Congenital erythropoietic porphyria: A case series of a rare uroporphyrinogen III synthase gene mutation in Nepalese patients

Abstract BACKGROUND Prevalence of MODY is 1.2% in pediatric diabetes population. SEARCH study reported most of these patients were misdiagnosed as T1DM or T2DM up to 36% and 51% respectively (1). GCK (MODY 2) and HNF1A/HNF4A (MODY3) are the most common forms of MODY. Despite improvement in testing strategy (panel testing instead of step-wise approach) and cost, MODY testing remains underutilized. These conditions do not require insulin therapy, and MODY 2 patients may even be discharged from clinic after diagnosis. We present 4 cases and valuable lessons learned. MODY 2 Case 1. 4 yo M referred for hyperglycemia in the 300s during surgery. A1c 6.4%. FBG at home 150s, asymptomatic. MGM and MGM’s siblings have diabetes. Diabetes autoantibodies (DAA) negative. C-peptide 5.4 (NL 0.78 - 5.19 ng/ml). MODY panel (GeneDx) showed heterozygous mutation in GCK gene (c.70 C>T). Patient remains off insulin, family reassured and advised to undergo genetic testing. MODY 2 Case 2. 8 yo M diagnosed at local ED with “T1DM” after presenting with polyuria, polydipsia, and random BG 237. A1c 6.7%, C-peptide 1.9, started on basal-bolus insulin. MODY panel (sent a year later when patient was found to have low insulin requirement, negative DAA) showed pathogenic variant in GCK gene. Weaned from insulin, A1c unchanged (6.3–7%). Mother found to have same mutation. MODY 3 Case 1. 16 yo F referred by PCP who started her on insulin a year prior after an incidental finding of hyperglycemia. A1c was 7.5% at diagnosis. Mom, MGM have diabetes, unknown type (MGM thin by report). DAA neg, C-Peptide 1.74. MODY Panel showed HNF1A heterozygous gene mutation for RI31Q. She was switched to Glyburide, blood glucose 90s. MODY 3 Case 2. 10 yo M referred from the ED for “T1DM” (weight loss, fatigue, A1c 7.6%) started on basal-bolus insulin, but lost to follow up for a year. Brother has MODY 3. DAA neg, C-Peptide 3.1. Targeted gene sequencing showed HNF1A gene mutation. He was switched to Glyburide, A1c improved to 6.7%. However, patient became noncompliant as teenager, A1c now 9.3%. CONCLUSION MODY remains underdiagnosed. A high index of suspicion should be maintained in nonobese, DAA-negative patients diagnosed with DM before 25yo. Although DAA and genetic testing can be costly, diagnosis can dramatically alter diabetes management as illustrated in all 4 cases, and overall cost of management may be lower in the end. Patients with MODY 2 do not develop vascular complications associated with diabetes, nor require pharmacotherapy. MODY 3 patients may be safely switched to sulfonylurea monotherapy, though degree of diabetes control depends on compliance with medication. Testing gives relatives previously misdiagnosed the opportunity to improve their own quality of life. More education for health care providers is warranted for prompt diagnosis and appropriate management of this condition. Reference:1. Pihoker, et al. JCEM 2013; 98:4055–62

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A case series of three patients presenting with isoniazid induced toxicity and N-acetyl transferase 2 gene mutation: A management conundrum for programmatic therapy of tuberculosis in India

Indian Journal of Tuberculosis ◽

10.1016/j.ijtb.2020.01.005 ◽

2020 ◽

Vol 67 (3) ◽

pp. 407-410 ◽

Cited By ~ 1

Author(s):

Parvan Shetty ◽

Falguni Panchal ◽

Renuka Munshi ◽

Uma Sundar ◽

Pramod Darole

Keyword(s):

Gene Mutation ◽

Case Series

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CBIO-18. TP53-MUTANT OLIGODENDROGLIOMA: A SINGLE INSTITUTION CASE SERIES

Neuro-Oncology ◽

10.1093/neuonc/noab196.118 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi30-vi31

Author(s):

Mason Webb ◽

Sani Kizilbash ◽

Thomas Kollmeyer ◽

Robert Jenkins ◽

Sarah Sung ◽

...

Keyword(s):

