The legacy of Lawson Wilkins: a new medical specialty, pediatric endocrinology
At this point, it is important to outline the contributions of Dr. Wilkins to the medical field. He is often referred to as the “Father of Pediatric Endocrinology.” Indeed, he came to the field of Pediatrics at a time when it was subdivided into specialties. He and his textbook “The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence” (1st Edition, 1950) were the basis of this new field.
How he came to this is well presented by one of his early fellows, Judson J. Van Wyk who gave a conference on the subject in October 28, 2003, and is reported here as follows:
Tale of Lawson Wilkins By Judson Van Wyk October 28, 2003
Many were surprised to learn that Dr. Wilkins was a general pediatrician in private practice until he was over 50. Wilkins’s father was a general practitioner in Baltimore whose hero was William Osler. Lawson sometimes drove the horse and buggy for his father on his rounds and later cited his Dad as one of the 3 most important influences on his career, the others being Fuller Albright and Edwards Park.
Lawson attended Johns Hopkins Medical School, but received his MD in France, where he had spent his 4th year as an orderly on the battlefields of World War I. On his return he took a medical internship at Yale and a pediatric residency in Pediatrics at the Harriett Lane Home under John Howland.
Wilkins’s solo practice as a private pediatrician in Baltimore gave him the freedom to spend part of each week in one of the specialty clinics: such as the syphilis clinic or the epilepsy clinic. His first paper in 1923 was on the potassium content of human serum, carried out by a laborious gravimetric assay method.
(He was also interested in calcium metabolism and rickets. He wrote a few early papers in collaboration with Drs. Orr WJ, Holt LE Jr, Boone FH and Kramer, B.)
In 1935, Dr. Edwards Park, chief of Pediatrics at the Harriett Lane Home had the wisdom to foresee that the new discipline of endocrinology might be of value in understanding the growth and development of children; He showed even greater wisdom by asking Wilkins to organize a pediatric endocrine clinic. Wilkins resisted: “Do you want to make a charlatan out of me?”
Nevertheless, Wilkins accepted the challenge and spent every evening into the small hours reading the fat tomes written by so-called “experts” in the field. Wilkins became increasingly frustrated by the absence of any science and the long convoluted descriptions of endless “glandular syndromes.” Lawson was never one to suffer fools gladly, and his most important act one night while reading in bed was to fling the volume against the wall while cursing the stuffed shirts who could write such garbage.
He decided to begin over from scratch and learn everything he could by carefully documenting every clinical feature of his patients, and exploiting every opportunity to learn about mechanisms. Wilkins had little knowledge of statistics, but had a penetrating eye for what each of his patients could teach him. He had long ago adopting the practice of plotting all of his patients’ findings graphically as a function of time in the hope that such graphs might provide correlations and insights that might otherwise be missed.
Lacking centile growth charts as we now know them, Lawson adopted the 1932 charts of Engelbach which gave average values for age of height, weight, span, segmental proportions, and circumferences of the head, chest, and abdomen. He adopted these charts because they permitted correlations of body proportions with growth parameters.
He also laboriously traced out the appearance of epiphyses in the wrist, elbow, shoulder, knee, and ankle and developed his own scheme for determining bone age long before Greulich’s Atlas based on wrist x-rays.
Hypothyroidism
He started by studying hypothyroidism, plotting the effect of thyroid substitution treatment and its withdrawal on parameters of growth and development. His 1938 paper [1] was his first contribution of the effect of an endocrine deficiency on growth. In it, he charted chronologic age versus the different measures of developmental age. He concluded from his many such graphs that bone maturation was the most sensitive indicator of adequate substitution therapy.
Wilkins recognized, however, that to understand the physiological effects of thyroid and other hormones, he had to turn to the laboratory, a task for which he was ill-prepared. But he was a good judge of talent and had the good fortune to meet Walter Fleischmann, a refugee Viennese physiologist. When the Journal of Clinical Endocrinology made its debut in 1941, the first 2 papers in each of the first 2 issues were by Wilkins and Fleischmann reporting their studies in hypothyroidism. [2–5]
Since there were no methods available to measure thyroid hormone levels directly, he measured the effects of thyroid on lowering the elevated cholesterol in hypothyroid children and raising the depressed levels of creatine in the urine. He found these measures far more reliable than measurements of basal metabolic rate.
It should come as no surprise, therefore, to learn that Wilkins had one of the first binary counters in Baltimore to study thyroid problems with radioactive iodine uptake studies, and one of the first to order the new protein bound iodine measurements on his patients.
In 1944, Wilkins went through a period of despondency following the tragic death of his only son. He was rescued by Dr. Park, who induced him to become a full time member of the Johns Hopkins Department of Pediatrics.
Wilkins brought with him his vast collection of case histories and photographs. He presented this extensive collection in a gigantic poster at the 1st International Congress of Pediatrics in Zurich in 1950.
He then collated this material into the first Textbook of Pediatric Endocrinology. This launched, his fame spread rapidly, and students from the US and many foreign countries flocked to study under him. His textbook was considered the “Bible” of the field at the time.
