Significant Family History Research Articles

A parent and child with Liddle syndrome diagnosed correctly with the child as the proband: a case report with review of literature.

Liddle syndrome (LS) is an autosomal dominant genetic disorder characterized by early onset hypertension, hypokalemia, and low plasma aldosterone or renin concentration. It is caused by mutations in subunits of the epithelial sodium channel (ENaC). The clinical phenotypes of LS are variable and nonspecific, making it prone to both misdiagnosis and missed diagnosis. Genetic analysis is necessary to confirm the diagnosis of LS. Herein, we report the case of a 42-year-old male with LS and a 30-year history of hypertension. He was being treated for possible primary aldosteronism (PA) over the preceding 7 years; however, his hypertension was poorly controlled despite intensive combination therapy. His 13-year-old son served as a proband for a diagnosis of LS, as he had hypertension, hypokalemia, and a significant family history of hypertension. Genetic testing revealed a heterozygous pathological variant in the SCNN1B gene. This led to a diagnosis of LS, as the father was found to harbor the same mutation. Both were treated with ENaC inhibitors and a salt-restricted diet, which improved their symptoms markedly. The son's genetic diagnosis facilitated the subsequent proper diagnosis and treatment of his father. LS causes early onset hypertension; hence, its early diagnosis and treatment can prevent complications. Hereditary hypertension should be considered in cases of early onset hypertension with a significant family history. Patients diagnosed with PA using outdated criteria may have concomitant LS and require careful evaluation of biochemical and endocrine tests according to the current criteria.

FLAIR-Hyperintense Lesions in Anti-MOG-Associated Encephalitis with Seizures: A Case Report

Introduction: Myelin oligodendrocytic glycoprotein antibody-associated disease (MOGAD) is an immune-mediated demyelinating disorder of the central nervous system. We described, a case of encephalitis associated with anti-MOG antibodies with hyperintense lesions on FLAIR and seizures (FLAMES). Case Report: We report a case of a 5-year-old girl, with no significant personal or family history, who entered the emergency room with paroxysmal events and anarthria, in a febrile context. On neurological examination she presented right sided facial paresis and pyramidal signs on the right. Lumbar puncture (LP), showed pleocytosis, hyperproteinorrhaquia and the absence of oligoclonal bands. Electroencephalogram revealed encephalopathy and slow paroxysmal left frontal activity. The brain MRI detected hyperintense lesions, however, with an area of left frontal cortico-subcortical hyperintense signal on T2/FLAIR and diffusion restriction. Anti-MOG antibody was detected. These findings pointed to the diagnosis of FLAMES. She completed 7 days of methylprednisolone (30mg/kg/day), with a good response. On the day of discharge, a repeat EEG was conducted, demonstrating significant improvement compared to the initial one, with slightly slow wake and sleep patterns for her age, and no evidence of epileptic activity. She was assessed approximately four months post-hospitalisation and was found to be asymptomatic, with no focal neurological deficits. A further EEG was performed, which showed a structurally age-appropriate wake and sleep pattern with no abnormal graphoelements. Conclusion: We highlight a rare clinical-radiological entity, which is still poorly described, particularly in the paediatric population, known as FLAMES, with a favourable response to steroids. Early recognition and timely diagnosis of his condition improve clinical and therapeutic management and minimize neurological damage. Immediate initiation of appropriate treatment is important for achieving a favorable outcome.

