A 5-year-old Chinese boy with mild symptoms despite severe congenital factor VII deficiency: A case report

Abstract

Congenital factor VII deficiency is a rare autosomal recessive bleeding disorder characterized by markedly heterogeneous clinical phenotypes and reduced plasma factor VII activity. We present the 5-year-old Chinese boy who exhibited only mild intermittent epistaxis despite a factor VII:C level of 1.5% and compound heterozygous missense mutations in the F7 gene, c.722C>A (p.T241N) and c.1165T>G (p.C389G). Notably, no gastrointestinal, intracranial, or joint hemorrhages occurred. Bleeding symptoms were effectively controlled using fresh frozen plasma followed by recombinant activated factor VII. This case highlights the discordance between biochemical severity and clinical phenotype in factor VII deficiency and underscores the importance of early coagulation testing and molecular diagnosis in pediatric patients with unexplained mucosal bleeding.

Introduction

Congenital factor VII deficiency (FVIID) is a rare autosomal recessive bleeding disorder caused by mutations in the F7 gene, with an estimated prevalence of 1 in 500,000.^1–3 As one of the mildest forms of rare coagulation factor deficiencies, approximately 54.7% of the affected individuals remain asymptomatic. Meanwhile, 38.4% of the patients exhibit mild spontaneous bleeding or posttraumatic bleeding, which may manifest as gingival bleeding, epistaxis, skin and mucosal ecchymosis, menorrhagia, or persistent posttraumatic bleeding. Furthermore, 6.9% of the individuals with FVIID may experience severe and potentially life-threatening hemorrhagic events, such as gastrointestinal bleeding, intracranial hemorrhage, and hemarthrosis.^4,5 The International Society on Thrombosis and Haemostasis currently classifies FVIID based on the following FVII activity levels: 1. values below 10% indicate a high risk of spontaneous major bleeding; 2. levels between 10% and 20% represent moderate deficiency, associated with mild spontaneous or provoked bleeding; and 3. levels between 20% and 50% are considered mild deficiency, typically presenting with an asymptomatic course. ⁶ Although FVII activity levels are closely associated with bleeding severity in certain coagulation disorders, such as FXIII or FX deficiency, this association is not significant in the context of FVIID.^4,7 As a result, paradoxical clinical scenarios may occur, wherein patients present with only mild or even occult bleeding symptoms despite profoundly reduced FVII:C levels. Moreover, because of the mild or absent nature of symptoms, profoundly low FVII:C levels may be overlooked by both patients and healthcare providers, potentially delaying diagnosis and management and increasing the risk of serious complications, including intracranial hemorrhage, massive gastrointestinal bleeding, and hemarthrosis with subsequent joint damage. Furthermore, patients harboring homozygous or compound heterozygous mutations tend to have lower circulating FVII activity and a higher risk of severe bleeding.^6,8 This case report describes a 5-year-old boy who presented with recurrent mild epistaxis that had been overlooked and inadequately managed for an extended period. He was ultimately diagnosed with FVIID through coagulation function screening and genetic testing. His FVII:C level was only 1.5%, and genetic analysis identified compound heterozygous missense mutations in the F7 gene: c.722C>A (p.T241N) in exon 8 and c.1165T>G (p.C389G) in exon 9.

