Familial Pattern Of Inheritance Research Articles

Primary Failure of Eruption: A Diagnosis of Exclusion

Primary failure of eruption is a rare condition, which results in partial or complete failure of a tooth or several teeth to erupt. The postulated cellular process is a malfunction in the eruption mechanism, which fails to completely drive the tooth along its eruption axis. The aetiology is genetic, with a specific link to a mutation in the parathyroid hormone 1 receptor gene, hence a familial pattern of inheritance may be observed. Diagnosis and treatment can be challenging, often necessitating an interdisciplinary approach. CPD/Clinical Relevance: Knowledge of the features of primary failure of eruption is useful for clinicians.

X-linked neuronal migration disorders: Gender differences and insights for genetic screening.

Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by anatomical cortical defects leading to varying degrees of neurocognitive impairment, developmental delay and seizures. Refractory epilepsy affects 15 million people worldwide, and it is thought that cortical developmental disorders are responsible for 25% of childhood cases. However, little is known about the epidemiology of these disorders, nor are their aetiologies fully understood, though many are associated with sporadic genetic mutations. In this review, we aim to highlight X-linked NMDs including lissencephaly, periventricular nodular heterotopia and polymicrogyria because of their mostly familial inheritance pattern. We focus on the most prominent genes responsible: including DCX, ARX, FLNA, FMR1, L1CAM, SRPX2, DDX3X, NSHDL, CUL4B and OFD1, outlining what is known about their prevalence among NMDs, and the underlying pathophysiology. X-linked disorders are important to recognise clinically, as females often have milder phenotypes. Consequently, there is a greater chance they survive to reproductive age and risk passing the mutations down. Effective genetic screening is important to prevent and treat these conditions, and for this, we need to know gene mutations and have a clear understanding of the function of the genes involved. This review summarises the knowledge base and provides clear direction for future work by both scientists and clinicians alike.

Genetic basis of ß-thalassemia in families of pashtun ethnicity in Dera Ismail Khan district of Khyber Pakhtun-Khwa province, Pakistan

ABSTRACT Objectives The objective of current genetic research was to verify the genetic basis of ß-thalassemia and its pattern of inheritance in families of Pashtun ethnicity in District Dera Ismail Khan, Pakistan. Methodology Blood samples from clinically diagnosed five unrelated ß-thalassemia families were collected and target Sanger Sequencing of HBB gene was done. Moreover, in silico analysis including protein modeling and Protein-Protein docking was aslo performed. Results and Discussion Clinical analysis of patients from family 1,2, 4, and 5 revealed Thalassemia Intermedia, while patient from family 3 was suffering from thalassemia major. The average Hb concentrations between the cases that were severe were found to be a little lower (6.3 mg/dl) than the patients with milder clinical manifestations (7.6 ± 1.4). Genetic analysis in family 1 identified compound heterozygous mutation of HBB (NM_000518) i.e. c.20A>T +c.92 G>A, in family 2 and 4 compound heterozygous mutations c.20A>T + c.27_28insG, in family 3 homozygous mutation c.27_28insG, while in family 5 we identified homozygous mutation c.92 + 5 G>C (IVS-1 + 5 G>C). Conclusion This study offers an effective incentive to establish a mutation detection as well as prenatal diagnosis (PND) centers at a larger scale in the Pashtun ethnicity residing in District Dera Ismail Khan, Pakistan.

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

Delayed puberty: How to approach?