Oral pharmacological management of Bertolotti syndrome presenting as chronic low back pain – A case report and review of literature

BackgroundBertolotti syndrome (BS) is often a missed cause of chronic lower back pain in young individuals, commonly associated with the presence of anomalous lumbosacral transitional vertebrae. Case presentationA 19-year-old female with no significant medical or family history presented with persistent lower back pain localized to the gluteal region and posterolateral aspect of the left lower back. The pain worsened over time and limited their movements, including walking. A Ferguson radiograph revealed fusion of the left transverse process of the L5 vertebral segment with the left sacral ala. History, examination findings, and radiological workup confirmed the diagnosis of BS. The patient preferred conservative management, receiving oral pharmacological therapy for six weeks, along with education on preventive measures and routine exercises for postural stability. At a six-month follow-up, the patient remained asymptomatic and managed well. ConclusionsConservative oral pharmacological treatment presents a unique and viable alternative to traditional methods for managing BS, which often involve surgery or steroids/anesthetics at the pseudo-articulation site. Given that BS is common yet underdiagnosed in young patients with chronic back pain, this report also underscores the importance of including it in differential diagnoses for chronic lower back pain in this demographic.

TTR associated leptomeningeal amyloidosis in a Sri Lankan patient

ObjectivesThis case report aims to contribute to the expanding genotypic-phenotypic spectrum of TTR associated leptomeningeal amyloidosis. MethodsNeuroimaging and targeted TTR Sanger sequencing were performed on a 52-year-old female presenting with cognitive and motor symptoms. ResultsThe proband, a Sri Lankan woman, presented with a gradually progressive cognitive decline, followed by a rapid deterioration in motor function and level of consciousness. She had a significant family history of an undiagnosed neurological disorder, characterized by cognitive impairment and early death occurring in the fifth decade of life. Analysis of cerebrospinal fluid (CSF) demonstrated elevated protein levels. CT scan of the brain showed extensive leptomeningeal calcifications and hydrocephalus, and gadolinium enhanced magnetic resonance imaging (MRI) demonstrated extensive leptomeningeal enhancement in the brain and spinal cord.Genetic analysis revealed c.113 A > G, p.D38G mutation in TTR, a rare mutation with characteristic clinic-radiological central nervous system features. DiscussionLeptomeningeal amyloidosis represents the least common subtype of familial transthyretin amyloidosis, which is a life-threatening condition. Among the over 150 identified mutations, few are specifically associated with central nervous system disease. The genetic spectrum and clinical phenotypes including neuroimaging findings continue to expand. It is important to maintain a high index of suspicion for leptomeningeal amyloidosis, particularly when the presentation is not acute or when there are relapsing-remitting symptoms. Consideration of family history and early genetic testing are essential to facilitate appropriate treatment and genetic counselling.

Atypical Desmoid Tumor, A Case Report

Desmoid tumors are rare and benign tumors of soft tissues, characterized by local invasion and high tendency to recur despite surgical resection, we study the case of a 19-year-old patient admitted for cervico-facial and parieto-costal swellings, without any significant family history, and we study the CT and magnetic resonance imaging aspects, with an unpredictable and recurrent evolution despite surgical excision, with many studies that affirm the hormonal factor with the progression of the swelling, as well as its decrease in size after menopause for the treatment, there is no consent using the different components, surgery, chemo-radiotherapy with different and uncodified effectiveness.