Case report

A boy aged 5 years and 3 months was admitted to the People’s Hospital of Quzhou in January 2024 with a 1-year history of mild intermittent epistaxis. He experienced up to three episodes of epistaxis per day, each lasting 3–10 min. The patient had no history of malignancy, hepatic or immune disorders, trauma, surgery, radiotherapy, medication use, or blood transfusion. His twin brother and both parents exhibited no symptoms of bleeding. He had been diagnosed with rhinitis at another hospital due to the epistaxis and received symptomatic therapy—including short‑course intranasal vasoconstrictor/decongestant drops and oral antihistamines—but the bleeding did not improve. Initial coagulation testing upon admission revealed the following: prothrombin time (PT), 45.3 s (normal: 10–14 s); international normalized ratio (INR), 4.34 (normal: 0.8–1.5); activated partial thromboplastin time (APTT), 26.6 s (normal: 20–40 s); fibrinogen, 2.64 g/L (normal: 2–4 g/L); TT, 20.4 s (normal: 11–14 s); and D-dimer, 0.11 mg/L (normal: 0–0.55 mg/L). No signs of bleeding were observed in common sites such as the head and digestive tract. The markedly prolonged PT with a normal APTT suggested a defect in the extrinsic coagulation pathway. To manage the bleeding, fresh frozen plasma (10–15 mL/kg per dose, once daily) was initially administered via intravenous infusion, followed by further testing of coagulation factor activity. The results revealed that the FVII:C level was 1.5%, which is considerably below the normal reference range. Taking into account the medical history and laboratory findings, the preliminary diagnosis was FVIID. To further elucidate the cause and determine whether the deficiency was congenital, F7 gene testing was conducted. Genetic analysis revealed compound heterozygous mutations in the F7 gene, c.1165T>G (p.C389G) in exon 9 and c.722C>A (p.T241N) in exon 8. ⁹ The final diagnosis confirmed FVIID. The child subsequently received treatment with fresh frozen plasma (10 mL/kg per dose, once daily) in conjunction with recombinant factor VIIa (rFVIIa, 30 µg/kg every 6 h), followed by rFVIIa monotherapy. During the treatment course, the child’s PT gradually improved, nasal bleeding ceased, no new bleeding events occurred, and his condition remained stable. Coagulation parameters at initial admission and prior to discharge are presented in Table 1. The PT and INR during treatment are illustrated in Figure 1.

Table 1.

Coagulation parameters at admission and discharge in the patient with FVIID.

Test	Result at admission	Result at discharge	Reference	Unit
PT	45.3(↑)	13.1	10–14	S
APTT	26.6	28.2	20–40	S
TT	20.4(↑)	15.8	11–14	S
Fib	2.64	3.1	2–4	g/L
D-dimer	0.11	0.1	0–0.55	mg/L
INR	4.34(↑)	1.23	0.8–1.5	–
II	108	108.2	70–120	%
VII	1.5(↓)	42(↓)	70–120	%
X	114.8	110	70–120	%
VIII	132.4	125.3	70–150	%
IX	128(↑)	118.8	70–120	%
XI	124.6(↑)	116.5	70–120	%
ALT	10.2	15.8	9–50	U/L
AST	18.6	21.2	15–40	U/L
PLT	184	215	125–350	109/L

II: blood coagulation factor II; VII: blood coagulation factor VII; VIII: blood coagulation factor VIII; IX: blood coagulation factor IX; X: blood coagulation factor X; XI: blood coagulation factor XI; ALT: alanine transaminase; APTT: activated partial thrombin time; AST: aspartate aminotransferase; Fib: fibrinogen; MPV: mean platelet volume; PLT: platelet count; PT: prothrombin time; TT: thrombin time; FVIID: congenital factor VII deficiency.

Figure 1.

Dynamic changes in PT and INR during hospitalization in response to key treatment interventions for congenital factor VII deficiency. INR: international normalized ratio; PT: prothrombin time.

Discussion

This case illustrates a rare instance of FVIID caused by compound heterozygous mutations. The patient initially presented with mild epistaxis, which remained undiagnosed for an extended period. The striking discrepancy between the extremely low FVII:C level and the relatively mild bleeding phenotype underscores the well-documented clinical heterogeneity of FVIID. This case further illustrates the diagnostic challenges associated with FVIID, especially when clinical symptoms are subtle or nonspecific. Timely coagulation screening and subsequent genetic testing proved essential for establishing a definitive diagnosis and guiding effective therapy.