Disorders of puberty can profoundly impact physical and psychosocial well-being. Delayed puberty is the absence of breast development in girls by 13 years of age and absence of testicular growth to at least 4 mL in volume or 2.5 cm in length in boys by 14 years of age. Hypogonadism occurs when there is a disruption in the hypothalamic-pituitary-gonadal axis. Two categories of delayed puberty are: hypergonadotropic (primary) hypogonadism and hypogonadotropic (secondary) hypogonadism. The etiology of delayed puberty varies from relatively benign to life threatening conditions, which may be either congenital or acquired. Constitutional delay of growth and puberty is the commonest cause of delayed puberty, which is a diagnosis of exclusion. There is a notable delay in puberty but eventually progress through normal stages of puberty. History concerns about stature are often present and a familial pattern of inheritance is usually present. Delayed bone age but corresponding to height age helps in diagnosis. Reversible hypogonadotropic hypogonadism may be observed due to associated conditions including chronic malnutrition, systemic disease, untreated hypothyroidism, hyperprolactinemia, anorexia nervosa. Permanent causes include structural damage either to hypothalamic-pituitary axis or linked to the sexual organs of the individual. Complete physical examination should include proper anthropometry, pubertal staging and assessment to look for any signs of chronic illness or stigmata of syndromes. In laboratory analysis, hypogonadotropichypogonadism (pHH) showing low serum testosterone or estradiol and blunted follicle-stimulating hormones (FSH) and luteinizing hormones (LH) levels may be due to abnormalities in the central nervous system. Magnetic resonance imaging is necessary to exclude morphological abnormalities and neoplasia. Low serum testosterone in male patients and low estradiol values in female patients, associated with high serum FSH and LH levels, suggest a diagnosis of hypergonadotropic hypogonadism due to dysfunction of peripheral sex organs. Abnormal growth velocity necessitates assessment of serum thyroid function, prolactin, and insulin like growth factor-1. Karyotyping can reveal a chromosomal abnormality like Turner syndrome or Klinefelter syndrome. Beside reassurance, in cases where the adolescent with CDGP is experiencing psychological difficulties, short courses of sex hormones may be used to allow individuals to catch up with their peers. Definitive treatment for underlying cause is worthy where possible. Long-term hormone replacement therapy is recommended for permanent causes of delayed puberty. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 192

Inheritance Patterns under Cultural Ecology Theory for the Sustainable Development of Traditional Handicrafts

Culture is the fourth pillar of sustainable development. The protection of intangible cultural heritage is an important way to safeguard the transmission of intangible heritage across generations. With the help of cultural ecology theory, this paper compares cases of inheritance and development in two different handicrafts: Bai tie-dyeing and Beijing carved lacquer. The results show that under the influence of different cultural ecologies, the family inheritance pattern of Bai tie-dyeing, and the master–apprentice inheritance pattern of Beijing carved lacquer have undergone qualitative changes in modern society. This paper puts forward the distinction between representative inheritance and group inheritance and suggests a protection mechanism accordingly. This paper further suggests that a modern mentoring model should be promoted as the inheritance pattern to further aid handicraft development, and a clear division of economic interests is also appointed to apply with the premiumization development and mass development.

S1733 Exceedingly Rare Coexistence of Metamorphosis of Tubulovillous Adenoma of the Ampulla to Adenocarcinoma with Small Bowel Gastrointestinal Stromal Tumor - Case Report and Review of the Literature