Gene Mutation ◽

Tp53 Mutation ◽

Case Series ◽

Molecular Testing ◽

Diffuse Glioma ◽

Who Grade ◽

Tp53 Mutations ◽

Grade Ii ◽

Who Grade Iii ◽

Grade Iii

Abstract TP53 mutations are frequent in IDH-mutant astrocytomas but unusual in oligodendroglioma and the clinical significance of TP53 mutations in oligodendroglioma are not well characterized. We reviewed genetically defined oligodendroglioma (i.e., IDH-mutant, whole-arm 1p/19q-codeleted diffuse glioma) cases that were molecularly profiled (2017-2020) at our institution and identified 7 cases with TP53 mutation (9%; n=76). Molecular testing was performed using targeted neuro-oncology NGS panel (50-gene mutation and/or 187-gene mutation/rearrangement) and OncoScan™ microarray. Four (of 7) patients were female. Median age at diagnosis was 43 years (range, 23-63). Most common presenting symptom was seizures (3 of 7). All tumors were supratentorial. Histologically, 3 tumors were WHO grade II and 4 were WHO grade III. Two (of 3) patients with a WHO grade II tumor underwent biopsy and radiotherapy at diagnosis followed by temozolomide at recurrence (progression at 67 and 157 months after diagnosis; overall survival of 124 and 201 months). Three (of 4) patients with a WHO grade III tumor were diagnosed within the last two years and are currently progression-free after standard therapy. Molecularly, in addition to TP53 mutation(s), all cases had an IDH1 and TERT promoter mutation as well as other gene mutation(s) including FUBP1 (n=5), SETD2 (n=4), PIK3R1 (n=4), PIK3CA (n=3), NF1 (n=3) and CIC (n=3). In 3 (of 7) cases, the mutational profile with high mutation count enriched for C >T/G >A transitions was highly suggestive of a hypermutation phenotype (2 cases were recurrent tumors treated with temozolomide; a recurrent and a treatment-naïve tumor had mismatch repair gene mutation). Five (of 7) cases, including the 3 hypermutant cases, lacked functional TP53 (1 case with 2 mutations, 2 cases with 1 mutation plus loss of other copy, 2 cases with 1 mutation plus copy neutral loss-of-heterozygosity). TP53 mutations are uncommon in oligodendroglioma and appear enriched in hypermutant tumors.

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Time to decide about risk-reducing mastectomy: A case series of BRCA1/2 gene mutation carriers

BMC Women s Health ◽

10.1186/1472-6874-7-3 ◽

2007 ◽

Vol 7 (1) ◽

Cited By ~ 13

Author(s):

Mary McCullum ◽

Joan L Bottorff ◽

Mary Kelly ◽

Stephanie A Kieffer ◽

Lynda G Balneaves

Keyword(s):

Gene Mutation ◽

Case Series ◽

Mutation Carriers ◽

Risk Reducing

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Nivolumab use for BRCA gene mutation carriers with recurrent epithelial ovarian cancer: A case series

Gynecologic Oncology ◽

10.1016/j.ygyno.2019.03.230 ◽

2019 ◽

Vol 154 (1) ◽

pp. e29 ◽

Cited By ~ 1

Author(s):

S. Spragg ◽

M. Ciccone ◽

E. Blake ◽

C. Ricker ◽

H. Pham ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Gene Mutation ◽

Case Series ◽

Brca Gene ◽

Mutation Carriers ◽

Brca Gene Mutation

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Siblings with Rare Hemophilia a Genetic Mutation and Normal Factor VIII Levels

Blood ◽

10.1182/blood-2018-99-117614 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5009-5009

Author(s):

Oluwaseun Olaiya ◽

Sana Farooki ◽

Shannon L Carpenter

Keyword(s):

