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Commentary From the Section of Endocrinology

September 5, 2023

Commentary From the Section of Endocrinology

The mission of the Section on Endocrinology is to provide an educational forum to discuss endocrinology problems and treatments, stimulate research and teaching of endocrinology, and disseminate knowledge of endocrinology through American Academy of Pediatrics (AAP) resources. The method we used to develop these commentaries was to search the archives of Pediatrics through the AAP website for the periods of 1948-2022 using as a filter the keyword “endocrinology or endocrine.” This generated a long list of articles and commentaries, which the 3 of us sifted through to identify topics for which Pediatrics articles provided what we felt were key contributions. We agreed on 3 topics, and it turned out that for each topic we selected, there were multiple articles in Pediatrics that told part of the story. 

Accelerated Prevalence of Type 2 Diabetes Mellitus in Children: Did We See It Coming?

Paola Palma Sisto, MD, FAAP

Affiliation: Associate Professor of Pediatrics, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI

Highlighted Articles From Pediatrics

  1. Scott CR, Smith JM, Cradock MM, Pihoker C. Characteristics of youth-onset noninsulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus at diagnosis. Pediatrics. 1997;100(1):84-91
  2. American Diabetes Association. Type 2 diabetes in children and adolescents. 2000;105(3):671-680
  3. Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus in children and adolescents. Pediatrics. 2013;131(2):364-382

Today we are familiar with the risk factors that predict a diagnosis of type 2 diabetes in a teenager with new-onset disease. However, 25 years ago, the concept that a child might have the “adult” form of diabetes was still relatively new, although some experts appreciated a significant increase in new-onset type 2 diabetes in children under 18 years old as early as the 1980s. One of the earliest papers on type 2 diabetes in children appeared in Pediatrics in 1997.1 Carla Scott and colleagues at the University of Arkansas were interested in determining what clinical characteristics at the time of diagnosis might distinguish a child with type 2 diabetes from the more prevalent type 1 autoimmune mediated diabetes. She described how, “up until recently, noninsulin-dependent diabetes mellitus (NIDDM) [as it was known at the time] had not been considered a pediatric disease.” Children with the signs and symptoms of type 2 diabetes were presenting to pediatric endocrinologists who had little guidance on diagnosis and treatment. Dr. Scott and colleagues sought to identify distinguishing features of type 2 diabetes in the pediatric population. They noted the rate of newly diagnosed patients with type 2 diabetes had significantly increased in their practice from 1-2 per year prior to 1992 to as high as 17 per year by 1995.

They concluded that children who presented without weight loss, with a BMI >85th percentile, with clinical findings of acanthosis nigricans and hypertension, and with measurable levels of endogenous insulin and c-peptide should be considered as having type 2 diabetes. In the setting of a 22% prevalence of childhood obesity at the time, 96% of those that were diagnosed with type 2 diabetes in their study were found to meet those criteria. They advised clinicians to consider the possibility of disease-related systemic complications, such as diabetes-related nephropathy and retinopathy, at the time of diagnosis but lacked data on how likely these conditions were to be present at that time. In fact, solid evidence that hyperglycemia was the causative agent for those complications had just been published in 1993, through the Diabetes Control and Complications Trial research group.

By 2000, with the accelerated pace of obesity and type 2 diabetes in children, the AAP and the American Diabetes Association issued a joint consensus statement in Pediatrics on type 2 diabetes in children and adolescents.2 This paper sought to define the classification, epidemiology, pathophysiology, screening approach, and treatment options for these children. The group still did not understand the additional contributing factors beyond obesity that led to type 2 diabetes in children, but they did characterize the degree of insulin resistance and the lack of autoimmune antibodies, a diagnostic tool that was less refined in the mid-1990s. At the time, treatment approved for children was limited to insulin, although many providers had witnessed improved diabetic control with use of off-label oral agents such as metformin. The article concluded that more studies were needed, and that a population health approach was vital to slow the incidence of the disease.

To understand the epidemiology and scope of diabetes mellitus in children more thoroughly, the National Institutes of Health, through the National Institute of Diabetes and Digestive and Kidney Diseases, funded a multicenter cohort study and registry called the SEARCH for diabetes in youth study. As a follow-up, the institute supported the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study, which sought to determine the safest and most effective treatment modality by comparing 3 interventions to treat adolescents and youth with type 2 diabetes.

