An 18-year-old man presents to his primary care provider with his parents for a sports physical. He was last seen in the clinic several months ago when he was diagnosed with attention deficit hyperactivity disorder (ADHD). He was started on methylphenidate at that time and the patient now reports improvement in his ability to concentrate in school and at home. He hopes to play baseball in college and has begun lifting weights daily in preparation for baseball season. The patient has a healthy diet to fuel his exercise regimen. His parents have no concerns and are pleased with the recent improvement in his grades. His temperature is 98.6°F (37°C), blood pressure is 115/71 mmHg, pulse is 72/min, and respirations are 12/min. On physical exam, the patient has tall stature with average muscle mass for his age. He has no dysmorphic features. His chest has a normal appearance other than mild gynecomastia. The patient has sparse facial hair and a moderate amount of coarse pubic hair that extends across the pubis and spares the medial thighs. His testes are small and firm. Laboratory testing is performed and reveals the following:

Follicle-stimulating hormone (FSH): 42 mIU/mL
Luteinizing hormone (LH): 38 mIU/mL

Which of the following is the most likely etiology of this patient’s presentation?
CGG trinucleotide repeat disorder
Anabolic steroid use
Failure of neuronal migration
Meiotic nondisjunction
Meiotic nondisjunction
This patient presents with tall stature, gynecomastia, and small testes with elevated FSH and LH, which suggests a diagnosis of Klinefelter syndrome. Klinefelter syndrome is usually caused by meiotic nondisjunction that results in a 47,XXY genotype.

Klinefelter syndrome is the most common cause of primary hypogonadism. Patients with Klinefelter syndrome present with tall stature, neurocognitive difficulties (ADHD), and features of hypogonadism including gynecomastia, small testes, small phallus, hypospadias, underdeveloped secondary sex characteristics, and cryptorchidism. Patients without hypospadias or cryptorchidism are often not diagnosed until after puberty when the symptoms of gynecomastia and small testes become more prominent. Because the hypogonadism in Klinefelter syndrome is caused by testicular fibrosis, laboratory results demonstrate low testosterone and elevated FSH and LH levels. Treatment for this condition includes androgen replacement therapy.

Lanfranco et al. review the evidence regarding the treatment of Klinefelter syndrome. They discuss how modern fertility augmentation therapy has allowed some of these patients to produce viable offspring. They recommend having a detailed discussion with these patients and their partners regarding possible outcomes.

Incorrect Answers:
Answer A: Anabolic steroid use causes decreased levels of FSH and LH due to the suppression of GnRH release by the hypothalamus. This results in decreased FSH and LH release by the pituitary gland. Anabolic steroid use would not present with signs of hypogonadism.

Answer B: The CGG trinucleotide repeat disorder characterizes fragile X syndrome. Fragile X presents with macroorchidism rather than hypogonadism and patients typically have dysmorphic features of a long, narrow face with large ears, a prominent forehead, and a prominent chin. Fragile X is the most common cause of inherited intellectual disability.

Answer C: The CTG trinucleotide repeat disorder characterizes myotonic dystrophy. Although myotonic dystrophy presents with hypogonadism, patients would also present with symptoms of progressive weakness, such as facial weakness, dysphagia, or hand grip weakness. Treatment is with cardiac pacemakers and ventilatory support.

Answer D: Failure of neuronal migration characterizes Kallmann syndrome. Kallmann syndrome presents with the classic symptoms of anosmia and hypogonadism, but patients with Kallmann syndrome have a low FSH and LH. Treatment is with hormone replacement therapy.

Bullet Summary:
Klinefelter syndrome results in primary hypogonadism and presents with tall stature, gynecomastia, small testes, a small phallus, hypospadias, and cryptorchidism.