Introduction: This is a unique case of a patient with 3 tumors, which include one benign tumor, tubulo-villous adenoma of the ampulla of Vater (TVAoA), and 2 extremely rare malignant tumors, adenocarcinoma of the ampulla of Vater arising from TVAoA and gastrointestinal stromal tumor (GIST) involving the jejunum. Based on literature review, this is the first case of ampullary adenocarcinoma coexisting with GIST. Distal duodenal polyps are uncommon and have preponderance to occur in and around the ampulla of Vater. We report a case of a 77-year-old male who was admitted for painless obstructive jaundice with a 40-pound weight loss over a 2-month period, and who was subsequently diagnosed with 3 tumors. Case Description/Methods: A 77-year-old man was admitted for generalized weakness with associated weight loss of 40 pounds in the previous 2 months and was noted to have painless obstructive jaundice. Computed tomography (CT) of the abdomen and pelvis and magnetic resonance cholangiopancreatography were consistent with a polypoid mass at the level of the common bile duct (CBD) and ampulla of Vater with CBD dilatation. The same lesions were visualized by endoscopic retrograde cholangiopancreatography. Histopathology of endoscopic forceps biopsy showed tubulo-villous AoA (TVAoA). Histopathology of the surgical specimen of the resected ampulla showed adenocarcinoma arising from the TVAoA. Abdominal and pelvic CT also showed a coexisting heterogeneously enhancing, lobulated mass in the posterior pelvis originating from the jejunum (Figure). The patient underwent resection of the mass and jejunojejunal anastomosis. The histopathology of the resected mass confirmed it as a high-grade GIST. Discussion: AoA can occur sporadically and in a familial inheritance pattern in the setting of FAPS. We emphasize screening and surveillance colonoscopy when one encounters AoA in upper endoscopy to check for FAPS. AoA is a premalignant lesion, particularly in the setting of FAPS, that carries a high risk of metamorphism to ampullary adenocarcinoma. Final diagnosis should be based on a histopathologic study of the surgically resected ampullary specimen, and not on endoscopic forceps biopsy.This case is unique because he had 3 tumors and rare coexistence, which included one premalignant TVAoA and 2 malignant tumors: ampullary adenocarcinoma arising from the TVAoA and coexisting jejunal GIST.Figure 1.: Figure1A: CT abdomen and pelvis with contrast. Obstructed distal common bile duct due to a 9 mm polypoid intraluminal (pointed yellow arrows) lesion in the distal CBD. Figure1B: CT of the abdomen and pelvis with contrast. Heterogeneously enhanced lobulated mass with punctate calcifications (pointed yellow arrows) in the posterior pelvis originating from the serosal surface of the pelvic small bowel. Figure1C: Endoscopic retrograde cholangiopancreatography (ERCP) showed abnormal papilla with polypoid mass. Sphincterotomy and deep cannulation procedures were performed and confirmed by fluoroscopy. It showed common bile duct dilatation, and there was an abrupt cutoff at the distal aspect. Figure1D: High-power photomicrograph showing high-grade glandular dysplasia (hematoxylin and eosin stain, 200 X original magnification) Figure1E: A broad base ampullary mass with red fogerty cath was advanced from the cystic duct down through the ampulla to the duodenum. Figure1F: Pedunculated GIST arising from the small bowel approximately 150 cm proximal to the ileocaecal valve.

WNT10A variants: following the pattern of inheritance in tooth agenesis and self-reported family history of cancer.

The aim of this study was the analysis of WNT10A variants in seven families of probands with various forms of tooth agenesis and self-reported family history of cancer. We enrolled 60 young subjects (aged 13 to 17) from the Czech Republic with various forms of tooth agenesis. Dental phenotypes were assessed using Planmeca ProMax 3D (Planmeca Oy, Finland) with Planmeca Romexis software (version 2.9.2) together with oral examinations. After screening PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes on the Illumina MiSeq platform (Illumina, USA), we further analyzed the evolutionarily highly conserved WNT10A gene by capillary sequencing in the seven families. All the detected variants were heterozygous or compound heterozygous with various levels of phenotypic expression. The most severe phenotype (oligodontia) was found in a proband who was compound heterozygous for the previously identified WNT10A variant p.Phe228Ile and a newly discovered c.748G > A variant (p.Gly250Arg) of WNT10A. The newly identified variant causes substitution of hydrophobic glycine for hydrophilic arginine. We suggest that the amino acid changes in otherwise highly conserved sequences significantly affect the dental phenotype. No relationship between the presence of WNT10A variants and a risk of cancer has been found. Screening of PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes in hope to elucidate the pattern of inheritance in families.