With the benefit of an expanded knowledge base about type 2 diabetes in children, the AAP in 2013 released a clinical practice guideline to guide providers in the management of newly diagnosed type 2 diabetes mellitus in children and adolescents.3 Thirteen years after release of this consensus statement, the distribution of type 2 diabetes in the United States had increased from 1 in 5 to 1 in 3 children with diabetes. In addition, there had been an explosion of new studies that helped define the diagnosis in children, elucidate the pathophysiology distinct from the process seen in adults, and direct the best approach to the initial management of the disease. Although this paper suggested that the approach to management in children should mirror the approach in adults, this guideline urged a more aggressive approach to the correction of hyperglycemia and advised using an approved oral formulation of metformin in newly diagnosed children with type 2 diabetes, whatever the degree of hyperglycemia.

Many had predicted the rapid increase in the number of children with newly diagnosed type 2 diabetes, as evidenced by just a few of the many articles on the subject published in Pediatrics since 1997. These observers warned that the tides of rising obesity and increasing sedentary lifestyles would bring us to where we are today. Now armed with a deeper understanding of the unique aspects of type 2 diabetes in children and a growing armament of treatment options, providers will be able to reduce the longer-term complications of the disease. Unfortunately, sustainable population health interventions to reduce the development of obesity and new-onset type 2 diabetes in children remain lacking.

The Ongoing Debate Over the Age of Onset of Puberty in Girls

Paul Kaplowitz, MD, FAAP

Affiliation: Professor Emeritus of Pediatrics, Children’s National Hospital, Washington DC

Highlighted Articles From Pediatrics

  1. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. 1997;99:505-512
  2. Kaplowitz PB, Oberfield SE, and the Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Reexamination of the age limit for defining when puberty in precocious in girls in the United States: implications for evaluation and treatment. Pediatrics. 1999;104:936-941
  3. Sun SS, Schubert CM, Chumlea WC, et al. National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics. 2002;110:911-919
  4. Biro FM, Galvez MP, Greenspan LC, et al. Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics. 2010;126(3):e583–e590
  5. Osinubi AA, Lewis-de los Angeles CP, Poitevien P, Topor LS. Are Black girls exhibiting puberty earlier? Examining implications of race-based guidelines. Pediatrics. 2022;150(2):e2021055595

I vividly recall the impact that the Herman-Giddens study on the onset of puberty in girls had on me when it was published in Pediatrics in 1997.1 The standard definition of when puberty in girls should be considered too early, 8 years, dated back to the classic Marshall and Tanner study of 1969. It was based on 192 White girls living in a group home in the United Kingdom and clearly did not reflect what I and others were seeing in the multiracial US population of the 1990s, where it was common to see healthy 6–8-year-old girls with breast or pubic hair development. However, in the absence of a large well-done study providing recent data on puberty onset in girls, it was difficult to convince primary care providers and parents not to worry about the 7-year-old girl with signs of puberty. In her classic paper, Marcia Herman-Giddens first detailed the inadequate and shaky data behind defining early puberty as onset before 8 years of age. She and her colleagues then presented the results of a study conducted in 65 pediatric offices around the United States in the Pediatric Research in Office Settings (PROS) network, which provided data on over 17,000 3–12-year-old girls. The key findings1 were as follows. For 7.0–7.9-year-old White girls, 5.0% had breast development and 2.8% had pubic hair compared to 15.4% and 17.7% of Black girls, respectively. The mean age of achieving Tanner 2 for breasts was 10.0 years for White girls (compared to 11 years from earlier studies) and 8.9 years for Black girls, and for pubic hair the difference was even greater, 10.5 years for White vs 8.8 years for Black girls. No wonder people in our field were getting so many referrals based on the traditional 8-year definition!

