Response to Letter to the Editor from Giovanelli and Quinton: "Distinguishing Self-limited Delayed Puberty From Permanent Hypogonadotropic Hypogonadism: How and Why?"

We thank Giovanelli and Quinton for highlighting the importance of prior probability in distinguishing constitutional delay of growth and puberty (CDGP or self-limited delayed puberty) from congenital hypogonadotropic hypogonadism (CHH) (1). We agree that it is important to inquire about “red flags,” and that the presence of such features (ie, bilateral cryptorchidism, micropenis, anosmia, and other syndromic features) can suggest, but not always confirm, the diagnosis of CHH (2). We also agree with Giovanelli and Quinton that data suggesting that some individuals do not receive treatment to induce puberty until age 18 years or after are inexplicable, regardless of the underlying diagnosis (3). And we agree that by the age of 18 to 20 years, CHH and not CDGP is the more likely diagnosis. However, we note that our commentary was focused on the need for diagnostic testing in the absence of distinguishing clinical features or advanced age (4). In fact, we stated, “. . . determining performance of (tests) in the most clinically challenging scenario is critical—the ability to separate the 12- to 13-year-old female or 13- to 14-year-old male with CDGP from those with CHH without clinical features suggestive of the underlying diagnosis.” Thus, we believe the authors are making important points that supplement but do not contradict our discussion.

Older youth, such as those referred to by Giovanelli and Quinton, are seen by pediatric endocrinologists. In some cases, the initial referral and evaluation only occurs later in adolescence; in other cases, the youth may be ongoingly followed and treated in clinic without evidence of endogenous pubertal development. Regardless, these older youth need assessment for not only for congenital hypogonadotropic hypogonadism but also acquired conditions if not already addressed. A brain magnetic resonance image is usually obtained to assess for central nervous system abnormalities or features of CHH; other testing (such as genetic testing) may also be warranted as part of the assessment for CHH.

Where our perspective differs from the authors is related to the consequences of false-negative and false-positive diagnoses. It is recommended practice for pediatric endocrinologists to repeatedly assess those diagnosed with CDGP for evidence of exogenous pubertal development during treatment, with more permanent forms of hypogonadotropic hypogonadism being diagnosed by lack of endogenous puberty by age 18 years. Hence, we would hope that the consequences of a false diagnosis of CDGP would not last for decades; instead, the youth would be reclassified by age 18 years. On the other hand, a false CHH diagnosis may have more consequences than suggested by creating psychosocial stress for the youth and family together with unneeded testing. With the consequences of misdiagnoses not known fully, it seems reasonable to us to continue to strive to make the correct diagnosis whenever possible and, therefore, to continue to explore new diagnostic tests that can accurately distinguish CDGP from CHH.