7354 A Case of Continuous Glucose Monitoring in Children with Glutamate Dehydrogenase Hyperinsulinism

Abstract Disclosure: K. Kim: None. E. Mun: None. C. Jung Eun: None. R. Lee: None. K. Hae Soon: None. A Case of Continuous Glucose Monitoring in Children with Glutamate Dehydrogenase(GLUD1) Hyperinsulinism Background: Continuous glucose monitoring (CGM) is increasingly being used in pediatric patients with diabetes. CGM can help prevent hypoglycemia and support the management of hypoglycemic problems. Congenital hyperinsulinism is a rare condition in which hypoglycemia occurs due to hyperinsulinemia caused by the dysregulation of insulin secretion, and it can lead to complications such as developmental delay and seizures. Case presentation: A 14 months years old, male infant was referred to the pediatric emergency room representing symptoms of GTC type seizure during 2-3 minutes and hypoglycemia. He had no perinatal problems with no significant family history. During seizure, He was found to have a blood glucose of 39mg/dL, ammonia of 183μmol/L, insulin of 28.3 mcg/mL and ketone 203.4μmol/L. C-peptide was 1.4 ng/mL (≥ 0.5ng/mL) and free fatty acid was 0.492mmol/L (<1.7mmol/L) for evaluation. He was thought to have GDH hyperinsulinism. Blood glucose level was followed up with feeding frequency and protein restricted diet. Congenital hyperinsulinism genetic test was requested. Brain CT showed normal. EEG revealed no focal abnormalities, no persistent asymmetries. CGM was used in patient. Diazoxide was started with 5mg/kg/day in 2 divided doses and then blood glucose level was observed below 60mg/dL 3-4 times for day. Complete blood counts and uric acid levels were measured at baseline and 5 days after starting diazoxide therapy, and thereafter increase to 6.25mg/kg/day Conclusions: In children with GDH hyperinsulinism, the utilization of CGM can serve as a tool to assess the impact of treatment before and after medication therapy, as well as also aiding in hypoglycemia prevention. Presentation: 6/2/2024

8592 Parathyroid Carcinoma: A Rare Cause of Primary Hyperparathyroidism

Abstract Disclosure: S.E. Koshy: None. C.F. Mulcahy: None. P.S. Kothari: None. E.M. Jacobi: None. T.D. Cubb: None. Introduction: Parathyroid carcinoma (PC) is a rare malignancy that accounts for <1% of cases of primary hyperparathyroidism (PHPT). Patients often present with symptoms of hypercalcemia, serum calcium (Ca) >14 mg/dL, large tumor size, and a very high parathyroid hormone (PTH) level. We report a case of an asymptomatic patient with incidentally found hypercalcemia consistent with PHPT who was ultimately diagnosed with PC. Clinical Case: A 31yo male was found to have elevated serum Ca of 12.7 mg/dL (8.6-10.3 mg/dL) on labs obtained during routine physical exam. He had no known significant medical or family history and notably had no laboratory evaluation within the prior 10 years. He denied constipation, polyuria, confusion, depression, bone pain, and history of fractures or nephrolithiasis. Workup showed an inappropriately elevated PTH of 505 pg/mL (16-77 pg/mL). Neck ultrasound demonstrated a left inferior 3.9 cm complex thyroid nodule. Sestamibi scan confirmed increased uptake in the inferior left thyroid. Left neck exploration was performed. Intraoperatively, a 3.7 cm left parathyroid mass weighing 13.0 grams was encountered and excised in an en bloc fashion. The left superior parathyroid gland was evaluated and found to be normal. Intraoperative PTH level decreased from 529 pg/mL to 48 pg/mL 10 minutes after excision. Left hemithyroidectomy was not performed. Surgical pathology revealed PC with lymphovascular invasion, suspected capsular invasion, and negative margins. Immunohistochemical staining showed a Ki67 proliferation index up to 5% and complete loss of nuclear staining for parafibromin. Next generation sequencing demonstrated a somatic CDC73 p.L8fs mutation, tumor mutational burden 4.7m/MB, and stable microsatellite instability. Germline testing was negative for a CDC73 mutation. Postoperative staging did not demonstrate evidence of metastatic disease in the neck or chest. Serum Ca remained within normal limits. After multidisciplinary discussion, no further surgical intervention was recommended and plan was for ongoing biochemical and imaging surveillance. Conclusion: Though rare, PC should be considered as a cause of PHPT. The primary treatment is complete surgical resection. Unfortunately, there is a high rate of recurrence, >50%, with most occurring 2-5 years after initial surgery with a median overall survival of 14 years. Thus, long-term surveillance is of utmost importance. Treatment of recurrent disease is surgical resection when feasible as well as medical management of hypercalcemia. Further research is needed to better understand the role of targeted systemic therapy in addition to immunotherapy. PC is most commonly sporadic but can be hereditary, thus genetic evaluation is recommended. Given its rarity and complexity, PC is best managed in a multidisciplinary setting. Presentation: 6/1/2024