Complex Inheritance of Rare Missense Variants in PAK2, TAP2, and PLCL1 Genes in a Consanguineous Arab Family With Multiple Autoimmune Diseases Including Celiac Disease

BackgroundAutoimmune diseases (AIDs) share a common molecular etiology and often present overlapping clinical presentations. Thus, this study aims to explore the complex molecular basis of AID by whole exome sequencing and computational biology analysis.MethodsMolecular screening of the consanguineous AID family and the computational biology characterization of the potential variants were performed. The potential variants were searched against the exome data of 100 healthy individuals and 30 celiac disease patients.ResultA complex inheritance pattern of PAK2 (V43A), TAP2 (F468Y), and PLCL1 (V473I) genetic variants was observed in the three probands of the AID family. The PAK2 variant (V43A) is a novel one, but TAP2 (F468Y) and PLCL1 (V473I) variants are extremely rare in local Arab (SGHP and GME) and global (gnomAD) databases. All these variants were localized in functional domains, except for the PAK2 variant (V43A) and were predicted to alter the structural (secondary structure elements, folding, active site confirmation, stability, and solvent accessibility) and functional (gene expression) features. Therefore, it is reasonable to postulate that the dysregulation of PAK2, TAP2, and PLCL1 genes is likely to elicit autoimmune reactions by altering antigen processing and presentation, T cell receptor signaling, and immunodeficiency pathways.ConclusionOur findings highlight the importance of exploring the alternate inheritance patterns in families presenting complex autoimmune diseases, where classical genetic models often fail to explain their molecular basis. These findings may have potential implications for developing personalized therapies for complex disease patients.

Familial partial atrioventricular septal defect in four related kindreds: case series and review of the literature

BackgroundAtrioventricular septal defects are common congenital heart defects and comprise a spectrum of anomalies, these defects were described in few pedigrees suggesting a familial pattern of inheritance, and they are more common in patients with chromosomal abnormalities. The familial occurrence of this particular type of congenital heart disease is uncommon and few cases have been identified as partial atrioventricular septal defect in adults apart from other chromosomal abnormalities.Case presentationWe report four cases of adult females who were diagnosed with partial atrioventricular septal defect in four related families, our patients do not have the morphology of Down syndrome.ConclusionsFurther researches on genotyping such patients might contribute to our knowledge regarding this particular cardiac malformation.

Toward a methodology for evaluating DNA variants in nuclear families.

The genetic underpinnings of most pediatric-cancer cases are unknown. Population-based studies use large sample sizes but have accounted for only a small proportion of the estimated heritability of pediatric cancers. Pedigree-based studies are infeasible for most human populations. One alternative is to collect genetic data from a single nuclear family and use inheritance patterns within the family to filter candidate variants. This approach can be applied to common and rare variants, including those that are private to a given family or to an affected individual. We evaluated this approach using genetic data from three nuclear families with 5, 4, and 7 children, respectively. Only one child in each nuclear family had been diagnosed with cancer, and neither parent had been affected. Diagnoses for the affected children were benign low-grade astrocytoma, Wilms tumor (stage 2), and Burkitt's lymphoma, respectively. We used whole-genome sequencing to profile normal cells from each family member and a linked-read technology for genomic phasing. For initial variant filtering, we used global minor allele frequencies, deleteriousness scores, and functional-impact annotations. Next, we used genetic variation in the unaffected siblings as a guide to filter the remaining variants. As a way to evaluate our ability to detect variant(s) that may be relevant to disease status, the corresponding author blinded the primary author to affected status; the primary author then assigned a risk score to each child. Based on this evidence, the primary author predicted which child had been affected in each family. The primary author's prediction was correct for the child who had been diagnosed with a Wilms tumor; the child with Burkitt's lymphoma had the second-highest risk score among the seven children in that family. This study demonstrates a methodology for filtering and evaluating candidate genomic variants and genes within nuclear families that may merit further exploration.

The genetics of congenital heart disease: The role of advanced genomic approaches

As the leading non-infectious cause of paediatric morbidity and mortality worldwide, congenital heart disease (CHD) is a significant social and healthcare burden, especially in low- and lower-middle-income countries, including South Africa. The aetiology of CHD is poorly understood, though heritable genetic factors have been shown to contribute to the risk of CHD in individuals of European ancestry. In this review, we highlight the impact that advanced genomic approaches have had on the understanding of the role of genetics in CHD. We also summarise current knowledge of the genetics of CHD in Africa, and the challenges and opportunities for conducting genomic research in these populations. Chromosomal microarrays and next-generation sequencing platforms allow for high-throughput screening of patients for genetic mutations and show great potential for the identification of genetic causes of CHD. Advancing our understanding of the genetic architecture and risk factors associated with CHD in patients of African descent is the fi rst step towards improving CHD diagnosis and management. Therefore, exploring the genetics of CHD has the potential to improve the quality of life for children born with CHD in Africa, by enabling clinicians to identify familial inheritance patterns and predict recurrent risks and prognostic outcomes pre- and post-surgical intervention.

