA was associated with higher LTPA in boys (r = 0.20, p = 0.029). For young adults aged &amp;gt;18 years, fathers’ LTPA was associated with higher LTPA in both young males (r = 0.21, p = 0.004) and females (r = 0.20, p = 0.003), while mothers’ LTPA was associated with higher LTPA in young females (r = 0.13, p = 0.009). High LTPA level in maternal grandfathers was associated with higher LTPA in grandboys (r = 0.34, p = 0.003). Conclusions The children’s LTPA levels associated independently with parents’ and grandparents’ LTPA depending on the child’s age and sex. Given the primary results available, further research is warranted to fully understand the interrelationships between parents' and grandparents’ LTPA and their children’s LTPA in order to create effective and targeted interventions.

Non-muscle myosin heavy chain 9 gene-related disorders with thrombocytopenia: report of two pedigrees and literature review

Objective: To summarize the clinical characteristics and gene variants of 2 pedigrees of non-muscle myosin heavy chain 9 related diseases (MYH9-RD) in children. Methods: The basic information, clinical features, gene variants and laboratory tests of MYH9-RD patients from 2 pedigrees confirmed in the First Affiliated Hospital of Zhengzhou University in November 2021 and July 2022 were analyzed retrospectively. "Non-muscle myosin heavy chain 9 related disease" "MYH9" and "children" were used as key words to search at Pubmed database, CNKI and Wanfang database up to February 2023. The MYH9-RD gene variant spectrum and clinical data were analyzed and summarized. Results: Proband 1 (male, 11 years old) sought medical attention due to epistaxis, the eldest sister and second sister of proband 1 only showed excessive menstrual bleeding, the skin and mucous membrane of the their mother were prone to ecchymosis after bumping, the uncle of proband 1 had kidney damage, and the maternal grandmother and maternal great-grandmother of proband 1 had a history of cataracts. There were 7 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that the proband 1 MYH9 gene had c.279C>G (p.N93K) missense variant, and family verification analysis showed that the variant was inherited from the mother. A total of 4 patients including proband 1 and family members were diagnosed with MYH9-RD. The proband 2 (female, 1 year old) sought medical attention duo to fever and cough, and the father's physical examination revealed thrombocytopenia. There were 2 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that there was a c.4270G>A (p.D1424N) missense variant in the proband 2 MYH9 gene, and family verification analysis showed that the variant was inherited from the father. A total of 2 patients including proband 2 and his father were diagnosed with MYH9-RD. A total of 99 articles were retrieved, including 32 domestic literatures and 67 foreign literatures. The MYH9-RD cases totaled 149 pedigrees and 197 sporadic patients, including 2 pedigrees in our study. There were 101 cases with complete clinical data, including 62 sporadic cases and 39 pedigrees. There were 56 males and 45 females, with an average age of 6.9 years old. The main clinical manifestations were thrombocytopenia, skin ecchymosis, and epistaxis. Most patients didn't receive special treatment after diagnosis. Six English literatures related to MYH9-RD caused by c.279C>G mutation in MYH9 gene were retrieved. Italy reported the highest number of cases (3 cases). Twelve literatures related to MYH9-RD caused by c.4270G>A mutation in MYH9 gene were retrieved. China reported the highest number of cases (9 cases). Conclusions: The clinical manifestations of patients in the MYH9-RD pedigrees varied greatly. MYH9 gene c.279C>G and c.4270G>A mutations are the cause of MYH9-RD.

Abstract P388: Thumbs Down: A Rare Familial Cause Of Hypertension Associated With Brachydactyly