8592 Parathyroid Carcinoma: A Rare Cause of Primary Hyperparathyroidism

Abstract Disclosure: S.E. Koshy: None. C.F. Mulcahy: None. P.S. Kothari: None. E.M. Jacobi: None. T.D. Cubb: None. Introduction: Parathyroid carcinoma (PC) is a rare malignancy that accounts for <1% of cases of primary hyperparathyroidism (PHPT). Patients often present with symptoms of hypercalcemia, serum calcium (Ca) >14 mg/dL, large tumor size, and a very high parathyroid hormone (PTH) level. We report a case of an asymptomatic patient with incidentally found hypercalcemia consistent with PHPT who was ultimately diagnosed with PC. Clinical Case: A 31yo male was found to have elevated serum Ca of 12.7 mg/dL (8.6-10.3 mg/dL) on labs obtained during routine physical exam. He had no known significant medical or family history and notably had no laboratory evaluation within the prior 10 years. He denied constipation, polyuria, confusion, depression, bone pain, and history of fractures or nephrolithiasis. Workup showed an inappropriately elevated PTH of 505 pg/mL (16-77 pg/mL). Neck ultrasound demonstrated a left inferior 3.9 cm complex thyroid nodule. Sestamibi scan confirmed increased uptake in the inferior left thyroid. Left neck exploration was performed. Intraoperatively, a 3.7 cm left parathyroid mass weighing 13.0 grams was encountered and excised in an en bloc fashion. The left superior parathyroid gland was evaluated and found to be normal. Intraoperative PTH level decreased from 529 pg/mL to 48 pg/mL 10 minutes after excision. Left hemithyroidectomy was not performed. Surgical pathology revealed PC with lymphovascular invasion, suspected capsular invasion, and negative margins. Immunohistochemical staining showed a Ki67 proliferation index up to 5% and complete loss of nuclear staining for parafibromin. Next generation sequencing demonstrated a somatic CDC73 p.L8fs mutation, tumor mutational burden 4.7m/MB, and stable microsatellite instability. Germline testing was negative for a CDC73 mutation. Postoperative staging did not demonstrate evidence of metastatic disease in the neck or chest. Serum Ca remained within normal limits. After multidisciplinary discussion, no further surgical intervention was recommended and plan was for ongoing biochemical and imaging surveillance. Conclusion: Though rare, PC should be considered as a cause of PHPT. The primary treatment is complete surgical resection. Unfortunately, there is a high rate of recurrence, >50%, with most occurring 2-5 years after initial surgery with a median overall survival of 14 years. Thus, long-term surveillance is of utmost importance. Treatment of recurrent disease is surgical resection when feasible as well as medical management of hypercalcemia. Further research is needed to better understand the role of targeted systemic therapy in addition to immunotherapy. PC is most commonly sporadic but can be hereditary, thus genetic evaluation is recommended. Given its rarity and complexity, PC is best managed in a multidisciplinary setting. Presentation: 6/1/2024

