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Presentation Details
| Combined Factor V and Factor VIII Deficiency Associated With Compound Heterozygous LMAN1 Variants: A Case Report Rida Haider 1, 2, Natalie Montanez1, 3, Joanna Larson1, 3, Harish Eswaran1, 4, Miguel Escobar1, 4. 1Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA.2University of Texas Health Science Center of Houston, McGovern Medical School, Department of Pediatrics, Division of Medical Genetics, Houston, TX, USA.3University of Texas Health Science Center of Houston, McGovern Medical School, Department of Pediatrics, Division of Hematology, Houston, TX, USA.4University of Texas Health Science Center of Houston, McGovern Medical School, Department of Pediatrics and Internal Medicine, Division of Hematology, Houston, TX, USA |
Abstract
Background:
Combined Factor V and Factor VIII Deficiency (CF5F8D) is a rare autosomal recessive bleeding disorder with reductions in factors V (FV) and VIII (FVIII), most commonly caused by biallelic variants in LMAN1 or MCFD2 (Type I familial combined factor deficiency). Clinical severity is typically mild-to-moderate but may vary. Recognition of genotype–phenotype relationships may guide diagnosis and management. Objectives:
To describe the clinical features, diagnostic evaluation, and genetic findings of a patient with CF5F8D due to compound heterozygous LMAN1 variants, including a novel deletion, and to contribute to the limited literature on bleeding manifestations in this disorder. Methods:
Clinical records, bleeding history, obstetric and procedural outcomes, coagulation studies, and genetic testing results were reviewed for a 31-year-old woman with confirmed CF5F8D. Baseline FV and FVIII activity (FV:C, FVIII:C) were measured using standard one-stage and chromogenic assays. Genetic testing was pursued due to persistently low FV and FVIII levels without alternative explanation, consistent with suspected Type I familial combined deficiency. Results:
The patient was diagnosed in childhood following prolonged oral bleeding with deciduous tooth loss. Genetic testing confirming compound heterozygous LMAN1 variants: a pathogenic nonsense variant (LMAN1 c.241C>T; p.Arg81*) and a novel intragenic 1.14 kb deletion, both predicted to result in loss of function. Baseline factor levels were FV:C 16%, one-stage FVIII:C 27%, chromogenic FVIII:C 53%. Her ISTH-BAT score was 7, consistent with clinically significant but non-severe bleeding phenotype. Bleeding manifestations were mild to moderate, including easy bruising, recurrent epistaxis, and heavy menstrual bleeding, with one acute episode managed with FFP and DDAVP. Obstetric history included a vaginal delivery supported by FVIII replacement and FFP, with three weeks of postpartum FVIII therapy without major hemorrhage. Procedural bleeding has been well-controlled; DDAVP prophylaxis was effective for dental extraction. She has no history of hemarthrosis, intramuscular hematomas, spontaneous deep-tissue bleeding, or need for long-term prophylactic therapy. Overall, her phenotype aligns with expected LMAN1-related CF5F8D, in which factor levels typically range from 5–30% and bleeding is primarily mucocutaneous. Conclusions:
This case illustrates a classic presentation of CF5F8D associated with compound heterozygous LMAN1 variants, including a truncating mutation and a large deletion. Despite significantly reduced FV and FVIII levels, the patient’s bleeding manifestations remain limited to mucocutaneous events, highlighting the variable but often mild clinical phenotype of this of Type I familial combined factor deficiency. Recognition of CF5F8D facilitates perioperative planning, individualized hemostatic management, and genetic counseling. This case contributes to the growing evidence regarding genotype–phenotype data for LMAN1-related combined factor deficiencies and underscores the importance of genetic testing in the evaluation of atypical coagulation profiles.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
Combined Factor V and Factor VIII Deficiency (CF5F8D) is a rare autosomal recessive bleeding disorder with reductions in factors V (FV) and VIII (FVIII), most commonly caused by biallelic variants in LMAN1 or MCFD2 (Type I familial combined factor deficiency). Clinical severity is typically mild-to-moderate but may vary. Recognition of genotype–phenotype relationships may guide diagnosis and management. Objectives:
To describe the clinical features, diagnostic evaluation, and genetic findings of a patient with CF5F8D due to compound heterozygous LMAN1 variants, including a novel deletion, and to contribute to the limited literature on bleeding manifestations in this disorder. Methods:
Clinical records, bleeding history, obstetric and procedural outcomes, coagulation studies, and genetic testing results were reviewed for a 31-year-old woman with confirmed CF5F8D. Baseline FV and FVIII activity (FV:C, FVIII:C) were measured using standard one-stage and chromogenic assays. Genetic testing was pursued due to persistently low FV and FVIII levels without alternative explanation, consistent with suspected Type I familial combined deficiency. Results:
The patient was diagnosed in childhood following prolonged oral bleeding with deciduous tooth loss. Genetic testing confirming compound heterozygous LMAN1 variants: a pathogenic nonsense variant (LMAN1 c.241C>T; p.Arg81*) and a novel intragenic 1.14 kb deletion, both predicted to result in loss of function. Baseline factor levels were FV:C 16%, one-stage FVIII:C 27%, chromogenic FVIII:C 53%. Her ISTH-BAT score was 7, consistent with clinically significant but non-severe bleeding phenotype. Bleeding manifestations were mild to moderate, including easy bruising, recurrent epistaxis, and heavy menstrual bleeding, with one acute episode managed with FFP and DDAVP. Obstetric history included a vaginal delivery supported by FVIII replacement and FFP, with three weeks of postpartum FVIII therapy without major hemorrhage. Procedural bleeding has been well-controlled; DDAVP prophylaxis was effective for dental extraction. She has no history of hemarthrosis, intramuscular hematomas, spontaneous deep-tissue bleeding, or need for long-term prophylactic therapy. Overall, her phenotype aligns with expected LMAN1-related CF5F8D, in which factor levels typically range from 5–30% and bleeding is primarily mucocutaneous. Conclusions:
This case illustrates a classic presentation of CF5F8D associated with compound heterozygous LMAN1 variants, including a truncating mutation and a large deletion. Despite significantly reduced FV and FVIII levels, the patient’s bleeding manifestations remain limited to mucocutaneous events, highlighting the variable but often mild clinical phenotype of this of Type I familial combined factor deficiency. Recognition of CF5F8D facilitates perioperative planning, individualized hemostatic management, and genetic counseling. This case contributes to the growing evidence regarding genotype–phenotype data for LMAN1-related combined factor deficiencies and underscores the importance of genetic testing in the evaluation of atypical coagulation profiles.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.