OBJECTIVE Penetrance, predictive value and female patients' perspectives on genetic testing were evaluated among Finnish patients with acute porphyria. We conducted a retrospective study to evaluate prognosis among at-risk female family members depending on the primary method of diagnosis. METHODS The penetrance was calculated among 23 genetically heterogeneous families selected from the Finnish porphyria registry (n = 515, AIP 333; VP 182). We included kindreds with ≥9 patients in a family (range 9-23 patients, total 216 AIP; 129 VP). In 2015, the registry included 164 living female subjects between 14 and 85 years of age. A questionnaire was sent to 143 women, of whom 107 (75%, AIP 67; VP 40) replied. Female at-risk relatives (AIP 54; VP 30) were divided into two groups based on the primary method of diagnosis: mutation analysis (Group A, n = 40) or biochemical analysis (Group B, n = 44). RESULTS Mean penetrance for all acute symptoms was 35% among AIP and 40% among VP families. In both study groups, the penetrance was higher among female (AIP 50%; VP 44%) than male patients (AIP 17%; VP 33%). Penetrance for hospitalized attacks was 30% among AIP families (range 10-80%, for women 41%) and 25% in VP (range 0-50%, for women 27%) demonstrating wide variations among families even with the similar genotype. Acute porphyria was diagnosed at the median age of 26 years (range 0-76 years) among female patients, commonly after the onset of acute symptoms. Diagnostic delay was an average of 7.4 years (range 1-30 years). Acute symptoms occurred at the median age of 24 years (range 10-57 years) and the first hospitalization at the median age of 26.5 years (range 15-57 years). At the onset of symptoms, 38% of the women were ≤ 20 years of age. According to the life table analysis, acute attacks occurred mainly during the following five years after the diagnosis and the attack risk diminished after 35 years of age. The annual risk for hospitalization due to an acute attack during fertile years was lower in Group A than Group B (0.002 vs. 0.010, p = .018), but the risk of all subsequent acute symptoms did not diminish (Group A 0.017 vs. Group B 0.019, p = .640). The cumulative risk of acute symptoms among asymptomatic patients at the time of diagnosis was 26.7% for Group A and 58.3% for Group B. The cumulative risk of the first subsequent attack requiring hospitalization after the diagnosis among all at-risk relatives was similarly less frequent in Group A than in Group B (OR 0.180; 95% CI 0.041-0.789, p = .041). If attacks were followed among symptomatic patients only, attack-free years were more frequent in Group A than in Group B. Patients preferred genetic screening before puberty to minimize the risk of acute symptoms and genetic discrimination was rare. 44% of the patients reported social, psychological or physical impairment due to acute hepatic porphyria, emphasizing the importance of supporting patients' emotional and resilience capacity. CONCLUSIONS Among female at-risk relatives the annual risk for hospitalization due to an acute attack is <1% and for acute symptoms <2% during the fertile years. Genetic testing of relatives diminishes the risk of acute attacks. Diagnosis before symptom onset is key for subjects to remain asymptomatic during follow-up, and genetic screening should be done earlier than currently.

中文翻译：

---

遗传性筛查在急性卟啉症中的渗透率和预测价值。

目的评估芬兰急性卟啉症患者的渗透率，预测价值和女性患者对基因检测的看法。我们进行了一项回顾性研究，以根据主要诊断方法评估处于危险中的女性家庭成员的预后。方法在芬兰卟啉症登记处（n = 515，AIP 333； VP 182）中选择的23个遗传异质科中计算外显率。我们纳入一个家庭中≥9位患者的亲属（9-23位患者，共216位AIP； 129位VP）。2015年，注册表中包括164位年龄在14至85岁之间的在世女性。向143名妇女发送了调查表，其中107人（75％，AIP 67； VP 40）答复。根据主要诊断方法，将女性高危亲属（AIP 54; VP 30）分为两组：突变分析（A组，n = 40）或生化分析（B组，n = 44）。结果所有急性症状的平均外显率在AIP中为35％，在VP家庭中为40％。在两个研究组中，女性（AIP为50％； VP为44％）的渗透率均高于男性患者（AIP为17％； VP为33％）。在AIP家庭中，住院发作的渗透率为30％（范围为10-80％，女性为41％），在VP中为25％（范围为0-50％，女性27％），表明即使基因型相似，家庭之间的差异也很大。在女性患者中，通常在出现急性症状后，诊断为急性卟啉症的中位年龄为26岁（范围为0-76岁）。诊断延迟平均为7.4年（范围1-30年）。急性症状发生在中位年龄为24岁（范围为10-57岁），首次住院发生在中位年龄为26.5岁（范围为15-57岁）。在症状发作时，38％的女性年龄≤20岁。根据生命表分析，急性发作主要发生在诊断后的五年内，而35岁以后发作的风险降低。A组在生育年因急性发作而住院的年风险低于B组（0.002对0.010，p = .018），但随后发生的所有急性症状的风险却没有降低（A组为0.017vs。 B组0.019，p = 0.640）。在诊断时无症状患者中，急性症状的累积风险在A组为26.7％，在B组为58.3％。在所有高危亲戚中，在诊断后需要住院治疗的第一次随后发作的累积风险相似地较少A组比B组（OR 0.180; 95％CI 0.041-0.789，p = .041）。如果仅在有症状的患者中进行发作，则A组的无发作年要多于B组。患者在青春期之前更喜欢进行基因筛查，以最大程度地降低急性症状的风险，而且遗传歧视很少见。44％的患者报告了由于急性肝卟啉症引起的社会，心理或身体损害，强调了支持患者情绪和适应能力的重要性。结论在高危女性亲属中，每年因急性发作而住院的风险小于1％，而在急性生育期间因急性症状而住院的年度风险小于2％。对亲戚进行基因检测可降低发生急性发作的风险。症状发作之前的诊断对于受试者在随访期间保持无症状的关键，并且基因筛查应比目前更早进行。