Editorial: Centennial Celebration – An Interview with Dr Perrin White on Pediatric Endocrinology

As part of the 2016 Centennial celebration of The Endocrine Society, this month's Editorial interview in Molecular Endocrinology will focus on advances in pediatric endocrinology. Here, we discuss progress in diagnostics and therapeutics with Dr Perrin White, who is the Audry Newman Rapoport Distinguished Chair in Pediatric Endocrinology at University of Texas Southwestern Medical Center in Dallas, TX. Dr White earned his MD from Harvard Medical School, received pediatrics training at Johns Hopkins and New York Hospital, Cornell Medical Center, and was a postdoctoral fellow in Developmental and Molecular Biology at Rockefeller University. Before taking his current position in 1994, he was a research associate at the Sloan-Kettering Cancer Institute and was a member of the pediatrics faculty at Cornell University Medical College, where he rose to the rank of professor.

Dr Perrin White

I am proud of the intellectual contributions made by pediatric endocrinologists over the course of my own career. But the model of the physician-scientist is now under severe duress … . . We must ameliorate the uncertainty in support for early-career physician-scientists if we are to continue to build on the progress of the last 40 years.

Molecular Endocrinology.

This month the focus is on pediatric endocrinology. Please identify and describe for us several key discoveries in the past few decades that have defined the molecular or biochemical basis of pediatric endocrine diseases.

Dr White.

It is hard to know where to begin, because the advances in molecular biology over the past 35 years have revolutionized our understanding of every endocrine system. As an example, let's consider steroid biosynthesis and metabolism, and inherited disorders thereof. Congenital adrenal hyperplasia (CAH) is a genetic disorder of cortisol biosynthesis. By the early 1980s, it was understood that any of 5 enzymatic defects could cause this disease, with 21-hydroxylase deficiency accounting for over 90% of cases; moreover, 21-hydroxylase deficiency was understood to encompass a phenotypic spectrum from mild “nonclassic” disease to severe “salt-wasting” patients who were also unable to synthesize aldosterone and who were thus prone to life-threatening adrenal crises. Starting when I was in Bo Dupont's lab at Sloan-Kettering and in collaboration with Dr Maria New, we isolated the cDNA and gene for the 21-hydroxylase enzyme, P450c21 (now termed cytochrome P21 (CYP21)), and mapped the gene to the middle of the human leukocyte antigen major histocompatibility complex on the short arm of human chromosome 6 (6p21). We also identified mutations in patients, showing that most of them were deletions and gene conversions generated by intergenic recombination between CYP21 and a nearby pseudogene. There were excellent genotype-phenotype correlations, and CYP21 genotyping is now widely available commercially. Further, we and other investigators found mutations in many additional enzymes and other proteins required for steroidogenesis and steroid metabolism; in particular, studies of steroidogenic acute regulatory protein defined the fundamental rapid (minutes to hours) regulation of transport of cholesterol into mitochondria and showed that congenital lipoid hyperplasia resulted from mutations in the steroidogenic acute regulatory gene. We now have a good idea of the processes involved in the development of steroidogenic tissues like the adrenals and gonads and how expression of steroidogenic enzymes is regulated, particularly the understanding that a common transcription factor, steroidogenic factor-1, is a critical regulator of both processes.