The F7 gene is located on the long arm of chromosome 13 (13q34) and comprises nine exons and eight introns, spanning a genomic region of 12.8 kb.^10,11 As of 2021, the European Association for Haemophilia and Allied Disorders database had documented 271 pathogenic variants in the F7 gene, including missense, nonsense, splice-site, insertion/deletion, and large-fragment deletions, which are widely distributed across the coding region. Among these, missense mutations are the most common.^9,12 The extensive diversity of F7 gene variants partially accounts for the high heterogeneity of the FVIID phenotype and the complexities associated with clinical diagnosis. Although accurate prediction of bleeding severity from genotype remains challenging, clinical severity shows a more consistent association with zygosity: individuals with homozygous or compound heterozygous F7 variants are more likely to experience severe or spontaneous bleeding, whereas simple heterozygotes generally present with mild symptoms or are asymptomatic. Simultaneously, approximately 50% of individuals with homozygous or compound heterozygous F7 mutations exhibit FVII:C levels below 10%, compared with only 7% among those with heterozygous variants. A study investigated the relationship between the clinical phenotype, F7 genotype, and FVII:C levels in 193 patients with FVIID registered in China. ² Of these patients, 55 underwent genetic testing, which revealed that missense mutations were the most prevalent, accounting for 62.5% of cases, with compound heterozygous mutations constituting 74.5% of these mutations. Notably, although severe bleeding events—such as gastrointestinal bleeding, intracranial hemorrhage, and hemarthrosis—were observed exclusively in patients with severe FVII:C deficiency (≤10%), some individuals with extremely low FVII:C levels (approaching 0%) exhibited only mild or asymptomatic bleeding. Furthermore, both compound heterozygous and homozygous mutations were significantly associated with reduced FVII:C levels. These findings reflect the complex interplay between genetic variation, coagulation activity, and clinical phenotype. Consequently, future research should focus on systematic association analyses among mutation types, FVII activity, and clinical manifestations, which are essential for elucidating the pathogenesis of the disease and explaining its high phenotypic heterogeneity.

This study reports a rare case in which the FVII:C level of the child was almost zero and the clinical manifestations were limited to mild intermittent epistaxis, with the characteristic asymmetry of “biochemically severe but clinically mild” conditions. Similar phenomena have been documented in other populations. For instance, a multicenter study involving Japanese patients with FVIID treated with rFVIIa indicated that among high-risk patients exhibiting FVII:C levels below 10%, only 4.8% presented with epistaxis as the initial symptom. ¹³ Therefore, the authors contend that early coagulation function screening and molecular diagnosis in children with recurrent bleeding are essential for clinical evaluation and management to avoid delayed diagnosis and treatment in cases with concealed symptoms.

This case report has several limitations. This case report presents a single pediatric patient with FVIID; therefore, its findings may not be generalizable to all patients with similar genotypes or FVII:C levels. The observed discordance between biochemical severity and clinical phenotype highlights a critical area of clinical heterogeneity; however, the underlying molecular mechanisms remain unclear, warranting further investigation. Furthermore, longitudinal follow-up and the inclusion of additional cases are essential to validate these observations, enhance the understanding of genotype–phenotype correlations in FVIID, and explore more reliable predictors of recurrent bleeding in affected patients.

Conclusion

In summary, this case describes a pediatric patient with FVIID resulting from compound heterozygous F7 mutations and significantly reduced FVII:C levels. Despite the biochemical severity, the patient only experienced mild intermittent epistaxis. This clinical–biochemical discordance underscores the limited predictive value of FVII:C alone. Early coagulation screening and genetic testing are essential for accurate diagnosis, and further studies are necessary to refine genotype–phenotype correlations and assess bleeding risk.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251380009 - Supplemental material for A 5-year-old Chinese boy with mild symptoms despite severe congenital factor VII deficiency: A case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605251380009 for A 5-year-old Chinese boy with mild symptoms despite severe congenital factor VII deficiency: A case report by Wei Luo, Rong Jiang, Hongyu Jiang and Min Gong in Journal of International Medical Research