21-ヒドロキシラーゼ欠損症とCHARGE症候群を合併し、小陰茎とクリプトルキディズムを特徴とした1例

A case of combined 21-hydroxylase deficiency and CHARGE syndrome featuring micropenis and cryptorchidism.

• Satoko Umino
• Miyuki Kitamura
• Yuko Katoh-Fukui
• Maki Fukami
• Takeshi Usui
• Shuichi Yatsuga
• Yasutoshi Koga

抄録

背景:

21-ヒドロキシラーゼ欠損症（21-OHD）は、CYP21A2遺伝子の変異により引き起こされる。男性では、過剰なアンドロゲンにより、様々な程度のペニスの肥大と精巣の小ささが生じます。CHARGE症候群（CS）には、幅広い症状があります。男性では、小陰茎やクリプトルキディズムなどの生殖器の特徴がCSの48％に認められます。21-OHDとCSを合併した患者の報告はないため、外性器で陰茎肥大を示すのか、微小ペニスがクリプトルキディズムの有無にかかわらず認められるのかは不明です。

BACKGROUND: 21-hydroxylase deficiency (21-OHD) is caused due to CYP21A2 gene variant. In males, the excess androgens produce varying degrees of penile enlargement and small testes. CHARGE syndrome (CS) has a broad spectrum of symptoms. In males, genital features such as micropenis and cryptorchidism are found in 48% of CS. There are no reports of patients with combined 21-OHD and CS; therefore, it is unknown whether the external genitalia shows penile enlargement or micropenis with/without cryptorchidism.

ケース:

先天性口唇裂、口蓋裂、小陰茎、クリプトルキディズム、心室中隔欠損のため、先天性口唇裂、口蓋裂、小陰茎、クリプトルキディズム、心室中隔欠損のため、妊娠37週5日に生まれた男児が当院に入院した。10日目に重度の低ナトリウム血症と高カリウム血症を呈した。21-OHDと診断された．外性器にはクリプトルキディズムと微小ペニスの両方が認められたが、ペニス増大は認められなかった。

CASE: A boy, born at 37 weeks and 5 days of gestational age with no consanguineous marriage, was admitted to our hospital due to congenital cleft lip, cleft palate, micropenis, cryptorchidism, and a ventricular septal defect. He had severe hyponatremia and hyperkalemia on day 10. He was diagnosed to have 21-OHD and CS. His external genitalia demonstrated both cryptorchidism and micropenis, but not penile enlargement.

方法:

標準的な手順を用いて末梢白血球からＤＮＡを抽出した。CYP21A2でSanger配列を行った。エクソーム配列を行い、CHD7のバリアントを中心にSanger配列を行った。

METHODS: DNA was extracted from peripheral leukocytes using standard procedures. Sanger sequence was performed in CYP21A2. Exome sequence was performed, and then, Sanger sequence was performed around variant in CHD7.

結果:

CYP21A2遺伝子の遺伝子スクリーニングを行い、染色体6p21.3にc.293-13A/C>G(IVS2-13A/C>G)とc.518T>A(p.I172N)の複合ヘテロ接合変異体が検出された。母親はc.293-13A/C>Gのヘテロ変異体、父親はc.518T>Aのヘテロ変異体であった。同時に染色体8q12に位置するクロモドメインヘリカーゼDNA結合タンパク質-7（CHD7）のc.7165-4 A>Gにde novo splicing acceptor alterationが検出され、21-OHDと診断された。

RESULTS: Genetic screening for CYP21A2 gene was performed and compound heterozygous variants of c.293-13A/C>G (IVS2-13A/C>G) and c.518T>A (p.I172N) were detected in chromosome 6p21.3. His mother had been heterozygous variant of c.293-13A/C>G, and his father had been heterozygous variant of c.518T>A. Simultaneously, a de novo splicing acceptor alteration in c.7165-4 A>G, in chromodomain helicase DNA binding protein-7 (CHD7), located in chromosome 8q12 was detected, and the patient was diagnosed with 21-OHD and CS.

結論:

この2つの疾患は異なる遺伝様式を示し，併存することは極めて稀であるが，我々は21-OHDとCSを併発した1人の男性患者に遭遇した．

CONCLUSION: Although these two disorders exhibit different modes of inheritance and their co-morbidity is extremely rare, we encountered one male patient who suffered from both 21-OHD and CS.

© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.