A 16-year-old boy presents to his primary care physician for a routine follow-up visit. He feels disappointed because his voice has not changed. He is concerned that he is not as tall as his classmates. He denies any headache, vision changes, nausea, or vomiting. He recently started playing for his high school basketball team and generally eats healthy food. He has no significant medical history and takes no medications. His temperature is 98.6°F (37.0°C), blood pressure is 115/70 mmHg, pulse is 70/min, and respirations are 12/min. On physical examination, the patient does not have facial hair or acne. His height is 60 inches and his arm span is 50 inches. His visual fields are full and he has no cranial nerve abnormalities. His strength is 5/5 in bilateral upper and lower extremities. Chest palpation and abdominal examination are unremarkable. He has no pubic hair and his testicles are symmetric with a volume of 3 mL. Which of the following is the most appropriate next step in management?
Testicular ultrasound
Radiograph of the hand and wrist
Karyotyping
Reassurance with close follow-up
Radiograph of the hand and wrist
This patient is greater than 14 years of age without the development of secondary sex characteristics (e.g., testicular volume < 4 mL), which is concerning for delayed puberty. The patient should have a radiograph of the hand and wrist to evaluate for discrepancies between bone age and chronological age.

Delayed puberty in boys is defined as the absence or incomplete development of secondary sexual characteristics (increased testicular volume and pubic hair) at 14 years or older. It has a variety of etiologies including chromosomal abnormalities, gonadotropin-releasing hormone (GnRH) deficiencies, and constitutional delay of puberty. In addition to obtaining a history and physical examination, initial diagnostic studies used to work up delayed puberty includes a radiograph of the hand and wrist to determine bone age, and serum studies (complete blood count, complete metabolic panel, follicular-stimulating hormone [FSH], luteinizing hormone [LH], and testosterone). Radiography can compare the patient's bone age to the chronological age (as constitutional delay presents with delayed bone age), and serum endocrine studies can help distinguish between primary causes of hypogonadism (high FSH and LH) and secondary causes of hypogonadism (low to normal FSH and LH). Treatment in cases with a specific cause of delayed puberty is aimed at the underlying cause. For male patients with presumed constitutional delay of puberty, therapy can include hormone replacement with testosterone.

Saengkaew et al. discuss the genetics of pubertal delay. The authors find that pathologic mechanisms that may underlie constitutional delay of puberty are largely related to GnRH neuronal development and biology. The authors recommend further study of GnRH neuronal biology and network functionality to provide the opportunity for improved therapies for patients with disorders of puberty.

Incorrect Answers:
Answer A: Karyotyping is a useful diagnostic study in patients with Klinefelter syndrome, which would demonstrate 47, XXY. Patients would present with a eunuchoid habitus (arm span at least 5 cm longer than height), gynecomastia, and testicular atrophy.

Answer B: Magnetic resonance imaging (MRI) of the brain with gadolinium is a useful diagnostic study in patients with neurological symptoms in addition to hypogonadism. These symptoms would suggest that the patient has a prolactinoma causing impingement of the optic chiasm leading to bitemporal hemianopsia and sometimes a headache. Laboratory studies consistent with a prolactinoma include elevated serum prolactin with low to normal FSH and TSH.

Answer C: Reassurance with close follow-up would be appropriate in some patients with constitutional delay of puberty, which is the most common cause of delayed puberty. It is believed to be caused by a transient defect in the production of GnRH. Patients typically have a family history of "late bloomers," characterized as family members having a late growth spurt or late puberty.

Answer E: Testicular ultrasound would be appropriate in patients with asymmetric testicles since gonadal tumors can occur in a number of intersex disorders (e.g., androgen insensitivity syndrome) and present with impaired sexual maturation.

Buller Summary:
Delayed puberty in boys is defined as a lack of testicular enlargement by age 14 and initial diagnostic evaluation should include radiography of the hand and wrist as well as serum testing (FSH, LH, and testosterone).