Heterozygous Variant Of Uncertain Significance Research Articles

Association of ANK2 Mutation and Massive Myocardial Calcification: A Case Report

<h3>Introduction</h3> A 35-year-old man with no prior history of cardiovascular diseases was admitted with progressive exertional chest discomfort. Physical examination revealed irregular heart rhythm and an ejection murmur at the aortic area. EKG showed atrial fibrillation, and chest X-ray, calcification within the cardiac silhouette. Laboratory tests were all within normal ranges, including serological and inflammatory tests. <h3>Case Report</h3> An echocardiogram demonstrated diffuse myocardium calcification and intense mitral- aortic fibrocalcification, causing severe stenosis and moderate regurgitation, with a dilated left ventricle (LV) and moderate systolic dysfunction, akinesia of the inferolateral walls and hypokinesia of the anterior walls. A 128-row multidetector CT showed massive calcification affecting the aortic and mitral valves, the right ventricle, the left atrium wall and all the segments of the LV, preserving only the basal septum. Cardiovascular magnetic resonance imaging 1.5T revealed diffuse myocardial thickening, matching the areas seen on CT (figure). These areas were hypointense on the SSFP cine images and on T1- and T2-weighted images and had no late gadolinium enhancement (LGE). However, there was LGE in the underlying myocardium, in a non-ischemic distribution. Pericardium and coronary arteries were preserved. Genetic analysis identified a rare heterozygous variant of uncertain significance, c.10702C>T(p.Arg3568Trp), in ANK2 gene. <h3>Summary</h3> Ankyrin-B, also known as Ankyrin-2, is encoded by the ANK2 gene, which plays critical roles in the localization and stabilization of ion transporters and ion channels in cardiomyocytes. The Ankyrin-B syndrome has been associated to long QT syndrome and torsades depointes, but there are no reports of myocardial calcification. The patient was found to be a candidate for cardiac transplantation and is currently on the waiting list.

M154 UNUSUAL PRESENTATION OF HETEROZYGOUS DOCK8 MUTATION FOUND DURING WORK-UP FOR DRESS

Autosomal recessive (AR) Hyper IgE syndrome (HIES) due to dedicator of cytokinesis 8 (DOCK 8) mutation is characterized by recurrent infections, atopic dermatitis and food allergies. We present the case of a child with a heterozygous variant of uncertain significance (VUS) of the DOCK8 gene identified during the workup for suspected drug reaction.

M159 OMENN SYNDROME ASSOCIATED WITH DNA LIGASE 1

Pathogenic variants in LIG1, which encodes for DNA ligase 1, have recently been reported in only two cases of SCID. We present a patient with Omenn Syndrome (atypical SCID) and two heterozygous variants of uncertain significance in LIG1.

M182 THE IMPORTANCE OF CLINICAL PHENOTYPES IN HETEROZYGOUS VARIANTS OF UNCERTAIN SIGNIFICANCE IN GATA2 DEFICIENCY

GATA2 deficiency is a germline disease that results in pancytopenia, leukemia, recurrent infections and lymphedema. Because it is determined by heterozygous mutations, encountering a patient with heterozygous variants of uncertain significance in GATA2 makes diagnosing GATA2 deficiency a challenge.

Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

Background/aimFamilial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia.Materials and methodsAll patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine nonresponsiveness, amyloidosis, and persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using international severity score for FMF (ISSF) and autoinflammatory disease damage index (ADDI), respectively.ResultsAmong 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p > 0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p = 0.006 and 0.004, respectively).ConclusionOur findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.

Identification of missense MAB21L1 variants in microphthalmia and aniridia.