I had just joined the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society and was asked to convene a group of members of that committee to evaluate if these new data should change our definition of when female puberty should be considered precocious, which would have implications for referrals, testing, and treatment. The result of these deliberations was a paper published in Pediatrics in 1999, which suggested that based on the PROS study, the cut-off for which girls should be considered precocious for either breast or pubic hair development be changed to 7 years for White and 6 years for Black girls.3 However, these recommendations received many negative responses, based largely on 2 issues: (1) the sample of girls studied was not random and could have been biased toward early-maturing girls, and (2) only 40% of girls had breast tissue evaluated by palpation with the rest by inspection only, which could have skewed the results in overweight girls where fat may simulate breast tissue. However, 2 subsequent studies largely confirmed the trend for earlier onset of puberty in girls and the approximately 1-year difference in onset between White and Black girls, with Hispanic girls being intermediate in their maturation. One study was based on NHANES III 1988-1994 published in Pediatrics in 2002, which used a nationally representative sample of 2000 8–16-year-old girls; the other, the Biro et al study of 6–8-year-old girls in 3 urban centers was published in Pediatrics in 2010 and used palpation to assess breast development. Thus, there was no longer any doubt that girls in the 1990s and early 2000s were maturing earlier than girls in the 1960s and 1970s, and that for whatever reason, Black (and Hispanic) girls were maturing significantly earlier than their White counterparts. And yet, in clinical practice, the 8-year-old definition of when breast or pubic hair development should be considered precocious remains the standard of care to this day, regardless of race and ethnicity. There are at least 2 reasons for this. First, many providers fear that changing the definition would risk missing serious underlying pathology, such as brain tumors in 6–8- or 7–8-year-old girls, despite ample evidence that tumors are a very rare cause of precocious puberty in girls older than age 6. Second, there is the concern that even if puberty onset before age 8 is more common than in the past, the psychological consequences of early physical changes and early menses (and adult short stature in some) may justify a course of treatment to delay puberty for a few years, despite its high cost of $20,000-$40,000 per year.

In 2022, another challenge to the 1999 paper emerged, this time based on the race-based puberty definition. In a commentary published in Pediatrics,Are Black Girls Exhibiting Puberty Earlier? Examining Implications of Race-Based Guidelines,”5 the authors argue against the widely held view that Black girls are maturing earlier because of genetic differences that might affect the timing of puberty. They state, “The idea that racial health disparities exist because of biological differences between racial groups perpetuates a tradition of race pathologization…the practice of attributing poor health outcomes to an individual race rather than to the sociopolitical factors that influence such outcomes.” Furthermore, they propose that “Race is a social construct, without any biological or genetic basis, and it may inadvertently be used as a proxy for variables including obesity, environmental exposures, psychological stress, and, importantly, racism itself.” The implications of this article for me were twofold. First, it is important to evaluate Black girls with signs of early puberty using the same decision-making process that we use for White girls of the same age, and not withhold treatment for a 7-year-old Black girl who may experience the same stresses as a White girl, just because early puberty is more common in Black girls. Second, further research is essential to understand recent trends and racial differences in pubertal development, because few studies have focused on why these differences may exist. Obesity is clearly a risk factor for early puberty, but that is true in both White and Black girls. It should be possible to independently assess the effects of income, living environment (including exposure to pollution), adverse childhood experiences, diet, and physical activity on observed racial differences in the onset of puberty.

In summary, articles published in Pediatrics in the 25 years between 1997 and 2022 present important implications for how providers manage this common problem, and they call into question past assumptions about the role of race in this process.

Congenital Hypothyroidism as Presented in Pediatrics Over 7 Decades

Jennifer M. Barker, MD, FAAP

Affiliation: Department of Pediatrics, Section of Endocrinology, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Aurora, CO 80045

Highlighted Articles From Pediatrics

  1. Smith DW, Blizzard RM, Wilkins L. The mental prognosis in hypothyroidism of infancy and children; a review of 128 cases. Pediatrics. 1957;19(6):1011-1022
  2. LaFranchi SH, Murphey WH, Foley Jr. TP, Larsen PR, Buist NR. Neonatal hypothyroidism detected by the Northwest Regional Screening Program. Pediatrics. 1979;63(2):180-191
  3. Fisher DA, Foley BL. Early treatment of congenital hypothyroidism. 1989;83(5):785-789
  4. Rose SA, Wassner AJ, Wintergerst KA, et al. Congenital hypothyroidism: screening and management. Pediatrics. 2023;151(1):e2022060419

Congenital hypothyroidism (CH) is one of the most common conditions identified through newborn screening (NBS) programs, and prompt treatment with levothyroxine allows children with CH to grow and develop typically. The importance of identification and prompt treatment of CH has been so thoroughly ingrained into pediatricians, neonatologists, and pediatric endocrinologists that it is easy to forget there was a time that neonates were not routinely screened for CH, and it was not clearly understood that early treatment led to improvements in intellectual development and growth.