I am also impressed by the elucidation of the many ways in which disorders of cAMP signaling affects the functioning of endocrine tissues. Space does not permit a discussion here of the seminal discoveries defining G protein-coupled receptors as mediators of the actions of many trophic hormones, of G protein-mediated signaling pathways, of second messenger-activated protein kinases, or of the DNA elements by which phosphorylated transcription factors such as cAMP response element-binding protein control gene expression. But in terms of endocrine diseases, in 1988, inactivating mutations were found in the gene encoding the Gs α-subunit of the G protein complex in patients with pseudohypoparathyroidism (Albright's hereditary osteodystrophy), and conversely, activating mutations were identified in the same gene in patients with McCune-Albright syndrome. Since then, mutations have been found in every component of the same signaling pathway in patients with disorders such as Carney complex (including thyroid, gonadal and pituitary adenomas, and primary pigmented nodular adrenocortical disease), and other cases of adrenal Cushing's syndrome. For example, activating mutations have been identified in the ACTH receptor melanocortin receptor 2, and inactivating mutations in several phosphodiesterase genes (phosphodiesterase 8, phosphodiesterase 11A), with both defects leading to intracellular persistence of cAMP. Moreover, activating mutations or genetic amplifications have been found in genes encoding the catalytic subunits of protein kinase A, and inactivating mutations in protein kinase A regulatory subunits.

Molecular Endocrinology.

As a follow-up to the last question, please describe for us the areas in which the most significant therapeutic advances been made during the past decades.

Dr White.

I started as a resident in pediatrics 40 years ago. One of the most important advances in pediatric endocrinology since then has been implementation of newborn screening, particularly for congenital hypothyroidism (starting in Quebec in the mid-1970s) but also for CAH starting in the late 1980s. Screening for congenital hypothyroidism has led to nearly complete ascertainment of this condition within the first few weeks of life, minimizing permanent intellectual disability from delayed diagnosis. Screening for CAH has reduced cases of adrenal crisis in the neonatal period, especially in males (affected females usually have virilized external genitalia, alerting the physician to the diagnosis). These advances depended on the development of high-quality RIAs for thyroxine and for 17-hydroxyprogesterone, respectively, that could be performed using the dried blood spots originally developed by Guthrie for newborn screening for phenylketonuria.

Also in the area of disease screening, we now have a good understanding of the genetic etiologies of multiple endocrine neoplasia (MEN), which results from mutations in the gene encoding menin (MEN1) or rearranged during transfection (RET) (MEN2); these discoveries have allowed identification of affected family members, have facilitated prospective screening, and for certain RET mutations, have led to prophylactic thyroidectomy to prevent medullary thyroid carcinoma.

Molecular Endocrinology.

What about type 1 diabetes?

Dr White.

Type 1 diabetes is a major part of the practice of most pediatric endocrinologists. Although a cure remains elusive, care has evolved dramatically over my career, in a manner roughly analogous to the evolution from a Model T to a Lexus. When I was a resident, most children with type 1 diabetes were treated with 1 or perhaps 2 daily injections of beef or pork insulin. Glycemic control was monitored mainly by the absence of reducing substances in the urine. Diabetic retinopathy was seen not infrequently in adolescents, and deaths from diabetic ketoacidosis were not uncommon, particularly secondary to cerebral edema. In 1993, the Diabetes Control and Complications Trial definitively demonstrated the benefits of glycemic control on long-term diabetes complications, including retinopathy, nephropathy, and neuropathy. Achieving good control has been greatly facilitated by many innovations, including recombinant human insulins, modified recombinant insulins with variable durations of action, which permit basal-bolus insulin regimens that more closely approximate the normal insulin secretory pattern, continuous sc insulin infusion pumps, inexpensive capillary blood glucose monitors, continuous glucose monitors, and hemoglobin A1c assays. Moreover, “closed loop” or “bionic pancreas” systems, in which an insulin infusion is automatically controlled by the output from a continuous glucose monitor, are in advanced stages of development, aided by the computing power of newer smartphones.

We now know that type 1 diabetes is an autoimmune condition with abnormal activation of cellular, humoral, and innate immune system components. Several autoantigens, such as glutamic acid dehydrogenase 65 (GAD65), have been defined, allowing detection of immune reactions directed against pancreatic β-cells. The heritability of type 1 diabetes is at least 0.5, with approximately 50% of the genetic risk residing in the HLA class II region. The remaining genetic risk is mostly associated with other immune regulatory loci and the insulin gene itself. The natural history of type 1 diabetes often includes activation of autoimmunity years before the development of overtly impaired glucose tolerance, thus providing a rationale for interventions aimed at abrogating the autoimmune reaction before all insulin-producing pancreatic β-cells have been destroyed.