While hypertension (HTN) is extremely common in adults, genetic HTN syndromes with onset in childhood are much less common and present a unique challenge for healthcare providers. Many of these syndromes are rare and children are only screened annually for HTN, leading to delayed initiation of antihypertensives. We present a case of an otherwise healthy 7-year-old male who was noted to have persistently elevated blood pressures (BP) associated with headaches. Echocardiogram revealed normal cardiac function and anatomy without hypertrophy. Basic metabolic panel, urinalysis, and renal ultrasound revealed normal renal structure and function with no evidence of renal artery stenosis on Doppler. Additional negative workup included a thyroid function panel, serum renin, and 24-hour urine catecholamines. On ambulatory blood pressure monitoring, maximum BP was 157/107 with average BP of 139/81. His HTN did not respond to a low salt diet, so lisinopril was initiated. As the patient aged, his HTN persisted despite appropriate medical therapy and he developed short stature (height 3.7 th percentile). He had short, thick fingers and toes on exam consistent with brachydactyly. On further questioning, there was a family history of pediatric onset HTN associated with suspected brachydactyly in his paternal grandfather, father, and paternal half-sister, however no family members had received a formal diagnosis. He was ultimately diagnosed with hypertension and brachydactyly syndrome (HTNB), a rare autosomal dominant disorder characterized by early onset severe HTN, short stature, brachydactyly, and increased risk of recurrent strokes under age 50. Incidence is unknown due to the rarity of reported cases, which makes screening and recognition more difficult. This case demonstrates the utility of recognizing phenotypic features of genetic hypertensive syndromes to aid in early diagnosis, resulting in reduced morbidity/mortality and counseling for family members. Blood pressure screening including ambulatory blood pressure monitoring should be considered in any patient with brachydactyly and/or short stature, even if phenotypic features are mild. Anti-hypertensive medication should be initiated early given the untreated clinical course of this disease.

Identification and precision therapy for three maturity-onset diabetes of the young (MODY) families caused by mutations in the HNF4A gene.

Heterozygous pathogenic variants in HNF4A gene cause maturity-onset diabetes of the young type 1 (MODY1). The mutation carriers for MODY1 have been reported to be relatively rare, in contrast to the most frequently reported forms of MODY2 and MODY3. Whole exome sequencing (WES) and Sanger sequencing were performed for genetic analysis of MODY pedigrees. Tertiary structures of the mutated proteins were predicted using PyMOL software. Three heterozygous missense mutations in the HNF4A gene, I159T, W179C, and D260N, were identified in the probands of three unrelated MODY families using WES, one of which (W179C) was novel. Cascade genetic screening revealed that the mutations co-segregated with hyperglycemic phenotypes in their families. The molecular diagnosis of MODY1 has partly transformed its management in clinical practice and improved glycemic control. The proband in family A successfully converted to sulfonylureas and achieved good glycemic control. Proband B responded well to metformin combined with diet therapy because of his higher body mass index (BMI). The proband in family C, with paternal-derived mutations, had markedly defective pancreatic β-cell function due to the superposition effect of T2DM susceptibility genes from the maternal grandfather, and he is currently treated with insulin. In silico analysis using PyMOL showed that the I159T and D260N mutations altered polar interactions with the surrounding residues, and W179C resulted in a smaller side chain. We identified three heterozygous missense mutations of HNF4A from Chinese MODY families. Structural alterations in these mutations may lead to defects in protein function, further contributing to the hyperglycemic phenotype of mutation carriers.

Molecular Challenges in the Diagnosis of X-Linked Chronic Granulomatous Disease: CNVs, Intronic Variants, Skewed X-Chromosome Inactivation, and Gonosomal Mosaicism.

Chronic granulomatous disease (CGD) is a prototypical inborn error of immunity affecting phagocytes, in which these cells are unable to produce reactive oxygen species. CGD is caused by defects in genes encoding subunits of the NADPH oxidase enzyme complex (CYBA, CYBB, CYBC1, NCF1, NCF2, NCF4); inflammatory responses are dysregulated, and patients are highly susceptible to recurrent severe bacterial and fungal infections. X-linked CGD (XL-CGD), caused by mutations in the CYBB gene, is the most common and severe form of CGD. In this study, we describe the analytical processes undertaken in 3 families affected with XL-CGD to illustrate several molecular challenges in the genetic diagnosis of this condition: in family 1, a girl with a heterozygous deletion of CYBB exon 13 and skewed X-chromosome inactivation (XCI); in family 2, a boy with a hemizygous deletion of CYBB exon 7, defining its consequences at the mRNA level; and in family 3, 2 boys with the same novel intronic variant in CYBB (c.1151 + 6T > A). The variant affected the splicing process, although a small fraction of wild-type mRNA was produced. Their mother was a heterozygous carrier, while their maternal grandmother was a carrier in form of gonosomal mosaicism. In summary, using a variety of techniques, including an NGS-based targeted gene panel and deep amplicon sequencing, copy number variation calling strategies, microarray-based comparative genomic hybridization, and cDNA analysis to define splicing defects and skewed XCI, we show how to face and solve some uncommon genetic mechanisms in the diagnosis of XL-CGD.