Microphthalmia, coloboma, and aniridia are congenital ocular phenotypes with a strong genetic component but often unknown cause. We present a likely causative novel variant in MAB21L1, c.152G>T p.(Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance, c.184C>T p.(Arg62Cys)/c.‐68T>C, and c.658G>C p.(Gly220Arg)/c.*529A>G, in two additional probands with microphthalmia, coloboma and/or cataracts. All variants were predicted as damaging by in silico programs. In vitro studies of coding variants revealed normal subcellular localization but variable stability for the corresponding mutant proteins. In vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss‐of‐function line demonstrated that though overexpression of wild‐type MAB21L1 messenger RNA (mRNA) compensated for the loss of mab21l2, none of the coding variant mRNAs produced a statistically significant rescue, with p.(Arg51Leu) showing the highest degree of functional deficiency. Dominant variants in a close homolog of MAB21L1, MAB21L2, have been associated with microphthalmia and/or coloboma and repeatedly involved the same Arg51 residue, further supporting its pathogenicity. The possible role of p.(Arg62Cys) and p.(Gly220Arg) in microphthalmia is similarly supported by the observed functional defects, with or without an additional impact from noncoding MAB21L1 variants identified in each patient. This study suggests a broader spectrum of MAB21L1‐associated disease.

Excellent response to secukinumab in an infant with severe generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) represents the rarest form of psoriasis, which may be potentially fatal. In the last decade, (likely) pathogenic variants in the IL36RN, CARD14 and AP1S3 genes have been associated with monogenic GPP forms. Despite these advances, the genetic basis of most patients with GPP remains unidentified. Treatment of GPP patients is often difficult, with no consensus about the best available options to date. We report herein an infant with severe GPP in whom the disease started at the age of 2months. Genetic investigations identified a heterozygous pathogenic variant in the IL36RN gene associated with a heterozygous variant of uncertain significance in the CARD14 gene. After previous treatment failures with acitretin, cyclosporin and anakinra, treatment with the interleukin-17 antagonist secukinumab resulted in a dramatic and prompt positive response that persisted at 12-month follow up. According to our experience, we believe secukinumab can be an effective and safe treatment for pediatric patients with GPP even before 1year of age.

Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families.

Background and Objectives: Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies. The objectives of this study were to report the clinical and genetic features of dHMN patients in a Chinese cohort.Aims and Methods: We performed clinical assessments and whole-exome sequencing in 24 dHMN families from Mainland China. We conducted a retrospective analysis of the data and investigated the frequency and clinical features of patients with a confirmed mutation.Results: Two novel heterozygous mutations in GARS, c.373G>C (p.E125Q) and c.1015G>A (p.G339R), were identified and corresponded to the typical dHMN-V phenotype. Together with families with WARS, SORD, SIGMAR1, and HSPB1 mutations, 29.2% of families (7/24) acquired a definite genetic diagnosis. One novel heterozygous variant of uncertain significance, c.1834G>A (p.G612S) in LRSAM1, was identified in a patient with mild dHMN phenotype.Conclusion: Our study expanded the mutation spectrum of GARS mutations and added evidence that GARS mutations are associated with both axonal Charcot-Marie-Tooth and dHMN phenotypes. Mutations in genes encoding aminoamide tRNA synthetase (ARS) might be a frequent cause of autosomal dominant-dHMN, and SORD mutation might account for a majority of autosomal recessive-dHMN cases. The relatively low genetic diagnosis yield indicated more causative dHMN genes need to be discovered.

M293 MORE THAN SKIN DEEP: SEVERE DERMATITIS, ELEVATED IGE, AND EOSINOPHILIA WITH HETEROZYGOUS DOCK8 MUTATIONS

Hyper IgE syndromes (HIES) are a group of primary immunodeficiencies characterized by elevated IgE, severe dermatitis, and recurrent skin and sinopulmonary infections. DOCK8 deficiency is an autosomal recessive type of HIES. We present two patients with atopic dermatitis, elevated IgE level, and eosinophilia consistent with DOCK8 deficiency, both found to have a heterozygous variant of uncertain significance (VUS) in DOCK8.