Congenital adrenal hyperplasia
Wilkins was particularly challenged by difficulties encountered by patients with congenital adrenal hyperplasia. He knew that the secretions of adrenal androgens were controlled by ACTH and he made several unsuccessful attempts to suppress ACTH secretion by administering biologically weak androgens. When cortisone became available for experimental use, Wilkins immediately saw it as a more likely participant in the ACTH feedback mechanism, and in short order was able to show that the secretion of adrenal androgens in girls with CAH could be inhibited by the administration of a glucocorticoid hormone.[6] Bartter and Albright in Boston made the same observation independently. Crigler and other postdoctoral fellows followed these initial reports with a series of classic studies that provided the essential data for long term adrenal suppression of these patients.[7]
Wilkins thought that the identification of steroid precursors in the urine of patients with CAH might reveal to us the biosynthetic pathways of human adrenal steroid biogenesis. Most steroid biochemists, however, were preoccupied with perfusing bovine adrenals with radio-labeled precursors and could not be bothered by clinical problems. Eventually he enlisted Dr. Seymour Lieberman in this endeavor and Lieberman accepted Wilkins’s prospective research associate, Dr. Alfred Bongiovanni, into his laboratory to learn advanced steroid methodology. As Wilkins had predicted, the studies of Bongiovanni led to the definition of the crucial enzymatic lesions in the different forms of adrenal hyperplasia. [8]
Al pioneered the pregnantriol method for monitoring adrenal suppression, and contributed greatly to our knowledge of the enzymatic defects in the several forms of CAH. Al and Walter Eberlein described and identified the defect in 11β-hydroxylase deficiency.
Syndrome of gonadal dysgenesis and sex differentiation
Another early interest of Wilkins was sexual development. He was particularly intrigued by the syndrome of short stature, sexual infantilism, and multiple congenital anomalies in girls. This syndrome was not uncommon, and Henry Turner’s description had previously been described by a number of other authors. In 1942, 2 groups, Varney, Kenyon, and Koch in Chicago and Albright and his coworkers in Boston, reported that these girls had elevated urinary gonadotropins, thus demonstrating that their sexual infantilism was due to primary gonadal failure rather than hypopituitarism as had been suggested by Henry Turner in 1938. To learn more about their gonadal failure Wilkins persuaded Richard Te Linde, the chief of gynecology to explore the pelvis in 5 such patients.
He found that the gonads in all patients consisted only of fibrous streaks composed exclusively of ovarian stromal cells.
There were no germ cells or ovarian follicles, although there were occasional mesonephric remnants.
In his classic 1944 paper, Wilkins reported his findings and pointed out that studies of patients with streak gonads might provide powerful evidence supporting or refuting the various theories of sex differentiation. He critically evaluated each of the theories that had been advanced, including that of Weisner who believed that in the absence of fetal gonadal secretions all embryos would be feminine, although androgen could influence male differentiation.
1949 meeting with Alfred Jost
The classic studies of Jost on the fetal castration in rabbits are very well known now. They demonstrated that the fetal testis is necessary for differentiation as a male, but in the absence of fetal gonads both the internal and external genitalia developed as a normal female. In 1949, Jost presented his findings on sex differentiation to an International Congress of Gynecology in Mexico City. On the way home, he arranged to visit the Carnegie Institute of Embryology in Baltimore which housed Streeter and Corner, the leading human embryologists of the day. After hearing Jost’s story, the embryologists insisted that he meet Dr. Wilkins who had a healthy interest in the hormonal control of sex differentiation.
Twenty-five years later, Jost recalled the encounter:
“He was 55 and I was 33 and not even a doctor of medicine. He calmly and patiently followed my description of the rabbit experiments and asked many penetrating questions. He then showed me his portfolio of clinical cases of sexual ambiguity asking me to help him interpret the pathophysiology. The discussions went on for many hours into the late afternoon and Dr. Wilkins finally concluded, “I am convinced that if what you say is true, half of my beautiful girls with ovarian agenesis are really boys!”
Unfortunately there was no way to determine genetic sex at that time. Nevertheless, Wilkins felt sufficiently secure with this interpretation that he cited this hypothesis as a footnote in his 1950 textbook.
Four or five years after Lawson’s encounter with Alfred Jost, when Mel Grumbach and I were fellows of Wilkins, we reported in journal club that a Canadian pathologist, named Murray Barr had discovered a cytological marker in nuclei of female cells but not in male cells. Lawson immediately phone Murray Barr and arranged for him to analyze skin biopsies from a group of our patients with what we then called ovarian agenesis.
In 1954, we reported that 6 of 8 patients lacked the chromatin dot and presumably were “genetic XY males.”[9] Grumbach followed up on this and became a world authority on sex differentiation. [10]
In the 1960s, Malcolm Ferguson-Smith and Barbara Migeon did the karyotypes of the patients showing that most of them had only one X-chromosome.