A-151 Cognitive Impairment in Amyotrophic Lateral Sclerosis

Abstract Objective Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease caused by degeneration of the upper and lower motor neurons. This literature review examines the recurring etiology of cognitive impairments in ALS through empirical literature. The current study explores ALS across different subtypes and potential cognitive impairments. Two classifications are primarily examined ALS, and ALS with frontotemporal dementia (ALS-FTD). Involving three categories: familial inheritance pattern, genetic mutation, or sporadic. Neuropsychological studies affirm cognitive impairments in individuals diagnosed with ALS and ALS-FTD. Data Selection Data was culled from the American Psychological Association (PsycInfo), PubMed, Google Scholar. Terms used in this literature review include cognitive impairment in ALS and ALS-FTD, executive function deficiencies in ALS, neuropsychology in ALS, neuropsychological deficits in ALS, neuropsychological assessments for ALS, cognitive impairments in familial ALS, genetic ALS, and sporadic ALS, familial ALS, sporadic ALS, genetic mutations involved in ALS. Search dates December 20–23 of 2020 and March 3–4 of 2021. A total of 40 studies were examined. Data Synthesis ALS-patients demonstrate a significant cognitive impairment. However, influencing comorbidities accompanying the disease may be contributing to these impairments. Researchers employed neuroimaging and neuropsychological batteries to further understand influencing factors involved in ALS and cognition. Conclusions Researchers now understand ALS as a multi-symptomatic disorder and acknowledge the presence of cognitive impairments at various encased levels. There are limitations in neuropsychological batteries that accommodate for executive dysfunctions observed in ALS patients. Future studies should explore neuropsychological assessments that accommodate for motor deficits and dysarthria when assessing cognitive impairment in ALS patients.

Association of Parental Consanguinity With Papillary Thyroid Carcinoma: A Case-Control Study.

Papillary thyroid carcinoma (PTC) is the most common type of nonmedullary thyroid carcinoma. Uncommonly, PTC is associated with multiple genetic alterations and chromosomal abnormalities and displays familial patterns of inheritance. Parental consanguinity increases susceptibility to many genetic disorders. This work aimed to investigate the association of parental consanguinity with PTC. This case-control study of PTC patients compared with healthy controls took place in a tertiary referral hospital. We recruited 200 PTC patients who were managed at the endocrinology outpatient clinics of the Jordan University Hospital, and we recruited 515 healthy controls from a nonclinical setting. We interviewed all participants and collected sociodemographic data. We reviewed the family pedigrees of each participant four generations back and excluded any participant who was related. We established whether the parents of each participant were first cousins, first cousins once removed, second cousins, or unrelated. We then used binary logistic regression to assess the association of parental consanguinity with PTC adjusted for age, sex, smoking status, body mass index, and parental education. We recruited 715 participants. The numbers of PTC patients and healthy controls were 200 (28.0%) and 515 (72.0%), respectively. The rate of parental consanguinity was 25.5% in PTC patients and 12.2% in healthy controls. Parental consanguinity was significantly associated with PTC (adjusted odds ratio, 2.60; 95% CI, 1.63-4.17; P < .001). Parental consanguinity is a risk factor for PTC. Our findings should be considered during familial risk assessment and genetic counseling, especially in populations with high rates of consanguinity.

An update on Heck's disease-a systematic review.