Mitochondrial Dysfunction Contributes to Ehlers-Danlos Syndrome - A Patient Presentation

A female patient with substantial history and physical findings of Ehlers-Danlos syndrome by systematic evaluation had a variant in the gene encoding the sixth subunit of mitochondrial ATP synthetase gene that produced a change from glycine to aspartic acid at position 132 of the MT-ATP6 protein (MT-ATP6 m.8921G&gt;A, p.Gly132Asp). The mutation was heteroplasmic, affecting 32% of the mitochondria in blood leucocytes, was qualified as a pathogenic variant because of its significant molecular change, but was not detected in the maternal blood sample as might be expected for its low degree of heteroplasmy. The patient was shown to have typical findings of Ehlers-Danlos syndrome by comparison of 48 history and physical findings in her and a peer group of 32 teenage females with that diagnosis. None of the classical neurosensory or developmental symptoms of mitochondrial disease were present in mother or daughter, but the patient had symptoms, metabolite alterations during rest or exercise, and muscle biopsy changes that suggested mild mitochondrial dysfunction. She also had heterozygous variants of uncertain significance in the nuclear PLOD1, FLNA, and ATP2A genes by concomitant whole exome sequencing that could also contribute to her arthritis-adrenaline disorder. Mitochondrial dysfunction is proposed to influence neuromuscular components of connective tissue, acting through an articulo-autonomic dysplasia cycle to cause the typical joint-skin laxity and dysautonomia of Ehlers-Danlos syndrome.

The combined use of Adrenocorticotropic hormone (ACTH) and Calcineurin inhibitor (CNI) in the treatment of Refractory Nephrotic Syndrome in a child

Background: Primary podocytopathies including Focal Segmental Glomerulosclerosis (FSGS) have been recognized to show variable responses to conventional treatment and overall prognosis. Persistent failure to respond to therapies remains a vexing problem for clinicians. ACTH has recently resurged as a therapy for treatment-resistant podocytopathies. We describe a case of steroid-resistant NS in a 10-year-old boy with a history of multiple failed secondary therapies, who showed partial response to biweekly ACTH therapy. Further clinical improvement was observed with the addition of the calcineurin inhibitor (CNI), tacrolimus. Case description: A 10-year-old Hispanic boy, diagnosed with frequently-relapsing steroid sensitive NS at the age of 2, and was largely relapse-free for 5 years on Cyclosporine A (CsA). Within two months after a trial off CsA, he relapsed. His course was complicated by more frequent relapses and steroid resistance. Renal biopsy performed at this time showed early focal segmental glomerulosclerosis (FSGS) and no signs of CsA-induced nephropathy. Whole exome sequencing revealed a heterozygous variant of uncertain significance in PLCE1 (Phospholipase C Epsilon 1). Trials of the steroid sparing agents tacrolimus and mycophenolate mofetil, both with and without steroids, were ineffective. He had several prolonged hospitalizations due to poorly controlled relapse. He became dependent on biweekly 25% albumin infusions. His renal function deteriorated from a baseline creatinine of 0.3 mg/dl to 0.7 mg/dl due to multiple episodes of acute kidney injury. ACTH initiated at a low dose of 40 units/1.73 m² biweekly was ineffective. Three months later, the dose was increased to 80 units/1.73 m² biweekly and he achieved partial remission and renal function returned to baseline. Tacrolimus was added at 6 months for synergy with trough levels maintained between 3-5 ng/ml. He achieved partial remission, and avoided further hospitalizations. Conclusion: ACTH alone or in combination with calcineurin inhibitor (CNI) can be a viable alternative for children who are resistant to other therapies. Variability in renal phenotype has been implicated with the PLCE1 (Phospholipase C Epsilon 1) gene. In this case, we suspect the role of his heterozygous variant PLCE1 mutation, or likely a compound heterozygous state with another unidentified mutation or modifiers or environmental factors, plays a role in the progression to a refractory NS state.

SAT-140 Determining the Undetermined: The Role of Tumor Tissue Staining for Interpretation of Inconclusive Genetic Testing Results in Patients with Pheochromocytomas and Paragangliomas