Mapping Obscura: Locating the Space and Non-Space of Memory and Home through the Photograph

ABSTRACT What does it mean to inhabit? Our many selves find dimensionality through time and in place. This is complicated through the event of mass migration and trauma. One is continuously mapped through a locating of interiority. Within this essay, Nayar traces the birth and evolution of place as interior, and the genesis of her hybrid, constructed photographic process. Through the lens of India’s 1947 Partition, a trajectory of trauma and the ways in which memory functions over time is traced and translated through a family’s resettlement home in New Delhi. Built by her maternal grandfather, a refugee and psychiatrist from East Bengal, this locus in Nayar’s memory sheds light on how one may understand the many intersections of belonging and place. Home is found in habitation, that of desire and the awakening of the Mother. In this way, attachment theory, Winnicott’s transitional object, and the uncanny are touchstones for an internal mapping of psychic space. Through this framework, one understands what it means to embody through time and what is, through the process, left behind.

Assessing the Brainstem Auditory Evoked Potentials in Subjects with Family History of Hypertension.

Hypertension (HTN) has a genetic predisposition and it also impairs microcirculation, thereby, affecting the well vascularized structures like the brainstem and causing changes in Brainstem Auditory Evoked Potentials (BAEPs). To find out the usefulness of BAEPs as a screening tool in apparently healthy individuals with a family history of HTN. One hundred and ten volunteers, aged 17 to 23 years, were enrolled in the study as participants with proper consent. After excluding the subjects with existing diseases or co-morbidities (e.g. diabetes, HTN, schizophrenia, neuropathy, etc.), those on ototoxic or neurotoxic drugs, a preliminary physical examination was performed, following which BAEPs were recorded with a proper device. Statistical analysis is done with SPSS 2016 software using the chi-square test. A consistent distortion in the inter-peak latency of III-V waves is noted when a family history of HTN is present in either parent or maternal grandparents. Other statistically significant findings are present in V/I% (HTN in mother), wave I (HTN in paternal grandfather), wave III (HTN in maternal grandfather), and inter-peak latency I-V (HTN in maternal grandmother). BAEP may be used as a screening tool in individuals with a family history of HTN with supportive evidence from further studies in the near future.

The research for various genotypes and phenotypes related to rare -90 (C&gt;T) β-thalassemia mutation in Ganzhou city, Southern China

Thalassemia is a heterogeneous group of genetic disorders affecting the hemoglobin genes leading to decrease synthesis of globin chains of hemoglobin and resulting in ineffective erythropoiesis. It usually contains α- and β-thalassemia, most of common mutation types of which can be detected. However, it’s inclined to miss rare thalassemia mutation types. Here, we analyzed the molecular and hematological characteristics of seven cases with rare β-thalassemia -90 (C&amp;gt;T) (HBB: c.-140 C&amp;gt;T) mutation. Five of them carried β-90 (C&amp;gt;T) heterozygous mutation with a β+ thalassemia trait. One case was αSEA/β-90 genotype with decreasing MCV and MCH obviously, and the other was a β+/β0 intermediate thalassemia patient with β-90/βCD17 genotype, presenting with moderate anemia. A pedigree of one case was analyzed subsequently. It was found that the proband’s maternal grandfather and mother were carriers of α3.7/β-90 double heterozygous thalassemia, who presented that MCV and MCH were decreased normally or slightly, and HbA2 was increased. The proband and his aunt were β-90 (C&amp;gt;T) carriers. It’s necessary to point that the MCV and MCH were much higher in carrier of α3.7/β-90 genotype compared with either αSEA/β-90 genotype or β-90 heterozygous mutation. In this study, we explore the genotypes and phenotypes of four diverse β-90、αSEA/β-90、α3.7/β-90、β-90/βCD17 thalassemia mutations, which enriches the gene profile of β-thalassemia mutation in Chinese population.