7971 The Role of PDX1 In Beta Cell Response To GLP1

Abstract Disclosure: C. Bheeman: None. K. Vann: None. O. Astapova: None. Mature Onset of Diabetes of the Young Type 4 is a rare form of diabetes mellitus caused by a defect in the Pancreatic and Duodenal homeobox 1 (PDX-1) gene, which is predominantly expressed in β-cells and is an important factor in insulin gene transcription. We aim to study the impact that a PDX1 mutation (modeled after a patient) has on the beta cell response to GLP1. This was a 33-year-old nonobese man who presented to the clinic with new onset diabetes without ketosis. He was treated with insulin and metformin and his hemoglobin A1c decreased from 16% to 6.1% in six months. Other labs showed c-peptide of 8.9 ng/mL in setting of a blood glucose of 231 mg/dL, negative islet cell antibodies and glutamic acid antibodies. Of note, patient also had significant family history of diabetes. Due to high probability of MODY, genetic testing was obtained. He was found to have a heterozygous frameshift mutation in codons 228 -233 leading to a 17 base pair deletion in the PDX1 gene causing replacement of the 56 C- terminal amino acids with a shorter, missense C-terminal tail. Patient was started on dulaglutide 0.75 mg weekly but was hypoglycemic on the smallest dose so he was then switched to Semaglutide and has been maintained on less than 0.25 mg weekly. The clinical question we aim to answer was why was this patient so sensitive to GLP1 agonist activity. To study how the mutation affects response to GLP1 we are using mouse beta-TC-6 cell as they are insulin secreting, and regulated by glucose. The PDX-1 gene is highly conserved among species and the mouse PDX gene is comparable to the human gene. We used CRISPR-Cas9 to introduce the same 17 base-pair deletion into the mouse PDX-1 gene in beta-TC-6 cells. We first measured the glucose stimulated insulin secretion in control cells to examine first and second phases of insulin secretion, determining that the first phase of insulin occurs in twenty minutes and the second phase starts at about two hours. We also evaluated if these cells responded GLP-1 by increasing insulin secretion. We found that these cells respond to glucose and GLP1 in an additive manner. Insulin was measured by enzyme-linked immunosorbent assay (ELIZA). In the next phase of the experiment we aim to determine the effect of the GLP-1 in cell lines with the PDX1 deletion mutation as compared to control cell line. We will measure insulin secretion by ELISA in both mutant and the control cells treated with and without glucose and GLP1. We will measure insulin at 0 minutes and 30 minutes and insulin mRNA at 0 minutes and 6 hours to determine the first and second phases of insulin production. Our results will help guide personalized treatment for patients with MODY type 4 and improve our understanding of beta cell response to GLP1. Presentation: 6/2/2024

Neuroglycopaenia as the first manifestation of MEN1 syndrome

Insulinoma is a neuroendocrine tumour of islet cells and a rare cause of hypoglycaemia in both adults and the paediatric population, with an incidence is 1–4 cases/million/year. Insulinoma may occur as an isolated tumour or as a component of multiple endocrine neoplasia syndrome 1. In the case presented below, a 15-year-old female patient with no significant medical history was brought to the emergency department by a medical rescue team, exhibiting symptoms of neuroglycopaenia for several hours. After excluding more common causes of hypoglycaemia, insulinoma was suspected. Given the patient’s very young age at onset and a significant family history, laboratory and imaging diagnostics were performed for multiple endocrine neoplasia syndrome 1. Once more common causes have been ruled out, insulinoma should be considered in the differential diagnosis of hypoglycaemia. If the diagnosis of insulinoma is confirmed, the possibility of multiple endocrine neoplasia syndrome 1 should be considered.

Glioblastoma Arising in Lynch-like Syndrome after Repeated Development of Colorectal Cancers: A Case Report.

We herein report a patient with Lynch-like syndrome in whom a brain tumor (glioblastoma) developed after repeated resection of colorectal cancer. The patient had a significant family history of cancer. Immunohistochemical expression of mismatch repair proteins was decreased in both brain and colon tumors, but no pathogenic variant of the related genes was detected. Although brain tumors occasionally develop in Lynch syndrome, they have not been reported in cases of Lynch-like syndrome. This first report of Lynch-like syndrome with the development of glioblastoma suggests the need for further investigation on the surveillance of brain tumors in patients with this syndrome.