Background:Paragangliomas and pheochromocytomas are neuroendocrine tumors that can occur in several hereditary tumor syndromes. While these are generally rare, individuals with germline loss of function mutations in the succinate dehydrogenase (SDH) genes are at high risk of developing these tumours, with a penetrance of 70% by age 50. Functional SDHB acts as a tumor suppressor. Consequently, pathogenic mutations in the SDHB gene predispose to familial paraganglioma syndrome type 4, with high incidence of extra adrenal paragangliomas and high rates of metastasis. SDHB mutation carriers are also predisposed to developing tumors in other sites such as renal cell cancer, gastrointestinal stromal tumors and pituitary adenomas. Genetic testing for hereditary syndromes is recommended in patients who present with paragangliomas and pheochromocytomas, especially in those with aggressive tumours or who present at a young age. It is recommended that mutation carriers are monitored with routine clinical and imaging surveillance, and effort is made to identify and screen at-risk family members. In some cases, genetic testing can identify variants that are not clearly pathogenic or benign. In such “variants of undetermined significance”, immunohistochemistry or family history can be a helpful tool in discriminating between SDHB related and non-SDH-related pheochromocytomas and paragangliomas.Clinical case:We report on three families who presented with manifestations of paraganglioma syndrome and were found to have Variants of Uncertain Significance (VUSs) in the SDHB gene. Absence of SDHB staining was seen on tumour histopathology in two of the families; staining was not performed in the third. The proband in the third case initially presented at the age of 22 with a cardiac pheochromocytoma. Subsequently, her son was diagnosed with metastatic renal cancer at the age of 37. Genetic test results from both these patients identified a heterozygous VUS in SDHB. The son passed away from complications of his aggressive cancer shortly after diagnosis. Had familial screening and surveillance been initiated sooner in this family, this poor outcome may have been prevented.Conclusion:Our case highlights the important diagnostic dilemma that can arise in patients with VUSs in risk genes for hereditary pheochromocytomas and paragangliomas. While universally treating these VUSs as pathogenic would be costly, low-yield and potentially harmful, the incorporation of family history and tumour tissue staining for SDHB should be considered in all individuals with pheochromocytomas and paragangliomas to help guide interpretation of inconclusive genetic testing results, inform subsequent management and help predict risk for inheritance and recurrence.

Possible dual contribution of a novel GUCY2D mutation in the development of retinal degeneration in a consanguineous population

Molecular characterization of novel mutations in Leber Congenital Amaurosis (LCA) disease improves the disease diagnosis and contributes to the development of preventive and therapeutic approaches. We studied an isolated inbred population in Iran with a high prevalence of retinal degeneration with clinical variability. The clinical examinations were performed on eight patients belonging to three consanguineous families. The identical-by-descent (IBD) mapping technique was employed to identify the shared loci in patients. Subsequently, Sanger sequencing of the GUCY2D gene, in silico analysis, as well as segregation study were conducted. The whole-exome sequencing method was applied for negative cases of GUCY2D mutation, followed by segregation study in suspected variants among families. A novel deletion mutation in the GUCY2D gene can explain the emergence of LCA-1 in most patients but not all. Besides, a heterozygous variant of uncertain significance (VUS) was observed in the BEST1 gene in some healthy and participant patients. These results further support inter/intra-familial clinical heterogeneity in retinal dystrophy and suggest that screening the GUCY2D gene would be needed for the diagnosis of LCA in Iranian people living in the central regions. The variant in the BEST1 gene might be considered a benign heterozygous variant; however, we hypothesized a possible double heterozygosity in both GUCY2D and BEST1 genes that may cause the pathogenesis of cone-rod dystrophy-6 (CRD-6) disease. This would propose a new scenario for the pathogenesis of a monogenic disorder such as CRD-6 disease in which other genetic elements may be involved in the development of the disease.

SUN-270 Heterozygous Mutation in ABCC8 in a Pedigree with Congenital Hyperinsulinism, Multiple Macrosomic Stillbirths, and Adult-Onset Diabetes Mellitus

