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

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.

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.

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.

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.

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.

Molecular genetics & genomic medicine. 2019 May 06 [Epub ahead of print]

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

Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan., Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan., Department of Medical Genetics, Shizuoka General Hospital, Shizuoka, Japan.

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