Previous research has suggested an ethnic association of Heck's disease with a prominent genetic and familial inheritance pattern, but no systematic review has been reported, which has collected all the evidence in one paper. The aim was estimation of the updated age estimates and gender predilection of this disease and also questioning its proposed link to ethnic and geographical factors. Heck's disease from 1966 until present are tabulated, including various descriptive characteristics. After removal of duplicates and adhering to all the inclusion criteria, we shortlisted 95 case reports. The quality assessment of all included studies has been done following STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines. We found an age range of 3-92years (mean: 23.1years) with a male to female ratio of 3:4. Geographical distribution revealed one of the main findings of this study, which was an increased incidence of Heck's disease in the European region. As already observed and established, there is a much greater prevalence of this disease in the indigenous populations of the world and more research should be encouraged to understand the correct transmission and pattern of spread of this disease.

Inherited syndromes involving pancreatic neuroendocrine tumors.

Inherited syndromes are important to recognize in the setting of a pancreatic neuroendocrine tumor (PNET) as there are significant implications for the patient's medical management and opportunity for early detection of subsequent manifestations. Although most PNETs are sporadic, approximately 10% are due to an inherited syndrome, which include multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). The general hallmarks of a hereditary endocrine neoplasia predisposition syndrome include any one of the following: multiple primary tumors (in the same or different organs), rare tumors (prevalence of less than 1 in 1,000 people in the general population), earlier age of diagnosis (usually under the age of 40), characteristic pattern of disease in the individual or family (phenotype and inheritance pattern). These syndromes are monogenic (due to a single gene disorder), highly penetrant (with all carriers of the disease exhibiting at least part of the phenotype) and can display variable expressivity (where affected individuals may have different presentations and features of the disease). A thoughtful approach to management is required, even if the presenting symptom is resolved, as these syndromes often involve multi-organ disease with a lifelong risk for tumor development. Additionally, the natural history of tumors in the setting of a hereditary condition may be different than would be expected in a sporadic form of the disease. For example, in some circumstances the risk of metastatic disease is lower, and therefor longer observation is the preferred approach over early surgical intervention. The unique aspects to management, challenges in hereditary disease recognition and accurate diagnosis, and rarity of these syndromes are all reasons to support referral to high-volume centers with the experience and knowledge to treat patients with hereditary endocrine neoplasia syndromes.

SAT-193 Clinical Case of ARMC5 Tumor Syndrome: A Rare Case of Cushing’s Syndrome from Primary Bilateral Macronodular Adrenal Hyperplasia Caused by ARMC5 Mutation with Concomitant Presence of Meningiomas and Primary Hyperparathyroidism

BACKGROUND: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a known rare cause of Cushing’s syndrome (CS). A mutation in the armadillo repeat containing 5 (ARMC5) sequence is associated with up to 55% of PBMAH cases. Recent studies have linked ARMC5 mutations to presence of other benign neoplasias suggesting that ARMC5 could be a tumor suppressor gene. Case: 72-year-old female with a history of obesity, HTN, DM2, osteoporosis, multiple meningiomas, and hypercalcemia with recurrent kidney stones was incidentally found to have bilateral adrenal nodules on CT imaging. She had mild cushingoid features with truncal obesity and moon facies. She had multiple low dose dexamethasone suppression tests with AM cortisol levels in 17-21 ug/dL range (<1.8 ug/dL). She had late night salivary cortisols of 0.885ug/dL and 1.935ug/dL (0.022-0.254 ug/dl in PM). The overall clinical picture of obesity, HTN and DM2 in combination with biochemical testing and presence of bilateral adrenal adenomas was suggestive of CS secondary to PBMAH. On her evaluation for recurrent kidney stones she had a PTH of 107.2 pg/mL (15-65 pg/mL), and a calcium of 10.8 mg/dL (8.3-10.5 mg/dL). She was diagnosed with primary hyperparathyroidism. Imaging studies found a 1.1 cm ectopic parathyroid adenoma situated at the aortic pulmonary window. Surgical evaluation was performed and surgery was not offered given the precarious location of the parathyroid tumor. She had a known history of four meningiomas, two of which were resected and two considered uncresectable. PBMAH in presence of all her other medical comorbidities prompted genetic evaluation for the patient. Analysis revealed a heterozygous ARMC5 mutation. Given the familial pattern of inheritance associated with ARMC5 mutations, patient’s daughter also underwent genetic testing. Daughter tested positive for the mutation as well. Patient was offered surgical and medical therapy options for her PBMAH. She is currently being evaluated for an unilateral adrenalectomy. Discussion: The pathophysiology of CS from PBMAH remains poorly understood leading to an insidious delay in diagnosis and treatment. Inactivating ARMC5 mutations of familial origins are known genetic triggers for development of PBMAH. ARMC5 is also a proposed tumor suppressor gene whose proteins are found in endocrine tissues all over body. Mutation of ARMC5 gene potentially can lead to multi-glandular tumor syndromes. Screening PBMAH patients and their family members for ARMC5 mutations may lead to earlier CS diagnosis/treatment times as well as better understanding of the gene’s neoplastic potential.