ABCC8 encodes the SUR-1 subunit of the ATP-sensitive potassium (K-ATP) channel on beta cells. Mutations in this gene are associated with K-ATP channel gain of function (diabetes mellitus) and loss of function (hyperinsulinism). We describe a family with a heterozygous variant of uncertain significance (VUS) in the ABCC8 gene that may be associated with both diabetes mellitus and congenital hyperinsulinism. A macrosomic boy (birth weight 3.86kg; >99th centile) was born to a mother with type 2 diabetes. On day 7 of life he was diagnosed with hyperinsulinism based on an insulin of 46.1mIU/L (2.6-24.9) and glucose of 2.2mmol/L. He responded to diazoxide and his hypoglycaemia appeared to resolve by 6 months old. The boy had an older half-sister who was also macrosomic at birth (>99th centile) and had diazoxide-responsive congenital hyperinsulinism which required treatment until two years of age. He also had an older brother who was stillborn with severe macrosomia at 36 weeks weighing 5.7kg (well above 99th centile). There was a family history of stillbirth of very macrosomic babies in five cases across two generations from three mothers. The boy’s mother was macrosomic and possibly hypoglycaemic as a neonate. She developed gestational diabetes in all of her pregnancies and diabetes at age 30 years. There is also adult-onset diabetes mellitus in the boy’s maternal grandmother, maternal great-aunt and maternal great-grandmother (diagnosed in the fourth or fifth decade). The cases of hyperinsulinism/foetal macrosomia and adult-onset diabetes follow an autosomal dominant pattern. Hyperinsulinism gene panel analysis revealed a heterozygous missense mutation in the ABCC8 gene (Ala1457Thr) in the boy, which was then found in his half-sister and mother. The VUS is in a highly conserved region of the SUR1 subunit and in-silico analysis tools suggest a deleterious effect. It has been reported in cases of hyperinsulinism (MacMullen 2011) and adult-onset diabetes mellitus (Ovsyannikova 2016), but never within the same pedigree. Genetic testing of other affected and unaffected family members is underway. This case suggests that a single heterozygous mutation (Ala1457Thr) in ABCC8, currently listed as VUS, may be responsible for both loss of function (hyperinsulinism) and gain of function (diabetes mellitus) of the K-ATP channel within a single pedigree. References MacMullen, C, Zhou, Q, Snider, E, Tewson, P, Becker, S, Aziz, A, Stanley, C. (2011). Diazoxide-Unresponsive Congenital Hyperinsulinism in Children With Dominant Mutations of the β-Cell Sulfonylurea Receptor SUR1. Diabetes, 60(6), 1797-1804. doi:10.2337/db10-1631 Ovsyannikova, A, Rymar, O, Shakhtshneider, E, Klimontov, V, Koroleva, E, Myakina, N, & Voevoda, M (2016). ABCC8 Related Maturity Onset Diabetes of the Young (MODY12) Clinical Features and Treatment Perspective. Diabetes Therapy, 7(3), 591-600. doi:10.1007/s13300-016-0192-9

SUN-373 Small Adrenal Incidentaloma Stable in Size Becoming a Stage IV Adrenocortical Carcinoma 10 Years Later in a Young Patient Carrying a Germline APC Variant of Uncertain Significance (VUS)

Recent guidelines on adrenal incidentalomas suggested that patients with an indeterminate adrenal mass on imaging choosing not to undergo adrenalectomy to repeat imaging with either unenhanced computed tomography (CT) or Magnetic resonance imaging with chemical shift analysis in 6 to 12 months. If the adrenal mass is non-functioning and stable in size, patients may not require any additional monitoring.We report here a case of a young woman known for a small adrenal mass, stable in size for 4 years who was ultimately diagnosed with a Stage IV adrenal cortical carcinoma (ACC) 10 years later. Case report. In 2006, a 32-year-old French Canadian woman was referred in endocrinology for evaluation of a left 2.7 x 2.0 cm incidentally discovered adrenal mass. On presentation, her hormonal work up included a normal 1mg overnight dexamethasone suppression test (DST) and dehydroepiandrosterone sulfate (DHEA-S) within normal limits. On unenhanced computed tomography (CT), the radiodensity of the adrenal mass was 23 Hounsfield units (HU). The patient was followed with adrenal imaging and hormonal investigation yearly for 4 years and the adrenal mass demonstrated no growth in 4 years. Ten years after initial presentation, in 2016, after five years lost to follow up the patient presented with renal colic. Urological CT has unexpectedly revealed that the left adrenal mass had significantly progressed measuring 9 x 8.2 cm and 2 new hepatic lesions were identified. Biochemical work up demonstrated hypercortisolism and hyperandrogenemia: plasma cortisol after 1 mg overnight DST was 486 nmol/L and DHEA-S was 14.0 mmol/L (N 0.9-6.5). Twenty-four-hour urine steroid profiling was consistent with an ACC co-secreting cortisol, androgens and glucocorticoid precursors. The diagnosis of ACC with hepatic ACC metastases was confirmed by histology. Following genetic analysis, germline heterozygous variant of uncertain significance (VUS) was identified in the exon 16 of the APC gene NM_000038.5:c.2414G>A,(p.Arg805Gln) (rs200593940). The patient had no clinical manifestations of familial adenomatous polyposis. Immunohistochemical staining of the ACC were positive for IGF-2 and cytoplasmic/nuclear β-catenin, however, no somatic APC or beta-catenin mutations were found. This case illustrates that 1) small adrenal incidentaloma stable in size may progress to ACC 2) better genetic characterization of these patients may eventually give clues to this unusual evolution.