Prior to the advent of the NBS for CH, infants with CH were not identified until they presented with clinical signs of hypothyroidism, such as constipation, enlarged fontanelle, lethargy, protruding tongue, developmental delay, and growth failure. As recently as the 1950s, it was not widely recognized that prompt treatment of CH could improve intellectual and developmental outcome. In an article published in Pediatrics in 1957 by Drs. Smith, Blizzard, and Wilkins, 3 giants in the field of pediatric endocrinology, entitled “The Mental Prognosis in Hypothyroidism of Infancy and Childhood: A Review of 128 Cases,” the authors describe the intellectual development of children diagnosed with hypothyroidism by categories of severe congenital, mild congenital, and acquired hypothyroidism.1 Strikingly to our modern eyes, the diagnosis of CH was made based on the presence of signs of hypothyroidism and absent or decreased radioactive iodine uptake, because thyroid hormone testing was not yet available. Additionally, the infants were treated with desiccated thyroid hormone titrated to clinical effect. They demonstrated that in children with severe CH, 45% (10/22) achieved an IQ greater than 90 if treatment had been started prior to age 6 months, compared with 7% (2/29) of those started after age 6 months. In infants with mild congenital hypothyroidism (defined as signs presenting after age 6 months), only 41% (13/32) achieved an IQ greater than 90. The data in this study demonstrated the effect of timing of initiation of treatment and the degree of intellectual disability in children with CH and provided a powerful basis for the later inclusion of CH in the newborn screen.

The ability to measure thyroid hormone levels was developed in the mid-1960s. At the same time, treatment with levothyroxine was available, which allowed for improved titration of thyroid hormone dosing. Shortly thereafter, NBS programs began to include screening for CH. In 1979, Dr. LaFranchi and colleagues published their experience with the newborn screen for CH in Oregon, Montana, Alaska, and Idaho.2 The program began in 1975 and used a primary T4 screen with follow-up TSH assessment. They identified 25 infants in the first 2 years of the program for an incidence of about 1:4,500 births. Most of the infants identified by the NBS did not have signs of hypothyroidism, and very few had physical examination findings characteristic of hypothyroidism. Treatment was initiated at a mean age of 59 days among these children, and the program set a goal to initiate treatment by 4 weeks of age. The authors commented that further follow-up of children identified with CH by the newborn screen would be necessary to document improvement in intellectual development. Over the past 5 decades, advances in the timing of both the initial screening and follow-up by a pediatric endocrinology provider have allowed for a prompter start of therapy and better developmental outcomes.

Among the questions to be answered regarding treatment of CH was the optimum dosing of levothyroxine. When newborn screening for CH was initiated, levothyroxine doses of 25-37.5 mcg/day were commonly used, which could be as low as 6 mcg/kg/day in a 4 kg neonate. In an “Experience and Reason” article published in Pediatrics in 1989, Dr. Del Fisher and BL Foley (RN) published their experience with dosing of levothyroxine at 10-15 mcg/kg/day, with attention to the identification of timing to normalization of T4 and adverse effects of increased dosing of levothyroxine.3 The authors showed they could normalize the T4 levels by 3-4 weeks after treatment initiation using doses of 10-15 mcg/kg/day.

The data presented by the studies described above, among others, have led to continued advancement in the field, well-described in the most recent update of guidelines for the screening for and treatment of CH, published in 2023 in Pediatrics.4 These guidelines emphasize the following 3 key principles: (1) prompt evaluation (preferable within 24 hours) of an abnormal newborn screen result by assay of serum TSH and free or total T4 levels; (2) treatment initiation in neonates with confirmed hypothyroidism with a TSH >40 mU/L and low T4 (free or total) within 2 weeks of life with a dose of levothyroxine of 10-15 mcg/kg/day; and (3) ongoing monitoring of thyroid function tests with a goal of normalizing the thyroid hormone levels. They also describe a plan for continued evaluation of thyroid hormone levels for neonates with mildly abnormal thyroid function tests, timing of laboratory evaluation and treatment targets, and procedures for trialing off levothyroxine in children older than age 3 years with mild hypothyroidism.

The identification and treatment of CH by the NBS is one of the success stories of pediatric endocrinology over the past half-century and has resulted in the near normalization of intellectual development and growth of children with CH. This success story is mapped out over the decades in the pages of Pediatrics and is a heartening tale of the impact health care providers can have on patients with careful attention to clinical presentations, novel approaches to clinical conundrums, and persistence to map out the optimum diagnosis and management strategies.

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