Wilkins later modified his nomenclature to include various forms of the syndrome under the umbrella designation, “Syndrome of Gonadal Dysgenesis.” He stoutly maintained, however, that this syndrome should never have been designated “Turner Syndrome.”
The Syndrome of Testicular Feminization
Androgen Insensitivity Syndrome (AIS)
In his 1950 textbook, Wilkins described another kind of sexual ambiguity. She was an attractive 30 year old woman who had never menstruated and who lacked sexual hair. Surgical exploration of her pelvis revealed absence of uterus, but presence of testes and rudiments of epididymis and vas deferens.
Her urinary 17 ketosteroids ranged between 15 and 20 mg/24 hr and her androgens measured by bioassay were similarly high for a female but normal for a male.
Wilkins treated her with methyl testosterone, up to 50 mg/day with no discernable effect on seborrhea, sexual hair, or clitoral enlargement. He therefore postulated that all of her findings were due to resistance to androgen action at the peripheral level. He called these patients “hairless ladies with testes.” Several other patients were followed later. Their karyotypes were shown to be 46 XY with a plasma testosterone level usually above normal male range. The locus of the gene for the androgen receptor was determined by Drs. Meyer W, Migeon B, and Migeon C. [11] The gene itself was isolated by Drs. DB Lubahn, TR Brown, JA Simental, HN Higgs, CJ Migeon, EM Wilson, and FS French. [12]
The name of testicular feminization was changed to androgen insensitivity syndrome by Money J and Migeon C.
Unfortunately, Wilkins’s observation including the correct pathophysiology of the syndrome, published in 1950 in his textbook, was ignored and the disorder was called Swyer’s Syndrome for a while.
Wilkins made many other seminal contributions to Pediatric Endocrinology during the short time that he was engaged in a full time academic career. Perhaps his single contribution that brought the nascent field of Pediatric Endocrinology into prominence was his poster session at the Sixth International Congress of Pediatrics in Zurich in 1950. This extensive display provided examples of each of the now common endocrine disorders in Pediatrics along with a delineation of diagnostic criteria and pathophysiologic basis, insofar as it was then known. This display was the foundation of his text, Disorders of Endocrine Secretions in Childhood and Adolescence.(13) Many European pediatricians came to Baltimore to study under Wilkins and on returning home, they founded the European Society of Pediatric Endocrinology (ESPE). Although the number of American postdoctoral fellows was not large, they and their fellows have made a very large impact on the development of Pediatric Endocrinology in America. Robert Blizzard and Claude Migeon, who succeeded Wilkins as codirectors of Pediatric Endocrinology at Harriett Lane honored their former chief by establishing an annual symposium in his name, and this symposium evolved into the Lawson Wilkins Pediatric Endocrine Society (LWPES).
The legacy left by Wilkins to the discipline of Pediatric Endocrinology is indeed remarkable for an individual who remained in the private practice of Pediatrics until well after his 50th birthday!
I have often wondered whether Wilkins should be included in the pantheon of great scientists. The word science comes from the Greek work “SCIO” which means “to know.” Wilkins’s major tool was insatiable curiosity – he could not stand not knowing. His curiosity led to great things, and I do not hesitate to classify him amongst the great scientists of all time.”
Table 1 shows Fellows of the Pediatric Endocrine Clinic, 1938-1963 (Figures 1, 2, 3, 4, 5, 6, 7, 8, 9)
A dinner at Old Point Comfort organized by the fellows in honor of the Wilkins family. Front, from left: Lytt Gardner, Mrs. Crigler, Lawson Wilkins, Mrs. Wilkins, Mrs. Klein, and Robert Klein. Back: Walter Eberlein, John Crigler, Claude Migeon, Judson Van Wyk, Alfred Bongiovanni, Melvin Grumbach, and Thomas Shepard. (1956)
The staff of the Pediatric Endocrine Clinic on the steps of the entrance of Harriet Lane Home. Front, from left: Bernadette Lauras, Claude Migeon, Lawson Wilkins, JoAnne Brasel, Robert Blizzard, John Money, Avinoam Kowarski, and Viola Lewis. Back: John Spaulding, Charles Snipes, Robert Chandler, James Wright, Jordan Finkelstein. (1962-1963)
A few months before his death, Lawson Wilkins had called a meeting of his past fellows. Front row, from left: Drs. James Wright, John Gerrard, Walter Eberlein, George Clayton, Jordan Finkelstein, Robert Klein. Second row: Drs. Robert Blizzard, Eugenia Rosemberg, Walter Fleischmann, Lawson Wilkins, JoAnne Brasel, Bernadette Lauras, John Money, Barbara Migeon. Third Row: Drs. William Cleveland, Alfred Bongiovanni, John Spaulding, Raphael David, Avinoam Kowarski, Claude Migeon, Frederic Kenny, Judson Van Wyk, David Alexander, Melvin Grumbach, Malcolm Martin, John Crigler, Robert Stempfel, David Mosier. Fourth Row: Drs. Donald Delahaye, Buford Nichols Jr., Charles Snipes, Wellington Hung, Orville Green, Thomas Aceto Jr. (1963)