ALPL mutations in adults with rheumatologic disorders and low serum alkaline phosphatase activity.

Tissue-nonspecific alkaline phosphatase (ALP), encoded by ALPL, is important for bone homeostasis and interacts with collagen type I. In the present study, we sequenced ALPL and a panel of collagen type I-related genes in 24 adults (age 22-80years; 20 female) with persistently low serum ALP (< 40 U/L) and a range of rheumatologic symptoms. We found heterozygous pathogenic or likely pathogenic variants in ALPL in 14 (58%) of these individuals. In addition, 7 study participants had potentially damaging heterozygous variants of uncertain significance in genes related to collagen type I. Patients who were positive for ALPL variants had similar age and serum ALP levels to patients in whom no ALPL variants were detected, but had higher serum pyridoxal-5-phosphate concentrations (median 214nmol/L vs. 64nmol/L; p = 0.02; U test). In summary, heterozygous ALPL variants are frequent in individuals with rheumatologic symptoms and low ALP serum activity. It is possible that variants in genes that are involved in collagen type I production have a modifying effect on the clinical consequences of such ALPL variants.

MISSENSE MUTATION IN NLRP12 ASSOCIATED WITH AN ATYPICAL PERIODIC FEVER SYNDROME

Introduction NLRP12 encodes for the protein NALP12, which regulates NF-Kβ activation. Mutations in this gene are associated with familial cold autoinflammatory syndrome type 2 (FCAS2), which presents with fever, joint pain, and urticarial rash upon exposure to cold temperatures. Few patients with NLRP12 related autoinflammatory disease have been identified, therefore there is little data on the phenotypic presentation of this syndrome. Case Description A 10-year-old African American boy presented to the ED with a 9-day history of fever and worsening stomatitis. Parents reported recurrent episodes of fever, oral ulcers, and joint pain lasting for 4-8 weeks. He was febrile, and exam demonstrated severe, hemorrhagic stomatitis. Labwork revealed elevated inflammatory markers. An extensive workup was negative. He was subsequently treated with methylprednisone and gradually improved. Sequencing showed a heterozygous variant of uncertain significance in NLRP12: c.193G>C (p.Gly65Arg). He was scheduled for outpatient evaluation but was lost to follow up. Several months later, he presented again to the ED with similar symptoms. As his clinical presentation and genetic testing made an NLRP12-associated autoinflammatory disorder likely, he was treated with anakinra. His symptoms dramatically improved within days. He was transitioned to prophylactic IL-1 blockade with canakinumab, which has prevented further attacks. Discussion This patient presented with episodes of fevers, stomatitis, and joint pain, which suggested an autoinflammatory syndrome. Genetic testing demonstrated a mutation in NLRP12, leading to successful treatment with IL-1 inhibition. This case expands the clinical phenotype of patients with NLRP12 mutations, as he lacked typical associated features of FCAS2. NLRP12 encodes for the protein NALP12, which regulates NF-Kβ activation. Mutations in this gene are associated with familial cold autoinflammatory syndrome type 2 (FCAS2), which presents with fever, joint pain, and urticarial rash upon exposure to cold temperatures. Few patients with NLRP12 related autoinflammatory disease have been identified, therefore there is little data on the phenotypic presentation of this syndrome. A 10-year-old African American boy presented to the ED with a 9-day history of fever and worsening stomatitis. Parents reported recurrent episodes of fever, oral ulcers, and joint pain lasting for 4-8 weeks. He was febrile, and exam demonstrated severe, hemorrhagic stomatitis. Labwork revealed elevated inflammatory markers. An extensive workup was negative. He was subsequently treated with methylprednisone and gradually improved. Sequencing showed a heterozygous variant of uncertain significance in NLRP12: c.193G>C (p.Gly65Arg). He was scheduled for outpatient evaluation but was lost to follow up. Several months later, he presented again to the ED with similar symptoms. As his clinical presentation and genetic testing made an NLRP12-associated autoinflammatory disorder likely, he was treated with anakinra. His symptoms dramatically improved within days. He was transitioned to prophylactic IL-1 blockade with canakinumab, which has prevented further attacks. This patient presented with episodes of fevers, stomatitis, and joint pain, which suggested an autoinflammatory syndrome. Genetic testing demonstrated a mutation in NLRP12, leading to successful treatment with IL-1 inhibition. This case expands the clinical phenotype of patients with NLRP12 mutations, as he lacked typical associated features of FCAS2.