Monogenic Diabetes due to ABCC8/KCNJ11 Mutation: Case Study and Review of Literature

Monogenic diabetes arises due to mutation in a single-gene and is recognized by their striking familial inheritance pattern. This form of diabetes is inherited in an autosomal dominant or recessive fashion, unlike polygenic Type 1 (autoimmune) or type 2 diabetes caused by the combined action of more than one gene [1-11]. Monogenic diabetes is classified into three main groups: Neonatal diabetes mostly presents in the first six months of birth, maturity onset diabetes of the young (MODY) and maternally inherited mitochondrial diabetes. These mutations run in the family and have a predictable course. Most of the monogenic diabetes is treated with oral medications like sulfonylurea rather than insulin. ABCC8/KCNJ11 gene mutations also cause monogenic diabetes. This gene mutation has been found in ~50% of congenital hyperinsulinemia (CHI) patients. In such cases diabetes commonly presents in the neonatal period (transient or permanent) or at adolescence / early adulthood [1]. We present a 58-year-old diabetic lady, who was detected with ABCC8 mutation during the cascade testing [8]. She was diagnosed with diabetes at the age of 12 [8]. Her son had history of neonatal hypoglycaemia and developed diabetes at the age of 15. He was the index case who was found to have ABCC8 mutation. The family has several other members diagnosed with diabetes. The aim of the article is to increase awareness and understanding of monogenic diabetes among the medical practitioners in adult population with diabetes so that the genetic testing can be offered in a cost effective manner.

The Role of Fibroblast Growth Factor 10 Signaling in Duodenal Atresia.

IntroductionDuodenal atresia (DA) is a congenital bowel obstruction requiring major surgery in the first week of life. Three morphological phenotypes are described, reflecting increasing degrees of obstruction and discontinuity of the duodenum. The cause of DA is not known. Tandler’s original “solid cord” hypothesis conflicts with recent biological evidence, and is unable to account for differing DA types. In humans, a genetic etiology is supported by the association between Trisomy 21 and DA, and reports of familial inheritance patterns. Interruption of FGF10/FGFR2b signaling is the best demonstrated genetic link to DA in mice, with 35–75% of homozygous knockout embryos developing DA.PurposeThis review examines the current evidence surrounding the etiology of DA. We focus on research regarding FGF10/FGFR2b signaling and its role in duodenal and other intestinal atresia. Further, we outline planned future research in this area, that we consider necessary to validate and better understand this murine model in order to successfully translate this research into clinical practice.ConclusionDetermining the etiology of DA in humans is a clinical and scientific imperative. Fgf10/Fgfr2b murine models represent current science’s best key to unlocking this mystery. However, further research is required to understand the complex role of FGF10/FGFR2b signaling in DA development. Such complexity is expected, given the lethality of their associated defects makes ubiquitous interruption of either Fgf10 or Fgfr2b genes an unlikely cause of DA in humans. Rather, local or tissue-specific mutation in Fgf10, Fgfr2b, or their downstream targets, is the hypothesized basis of DA etiology.

Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.

BackgroundThe purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D.MethodsWe analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided.ResultsPathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC.ConclusionsThese estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.