イラン人小児における全ゲノムシークエンシングによるヘムオキシゲナーゼ-1欠損症の死後診断

Post-mortem Diagnosis of Heme Oxygenase-1 Deficiency by Whole Exome Sequencing in an Iranian Child.

• Fatemeh Tahghighi
• Nima Parvaneh
• Vahid Ziaee

抄録

ヘムオキシゲナーゼ-1（HO-1）は、ヘムのビリベルジンへの変換触媒作用に関与する誘導性酵素である。我々は、HO-1欠損症の原因となるコーディング配列に新規のストップゲイン変異を有する患者を報告する。発熱，頻脈，呼吸困難の症状を呈する17ヶ月の女性が当センターに紹介された．8ヶ月間の経過観察中に4回の入院があった．腹部超音波検査で肝腫大を確認し，白血球症，血小板症，溶血性貧血，炎症性マーカーの上昇，肝転移酵素，トリグリセリド，フェリチンの上昇，フィブリノーゲンの低下を認めた．その他の検査項目は、血液培養陰性、骨髄吸引正常、血清学的ウイルス感染症正常であった。免疫不全と自己炎症性症候群は除外された。肝生検では鉄沈着を認めた。副腎皮質ステロイドの投与を開始したが，病状は徐々に悪化し，発熱，出血，心不全，腹水の再発で死亡した．死後の全エクソームシークエンシングの結果，この遺伝子にホモ接合変異（exon3：c.A610T，p.K204X）が認められた．両親はその変異に対してヘテロ接合体であることが判明した．この患者の検査所見や臨床所見は、以前に報告されたHO-1欠損例やノックアウトマウスと何となく類似していた。我々は、HO-1欠損者の臨床症状は、遺伝する変異の種類に部分的に依存しているのではないかと推測している。

Heme oxygenase-1 (HO-1) is an inducible enzyme involved in the catalysis of heme conversion into biliverdin. We describe a patient with a novel stop-gain mutation in the coding sequence resulting in HO-1 deficiency. A 17-month-old female with fever, tachypnea, and signs of respiratory distress was referred to our center. Four admissions ensued during the eight months follow up. At the first admission, she had massive pericardial effusion without any laboratory findings for tuberculosis, viral infectionsor malignancies.An abdominal ultrasound examination confirmed hepatomegaly.Laboratory findings showed leukocytosis, thrombocytosis, hemolytic anemia, elevated inflammatory markers, increased levels of the hepatic transferase, triglycerides and ferritin as well as decreased level of fibrinogen. Other laboratory investigations were negative blood cultures, normal bone marrow aspiration, and normal serology viral infections. Immunodeficiency and auto-inflammatory syndromes were ruled out. Hepatic biopsy showed iron deposits. The patient was initiated on corticosteroids; however, her clinical condition was progressively deteriorated, and she died of recurrent fever, bleeding, heart failure, and ascites. Post-mortem whole exome sequencing revealed a homozygous mutation (exon3: c.A610T, p.K204X) on the gene. The parents were found to be heterozygous for that mutation. The laboratory findings and clinical features of our patient were somehow similar to that of HO-1 deficient cases reported previously, as well as knocked out mice. We speculate that the clinical manifestations of HO-1 deficient patients can be partially dependent on the type of mutation they inherit.