Coparenting relationship, parenting self‐efficacy, and child adjustment in Chinese mother–grandmother coparenting families: Grandmother role difference

AbstractObjectiveThe study tested the grandmother role difference hypothesis (GRDH) in Chinese three‐generation families by investigating the effects of mothers' and grandmothers' perceptions of the coparenting relationship on child adjustment and the potential mediating effect of parenting self‐efficacy.BackgroundMother–grandmother coparenting has become the prevalent parenting mode in urban China, yet previous studies have failed to recognize the differences between the grandmothers by lineage. By reviewing biological theories and sociological contexts, this study proposed the GRDH. The hypothesis posited that in addition to maternal grandmother's benefits on grandchildren over paternal grandmother due to biological drives, maternal and paternal grandmothers exert their effect on child outcomes disparately by developing different relationships with the mother in coparenting.MethodIn total, 409 mother–grandmother coparenting families were recruited. Two identical structural equation models were examined separately for maternal and paternal grandmother groups.ResultsThe results of multigroup analysis showed a stronger direct effect by maternal grandmother's perception of coparenting relationship than paternal grandmother on child social competence. The relation between maternal parenting self‐efficacy and child social competence was stronger in households with paternal grandmothers. Furthermore, the mothers' evaluation of the coparenting relationship had a significant spillover effect on the paternal grandmother's parenting self‐efficacy only. The findings also showed the exclusive mediating effect of maternal parenting self‐efficacy linking the mother's perception of the coparenting relationship to child problem behavior in the mother–paternal grandmother group only.Conclusion and implicationsThe results overall validated the GRDH while providing further contextual information on the roles of mothers and grandmothers in different types of coparenting families.

Diabetes mellitus associated with type A insulin resistance

Insulin resistance type A is a monogenic disorder with insulin action defect, observed in females with acanthosis nigricans (AN), hyperandrogenism, hyperinsulinemia, insulin resistance (IR) without obesity. We present a family case of diabetes mellitus (DM) with IR in two sisters with obesity and positive family history of DM in three generations. Hyperglycemia was identified at the age of 13 in the older sister and at 11 in the younger sister after COVID-19. Type 2 diabetes (DM2) was diagnosed in mother in the same time with children. Maternal grandmother was diagnosed with DM2 in 58 years old. Patients were examined in 6 months after diagnosis hyperglycemia in Endocrinology Research Centre. The older sister had obesity, AN, and striae distensae. Glycosylated hemoglobin (HbA1c) 6.2%. Impaired glucose tolerance (IGT), hyperinsulinemia and IR, hyperandrogenism, non-alcoholic fatty liver disease (NAFLD), arterial hypertension were diagnosed. The younger sister had obesity, striae distensae. HbA1c — 6.0%. Impaired fasting glucose (IFG), IGT, hyperinsulinemia, IR, NAFLD were diagnosed. Antibodies (AAb) to ZnT8A, IA2, GAD absented in both sisters. A genetic test was provided, a heterozygous mutation in the INSR gene p.V167M was identified in both sisters, mother and grandmother. IR type A was identified in a family with the phenotype of DM2 in this case. This case demonstrated that children with carbohydrate metabolism disorders and obesity without Islet cell autoantibodies have to reffered for a genetic testing. Disordered carbohydrate metabolism was diagnosed in the same time after a COVID-19 in three family members who did not previously have disordered carbohydrate metabolism. We suppose that SARS-CoV-2 can be a trigger for the development of carbohydrate metabolism disorders in IR type A.

Communication between grandparents and young grandchildren over distance: Establishing contact with constitutive nonhumans

Physical items are often taken for granted in mediated communication between grandparents (GP) and young grandchildren (GC). This article puts “constitutive nonhumans” at the center of inquiry to understand the potential of physical items and communication technologies to communicate over distance. The notion of phaticity operationalizes the role of constitutive nonhumans to establish and maintain contact over distance, which might have pleasurable or unpleasurable outcomes. A relational view on agency supports the entanglement of humans and nonhumans when they cooperate to communicate over distance. The article reports on a two-phase qualitative study that was conducted in two European countries with 10 GP (aged 60–75 years) and 10 GC (aged 6–11 years). The results identify how the entanglement between constitutive nonhumans conflates emotional connection and contact. Furthermore, the results suggest that the condition of familiarity can direct contact to pleasant or unpleasant outcomes that might differ across mediated and co-located communication.