EP04.33: Idiopathic intermittent dilated cardiomyopathy: in the fetal and the postnatal periods

Background: Transient fetal dilated cardiomyopathy (DCM) is associated to maternal chemotherapy treatment and fetal distress. We report here a case of transient intermittent fetal and neonatal cardiomyopathy unrelated to the above etiologies. Case description: A 28 y.o. G4P3 with gestational diabetes and chronic hypertension presented at 31 weeks gestation for a routine fetal growth scan. Maternal and fetal echocardiograms obtained at 24 weeks were both normal; however, fetal ultrasound at 31 weeks demonstrated marked cardiac dilation with ventricular wall thickening and globally depressed contractility. No hydrops was noted. The patient reported a viral illness two weeks prior to presentation, and serum Coxsackie B titers were elevated at 1:80. She was admitted to the inpatient service for betamethasone administration and monitoring, and discharged after serial echocardiograms demonstrated stable ventricular dilation with improved contractility. The patient underwent Caesarean delivery at term, with delivery of a vigorous 2860g female infant. Postnatal echocardiogram demonstrated only mild right-sided dilation and mildly decreased systolic function. On the fourth day of life, however, the infant was readmitted to the intensive care unit with heart failure. Labs were notable for NT pro-BNP of 614 and CK of 207, negative Coxsackie titers, and a negative workup for metabolic storage disease. Genetic testing demonstrated two heterozygous variants of uncertain significance in MYH7 and DSG2. The infant's cardiac status improved and she was subsequently discharged on digoxin and captopril. At 4 months, the infant was developing appropriately. Conclusion: To our knowledge, this is the first case of fetal DCM with antenatal improvement, followed by exacerbation in the postnatal period, which may be related to MYH7 and DSG2 variants or possible genetic susceptibility to viral cardiomyopathy.

EP04.30: Fetal dilated cardiomyopathy: genetic susceptibility?

Fetal dilated cardiomyopathy (DCM) may occur as the end result of both intrinsic and extrinsic cardiac disease. We present a novel case associated with two MYH7 and DSG2 gene variants in the setting of maternal Coxsackie seropositivity. A 28 year old G4P3 with chronic hypertension presented at 31 weeks gestation for a routine growth scan. Her fetal echocardiogram at 24 weeks gestation was normal; however, repeat ultrasound demonstrated biventricular dilation, wall thickening and poor contractility (figure 1), but no hydrops. The patient reported a viral illness two weeks prior to presentation, and serum Coxsackie B titers were highly positive at 1:80. She was admitted for betamethasone administration and discharged after serial echocardiograms demonstrated stable ventricular dilation and improved function. She underwent Caesarean delivery at term for a vigorous 2860g female infant. Postnatal echo demonstrated mild right-sided dilation and low normal systolic function; however, on the fourth day of life the infant was readmitted with heart failure. Labs were notable for NT pro-BNP 614, CK 207, negative Coxsackie titers, negative metabolic panel, and two heterozygous variants of uncertain significance in MYH7 and DSG2 on microarray. The infant was started on digoxin therapy and at 4 months was developing appropriately. Supporting information can be found in the online version of this abstract Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.