Genetic Testing ◽

Factor Viii ◽

Gene Mutation ◽

Von Willebrand Factor ◽

Hemophilia A ◽

Case Series ◽

Factor Viii Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen

Abstract BACKGROUND Hemophilia A is an X-linked inherited disorder which affects 1 in 5,000 males and is caused by mutations in the factor VIII (FVIII) gene. Hemophilia is typically diagnosed by measurement of FVIII procoagulant (FVIII:C) activity. Molecular genetic testing of the FVIII gene identifies pathogenic variants in as many as 98% of individuals with hemophilia A. The specific genetic test performed varies and must take into account the severity of hemophilia and the gene affected. Hemophilia A families with severe disease may have genetic analysis for intron 22 and intron 1 mutation performed followed by DNA sequencing if intron analysis is uninformative. Families with mild to moderate disease often need upfront gene sequencing for diagnosis. OBJECTIVE To describe a case series of siblings with FVIII gene mutation having normal Factor VIII activity levels, with grandfather found to have similar gene mutation DESIGN/METHOD: Case Series RESULTS Case 1 An 8 year old boy with presumed Von Willebrand disease (VWD) was seen in our clinic for evaluation for bleeding disorders. Testing prior to being seen in clinic showed Factor VIII level of 37%, Von Willebrand factor activity of 53% and Von Willebrand factor antigen of 103%. He had post-operative hemorrhage after tonsillectomy and adenoidectomy at 3 years of age, as well as frequent epistaxis. Family history was significant for sibling with epistaxis, a maternal grandfather with VWD and sister with menorrhagia. Subsequently, his maternal grandfather was found to have mild hemophilia A based on genetic testing which brought into question the child's diagnosis of mild Type 1 VWD. Repeat testing showed Factor VIII 64%, Von Willebrand factor antigen 126% and Ristocetin cofactor activity 93%. Genetic testing revealed he was hemizygous for the pathogenic variant, c.1621A>T (p.Thr541Ser), in the FVIII gene. He is doing well with normal Factor VIII levels, without significant bleeding episodes and remains on DDAVP as needed. Case 2 A 7 year old boy with presumed history of type 1 VWD was seen in our clinic for evaluation for a bleeding disorder. He had a history of cephalohematoma after skull fracture, as well as frequent epistaxis. Testing prior to being seen in our clinic showed Von Willebrand factor antigen of 87%, Von Willebrand factor activity of 69%, and Factor VIII activity of 32%. Family history was as reported for his sibling (Case 1). In our clinic, he had genetic testing performed that was not consistent with VWD Type 2N (Normandy phenotype). Repeat labs in our clinic showed Von Willebrand factor antigen of 100%, Von Willebrand factor activity of 92%, and Factor VIII activity of 50%. He was treated with Von Willebrand factor replacement prior to planned foot surgery as well as DDAVP. Subsequent to identification of a FVIII gene mutation in his maternal grandfather and brother, testing revealed he was hemizygous for the same mutation detailed in Case 1. He is doing well with normal Factor VIII levels, no significant bleeding and remains on DDAVP as needed for bleeding. CONCLUSION The c.1621A>T (p.Thr541Ser) variant which occurs in exon 11 of the FVIII gene, has been is known to cause mild hemophilia A. The Thr541Ser substitution is rare and is present in ~0.009% of the NHLBI exome sequencing project. This is a unique case series of siblings with a rare mutation having normal Factor VIII levels and grandfather with similar mutation who was eventually also diagnosed with mild hemophilia A. The underlying gene mutation is an important but not sole determinant of residual FVIII:C in hemophilia A patients. As our understanding of pathophysiologic process of causative genetic event and baseline FVIII:C in patients is limited, this case series highlights the current diagnostic challenges in the mild Hemophilia A population and the importance of appropriate diagnostic techniques to avoid delayed diagnosis. Correct identification of mutations also provides the opportunity to define molecular consequences and identify residues important for factor VIII activity. Disclosures Carpenter: Bayer: Honoraria; Kedrion Biopharmaceuticals: Consultancy; Nationwide Children's Hospital: Speakers Bureau; Kane County State's Attorney: Consultancy; 4th Judicial District Attorney's Office- Colorado: Consultancy; Kedrion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Consultancy; CSL Behring: Speakers Bureau; National Hemophilia Foundation (Impact Education): Speakers Bureau; Genentech Incorporated: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk Pharmaceuticals, Inc: Consultancy; Novo Nordisk: Consultancy.

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A case series of Lynch syndrome-associated breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.432 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 432-432

Author(s):

Kevin M. Zbuk ◽

Mira Goldberg ◽

Kathleen Bell ◽

Kara Semotiuk ◽

Steven Gallinger ◽

...

Keyword(s):

Breast Cancer ◽

Lynch Syndrome ◽

Gene Mutation ◽

Cancer Registry ◽

Familial Cancer ◽

Case Series ◽

High Grade ◽

Cutaneous Manifestations ◽

Amsterdam Criteria ◽

Chi Squared

432 Background: Studies suggest breast cancer (BC) might be a feature of Lynch syndrome (LS). Further characterization of this risk is required before recommending increased surveillance for BC in LS families. This study describes the prevalence and characteristics of BC amongst LS families in a large familial cancer registry. Methods: The pedigrees of 325 families carrying an MMR gene mutation (149 MSH2 46%, 113 MLH1 35%, 38 MSH6 12%, 19 PMS2 5%, and 6 EPCAM 2%) within the Familial Gastrointestinal Cancer Registry (FGICR) were screened for a diagnosis of BC. The analysis was limited to known or obligate carriers of a MMR gene mutation. The diagnosis and age of diagnosis of BC was confirmed utilizing clinic records and pathology reports where available. Descriptive and Chi-squared statistics were utilized. Results: 39 female mutation carriers from 33 unrelated families with a diagnosis of BC were identified. The average age of BC diagnosis was 53y. The vast majority of families (25/33, 76%) carried MSH2 mutations. Of the 8 remaining families there were 6 (18%) MLH1 carriers, 1 (2.5%) MSH6 carrier, and 1 PMS2 carrier. The mutation distribution amongst the LS patients with BC was statistically different from those without BC (p = 0.008), reflecting the predominance of MSH2 mutations amongst patients with BC. Twenty-nine of 33 LS families with BC met Amsterdam Criteria (88%), compared with 142 of 292 LS families without BC in a known carrier (48%) (p = 0.03). LS associated BCs tended to be high grade (10 of 19 were grade 3), and 50% were ER/PR/Her2 negative. Additional manifestations in patients with BC included 9 women with colorectal cancer, 4 with multiple (2-4) colorectal cancers, 20 with endometrial cancer, 7 with cutaneous manifestations of LS, and 5 with genitourinary cancers. The mean number of additional LS related manifestations for these patients with BC was 1.5 (range 0-8) per patient. Conclusions: Within the registry utilized in this study, LS associated BC is strongly associated with MSH2 mutation status. Most patients with LS associated BC harbored multiple manifestations of LS, and their families almost always met Amsterdam criteria. LS associated BC was frequently high grade and often hormone receptor negative, suggesting an aggressive histology.

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