Familial hypokalemic periodic paralysis: a case induced by concurrent hyperthyroidism

BackgroundFamilial hypokalemic periodic paralysis (HypoPP) is an uncommon genetic disorder characterized by recurrent episodes of muscle weakness and hypokalemia, typically starting in early adulthood. The existence of hyperthyroidism in the presence of HypoPP is more strongly associated with a diagnosis of thyrotoxic periodic paralysis (TPP), with most cases occurring in Asian males with pathogenic KCNJ2 or KCNJ18 variants and without a family history of the condition. This case is novel due to the combination of familial HypoPP and hyperthyroidism induced by Graves’ disease, a rare occurrence especially in non-Asian populations.Case presentationA 40-year-old African American man presented with profound muscle weakness after consuming a high-salt meal. He had a significant family history of hyperthyroidism and hypokalemia. On examination, he showed profound weakness in all extremities. Laboratory tests confirmed hypokalemia and hyperthyroidism, and genetic testing identified a pathogenic variant in the CACNA1S gene (c.1583 G > A, p. R528H), with normal SCN4A, KCNJ2 and KCNJ18 sequencing. He was diagnosed with familial HypoPP and hyperthyroidism due to Graves’ disease. He was started on PO methimazole 10 mg three times a day and PO acetazolamide 250 mg twice a day. He was advised to follow a low carbohydrate and low salt diet.ConclusionsThis case highlights the importance of considering a genetic basis for HypoPP in patients with a family history of the condition, even when hyperthyroidism is present. The combination of familial HypoPP and Graves’ disease is rare and emphasizes the need for careful genetic and clinical evaluation in similar cases. Management should focus on correcting hypokalemia, treating hyperthyroidism, and lifestyle modifications to prevent recurrence.

Pathogenic BAG3 Variant in Peripartum Cardiomyopathy and Significant Family History of Sudden Death

Pathogenic BAG3 Variant in Peripartum Cardiomyopathy and Significant Family History of Sudden Death

Peutz-Jeghers syndrome: A case series

IntroductionPeutz-Jeghers syndrome (PJS) is a rare hereditary disorder characterized by gastrointestinal hamartomatous polyps, due to mutation of the STK11/LKB1 gene located on chromosome 19p. The polyps are most commonly found in the small bowel followed by colon. Case presentationOur case series includes 4 patients, three being male and one female. Each of them either presented with abdominal pain and other associated symptoms. Oral cavity and lip melanin pigmentation were common. CT abdomen revealed multiple large jejunal, ileal, gastric and colon polyps. Cancer was found in one patient. Different surgical approaches were adopted. All recovered well. DiscussionPJS is an autosomal dominant disorder with an estimated incidence of 1:50,000 to 1:200,000 cases with a significant family history. Mostly found in small bowel followed by colon, it can also occur in a rare organ like gall bladder as evident in our case. PJS carries a substantial risk for gastrointestinal cancer. The treatment modality depends on the site of polyp, mode of presentation and availability of the expertise. ConclusionPJS is a common disease in our part which is usually observed in teen age groups male. They have a varied presentation, from intestinal obstruction (due to intussusception) to GI bleeding. Colonic malignancy at young age may be the first presentation of the disease. Observation of melanin pigmentations on lips helps diagnose the disease; and one should always look at this findings in a young patient with pain abdomen or in intestinal obstruction to confirm/exclude the disease.

Not all ketosis is type 1 – remember Flatbush

A 35-year-old otherwise healthy gentleman from Togo, was referred as a ‘walk-in’ to our clinic with polyuria and polydipsia, and a glycated haemoglobin (Hba1c) of 119 mmol/mol (13.1%). The patient also noted 5kg weight loss over a short span of time. He had a significant family history of Type 2 Diabetes Mellitus (T2DM). Initial blood tests revealed a blood glucose of 22.84 mmol/L, with positive ketones (1.2 mmol/L). Urinalysis showed glycosuria (1000 mg/dL) but was negative for nitrites and white cells. Renal, liver and thyroid function tests were all within normal limits. He had mild metabolic acidosis.