Unfortunately, modulating the immune system has proven challenging, and no single intervention seems to delay the development of type 1 diabetes by more than a year or so. Perhaps combination immunotherapy would be more efficacious and still have an acceptable risk profile, but as yet, there are not good rationales for selecting particular combinations of agents.

Much progress also has been made in understanding the development of pancreatic endocrine tissue and the differentiation of stem cells into insulin producing β-cells. Transplants of human islets have a lifespan of a few years at most, limiting their utility, but implants in which cells are protected from attack by a permeable membrane are under development.

Molecular Endocrinology.

Transgender individuals have been in the news recently, as society is adjusting to their greater visibility and demands for their civil rights. The transgender concept is also undergoing a reevaluation in medicine. How do pediatric endocrinologists deal with potential transgender children?

Dr White.

This has indeed become a high-visibility area, and one in which our thinking has evolved dramatically over the past 2 decades. Transgender individuals may have severe emotional distress from gender dysphoria, as a consequence of the lack of congruence between gender identity and sex assigned at birth. This may become much worse with development of secondary sexual characteristics during puberty, with among other challenges, an increased risk of suicide. Twenty years ago, there was little we could offer transgender adolescents, because administration of cross-sex hormones to minors (testosterone for female-to-male patients, estrogens for male-to-female patients) was generally considered to be ethically problematic given the permanent changes that would be induced in body habitus and facial appearance. In 1998, a report from The Netherlands first proposed delaying progression of puberty in transgender adolescents with a GnRH agonist. This approach has minimized gender dysphoria, thus allowing time for confirmation of gender identity, and for psychotherapy as needed. In individuals who remain transgender, administration of cross-sex hormones begins at approximately 16 years of age, with possible gender-reassignment surgery at age 18 or later. This approach was pioneered in the United States at Boston Children's Hospital starting in 2007, but it has become widespread in recent years. There are now more than 20 such clinics in the United States alone. Long-term follow-up data from The Netherlands published in 2014 has documented the benefits of this therapeutic approach, which has now become the worldwide standard of care. The availability of multidisciplinary clinics as well as the dramatically increased visibility of transgender individuals in the lay press has led to an explosion of demand for treatment. We officially opened such a clinic - the only one in the southern United States, at University of Texas Southwestern/Children's Medical Center Dallas in 2015, headed by my colleague, Dr Ximena Lopez. As of May 2016, we had over 270 referrals, and the number continues to increase exponentially. It is important to emphasize that the pediatric endocrinologist becomes involved with the medical aspects of treatment of a transgender individual only after extensive psychological evaluation of each patient by a team of mental health professionals. It also should be kept in mind that the etiology of gender dysphoria is poorly understood and remains an important area for further study.

Molecular Endocrinology.

As we enter the second century of The Endocrine Society, what do you feel should be the role of the Society with regard to promoting pediatric endocrinology?

Dr White.

As a clinical division director, I am discouraged by the relatively low incomes earned by pediatric endocrinologists, including our former trainees and those of my colleagues. It has been estimated that a pediatric endocrinologist has lifetime earnings that are $800 000 less than a general pediatrician, who does not undertake fellowship training, which adversely impacts the number of pediatricians going into the specialty. Pediatric endocrinologists have no procedures; we only do “evaluation and management,” meaning we spend most of our time talking to our patients and their families, and prescribing medication. The Society must continue to lobby for increased relative value unit assignments for evaluation and management codes, which will benefit all clinical endocrinologists.

I am proud of the intellectual contributions made by pediatric endocrinologists over the course of my own career. But the model of the physician-scientist is now under severe duress, with very limited NIH funding for individual career development awards, and low pay lines for individual research grants after that. We must ameliorate the uncertainty in support for early-career physician-scientists if we are to continue to build on the progress of the last 40 years.