BG09 RASA1 exon deletion in a neonate with vascular malformations

Abstract A full-term infant was noted to have a large, macular, pale-pink vascular birthmark across the left side of the chest, extending to the upper arm. Three smaller pale-pink irregular birthmarks on the elbow, thigh and flank were noted, as was an enlarged left upper arm. He had an oxygen dependency shortly after birth for which he required admission to the neonatal unit. A detailed history revealed that his father, paternal grandmother and aunt had similar birthmarks. His paternal aunt had an episode of bleeding from a spinal arteriovenous malformation (AVM) in her teens, which had been investigated with genetic testing by Sanger sequencing, but this did not identify a variant in RASA1. Following involvement from the dermatology, neonatology, genetics and radiology teams, investigations were organized. Findings included a high-flow vascular malformation with arteriovenous shunting on magnetic resonance imaging (MRI) of the left arm, normal MRI head and spine, and normal cardiac anatomy. Genetic testing by next-generation sequencing detected a heterozygous exon 21–23 deletion in RASA1. A diagnosis of capillary malformation–AVM syndrome (CM–AVM) was confirmed. Results of genetic testing of the father are awaited. Referral to a tertiary centre for consideration of management of AVM is underway. CM–AVM is a rare autosomal dominant condition. Pathogenic variants in RASA1 result in a lack of functional p120-RasGAP protein, which leads to abnormalities in angiogenesis, although this pathway is not well understood (Wooderchak-Donahue W, Johnson P, McDonald J et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet 2018; 26:1521–36). Cutaneous vascular malformations, classically pink–red with a pale halo, are the most consistent cutaneous manifestation, but they may be subtle and can mimic other vascular birthmarks such as segmental infantile haemangioma, salmon patches or port wine stain. In our patient, pale halos were not apparent until 4 months of age. Identification is important as life-threatening complications from cutaneous vascular arteriovenous fistulas can occur (Wooderchak-Donahue et al.). This case highlights the importance of clarifying a family history, classifying vascular birthmarks and working with the multidisciplinary team. Genetic testing should be considered, even with previous negative analysis, as test sensitivity has improved and will now include analysis of EPHB4, which has also been associated with CM–AVM.

CPC12 Coinheritance of BRCA2 and CYLD germline pathogenic variants associated with targetable metastatic malignant cylindroma

Abstract CYLD cutaneous syndrome (CCS) presents during puberty with the development of hair follicle tumours, including cylindromas, spiradenomas or trichoepitheliomas, and is associated with pathogenic variants in the tumour suppressor gene CYLD. Germline pathogenic variants of BRCA2 are associated with an increased risk of breast, ovarian, pancreatic and prostate cancer. Coinheritance of pathogenic variants in both genes has not been previously reported, and here, we present a 29-year-old man with metastatic malignant cylindroma, where knowledge of the germline variants has targetable therapeutic implications. The proband presented with cylindromas on his scalp from the age of 8 years, inherited from his mother who had CCS. The proband’s father and paternal grandmother both had early-onset breast cancer. The proband’s 33-year-old sister had been diagnosed with breast cancer and CCS; genetic testing revealed germline pathogenic variants in both BRCA2 and CYLD. Aged 28 years, the proband presented with a growing, ulcerated cylindroma on the scalp. Histology revealed a biphasic neoplasm, showing malignant cylindroma with high-grade features arising within a pre-existing benign cylindroma. The malignant epithelioid component of the tumour showed brisk mitotic activity (25 mitoses per mm2) and large infiltrative nests with central comedo-type necrosis. Immunohistochemistry showed positivity for epithelial membrane antigen, CK7, p63 and patches of CK5/6, whereas carcinoembryonic antigen, S100 and human melanoma black-45 were negative. Several weeks after excision of the malignant scalp cylindroma, a lump presented on the left side of the patient’s neck; biopsy revealed histology consistent with the malignant scalp cylindroma. Radiological imaging revealed metastatic deposits of malignant cylindroma in the right axilla, both lungs and the brain. Genetic testing of the proband revealed germline pathogenic variants in both BRCA2 and CYLD, as seen in his sister. The patient received radiotherapy for the tumour in his neck, with partial resolution of symptoms and gamma-knife ablation of brain metastases. DNA extracted from the patient’s tumour was analysed using a high-resolution single-nucleotide polymorphism array, which demonstrated loss of heterozygosity including the BRCA2 and CYLD loci. The germline and somatic pathogenic variants in this patient support the use of unlicensed therapeutics that target BRCA deficiency, such as poly-ADP ribose polymerase inhibitors, which have not previously been used to treat malignant cylindroma. This case emphasizes the importance of recognizing coinheritance of tumour suppressor genes in rare genetic conditions, as this can provide novel management options and improve patient outcomes.