Chromosome Xp22.3 deletion syndrome with X-linked ichthyosis, Kallmann syndrome, short stature, generalized epilepsy, hearing loss, attention deficit hyperactivity disorder, and intellectual disability – A rare report with review of literature

Chromosome Xp22.3 deletion syndrome is a very rare contiguous gene deletion syndrome with variable phenotype due to the deletion of genes from the distal short arm of the X chromosome (Xp), including the short-stature homeobox (SHOX), anosmin-1 (ANOS1), arylsulfatase (ARSL), neuroligin-4 (NLGN4), and steroid sulfatase (STS) genes. We have reviewed the available literature on the chromosome Xp22.3 deletion syndrome. A 10-year-old boy presented with global developmental delay, generalized epilepsy, decreased hearing, and hyperactivity. He had no significant family history. Examination revealed microcephaly, short stature, and dry and scaly skin lesions on the trunk. He had thick arched eyebrows, a depressed nasal bridge, a long philtrum, high arched palate, retrognathia, brachytelephalangy, brachymetatarsia, and mild scoliosis. Brainstem-evoked response audiometry testing revealed moderate hearing loss. Magnetic resonance imaging showed cerebellar tonsillar ectopia. Clinical exome sequencing revealed a likely pathogenic contiguous deletion (~8.10 Mb) spanning genomic location chrX:g.(_630898)_(8732037_)del encompassing ANOS1, ARSL, NLGN4X, SHOX, and STS genes. We have reviewed the available literature for reported associations of Chromosome Xp22.3 deletion syndrome and report a novel association of X-linked ichthyosis, Kallmann syndrome, global developmental delay, short stature, bilateral hearing loss, generalized epilepsy, attention deficit hyperactivity disorder, and intellectual disability.

Uncommon presentation of a patient with hereditary haemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder. It is clinically characterised by telangiectasia, recurrent epistaxis, and visceral vascular lesions. We report a case of HHT without a significant family history. A 16-year-old girl presented with multiple episodes of bleeding, including uncommon sites, over a period of ten months. She denied a family history of bleeding. Her clinical examination was unremarkable. Investigations including basic and second-line coagulation tests were normal. Subsequently multiple telangiectasias in the right nasal septum and capillary dilatation in the bladder wall were detected. According to Curaçao diagnostic criteria, a diagnosis of HHT was made. As her bleeding was self-limiting, follow up was arranged to monitor complications.

Kertoacanthoma: To Excise or Not to Excise?

Background Although surgical excision is considered the gold standard for management of keratoacanthoma, there is lack of consensus regarding its best management options. This confusion originates due to the few number of reports describing keratoacanthoma cases. This report presents a case of keratoacanthoma that was managed using the conservative choice. A 49-year-old woman presented with a disfiguring exophytic mass at her lower lip that enlarged continuously over 3 weeks’ time. The patient had no significant medical, dental or family history or lymphadenopathy. The midline of the lower vermilion border showed a solitary soft sessile dome-shaped papule that was covered by non-keratinized mucosa with a central keratin plug at the top. The lesion was managed conservatively with favorable outcomes. The self-healing potential of the lesion provides amazing results. When signs of regression are seen, conservative approach is advised.

LGG-08. DIFFUSE ASTROCYTOMA IN A PATIENT WITH POSSIBLE MBD4-ASSOCIATED NEOPLASIA SYNDROME (MANS)- EXPANDING THE SPECTRUM OF MANS-ASSOCIATED NEOPLASM

Abstract BACKGROUND MBD4-associated neoplasia syndrome (MANS) is a recently identified genetic syndrome characterized by the development of colorectal polyps, acute myeloid leukemia, and uveal melanoma, with an elevated mutation burden. MANS is attributed to bi-allelic germline variations in the MBD4 gene. METHOD We present a case of a pediatric patient with diffuse astrocytoma WHO-grade II and bi-allelic germline variations in the MBD4 gene. CASE REPORT A previously healthy 10-year-old female with a significant family history of high-grade IDH wild type-glioma in the deceased older brother presented with vague symptoms and was found to have abnormal brain MRI with multiple foci of subcortical FLAIR/T2 hyperintensity involving the right frontotemporal lobe, left frontal lobe, and left thalamus. She had intact neurologic exam findings and was followed with serial brain MRIs. Over the next 2 years, she continued to be asymptomatic, but her MRI showed an increase in the size of her brain lesions. Following a stereotactic biopsy of the right temporal lesion, a diagnosis of diffuse astrocytoma (WHO-grade II) was confirmed. Molecular analysis showed point mutations in IDH1, TP53, and PTEN genes, along with LOH at 17p (including TP53 gene), and outline gene expressions for NTRK2, OLIG2, GRM3, FGF1, SOX8, MBP, MGMT genes. Given the low grade of the tumor and the absence of tumor-related symptoms, a decision was made to continue monitoring with serial MRIs. Whole exome sequencing identified germline bi-allelic missense variations in the MBD4 gene, specifically C.1405A>G and C.1573A>C. Both parents were found to be heterozygous for one of these mutations. CONCLUSION The significance of MBD4 mutation remains unknown in our patient, but bi-allelic variations coupled with the presence of a brain tumor and positive family history raise concerns about MANS in our patient. Additional studies are needed to elucidate the potential association between brain tumors and MANS.

Profile of breast cancer in patients with Li-Fraumeni syndrome: An institutional experience.

e13042 Background: Li Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome, associated with multisystem cancer predisposition. Considering the rarity of this syndrome, studies are very sparse on survival outcomes of breast cancer with germline TP53 mutation and there exists discrepancy amongst the results. Methods: This retrospective observational study included 17 patients with germline TP53 mutated breast cancer registered at All India Institute of Medical Sciences (AIIMS), New Delhi, India between the period of 1st April 2016 to 31st Dec 2023. Among the 577 high-risk breast cancer patients, who underwent germline mutation testing, 231 (40.03%) cases had pathogenic mutation [145(25.12%) were BRCA mutated,15 (2.59%) were TP53 mutated, and the rest were others pathogenic variant]. All the TP53 mutations were crosschecked via the ClinVar mutation database to be classified as pathogenic. Results: The median age of 15 patients was 31 years (23-55) and 12 (80%) cases were premenopausal. All the patients had breast cancer as the index malignancy. The Stage distribution (AJCC-7th edition) Stage I, 1(6.6%); Stage II, 7 (46.6 %); Stage III, 4 (26.6 %); and Stage IV, 3 (20 %). Eight cases (53.3%) were HER2 positive, 4 (26.6%) were hormone receptor-positive, and 3 (20%) were Triple-negative breast carcinoma (TNBC). Ten (10) patients received neoadjuvant chemotherapy and 6 (60%) had a complete pathological response. Eight cases (53.3%) cases had a significant family history with 9 (60%) of them having at least one first-degree relative with cancer and two had more than one first-degree relative with cancer. One patient had a family history of LFS. The most common familial cancer was breast, followed by lung, GI malignancies, brain tumor, and sarcoma. Synchronous breast cancer was seen in 2 patients, synchronous malignancies were seen in 4 cases (one patient: each with lung adenocarcinoma, periampullary carcinoma, carcinoma colon, and synovial sarcoma, along with breast cancer), Four patients (26.6%) had metachronous cancers: lung cancer, ovarian carcinoma, contralateral breast cancer, and high-grade sarcoma respectively. The most common mutations were point mutations ( n = 11, 73.3%) followed by frameshift mutations ( n = 4, 26.6%). The subtypes of point mutations included missense mutations ( n = 9) and nonsense mutations ( n = 2) with the most common aberration being a replacement of arginine with glycine (c.743G>A, p. Arg248Gln) and locus being exon 7. The median disease-free survival was 41 months and progression-free survival was 15 months. Conclusions: The prevalence of TP53 mutation in our breast cancer patients is 2.5%. With standard treatment protocols, the overall survival of LFS-associated breast cancer is similar to the historic cohort of patients without any germline mutation. Active surveillance of the patient and family screening is imperative, for all positive cases.