Profile of the Pediatric Endocrine Clinic at New York–Presbyterian Hospital, New York Weill Cornell Center1

Maria I. New, Jihad Obeid, Robert C. Wilson, Monina S. Cabrera, Amanda Goseco, Maria C. Macapagal, Ian Marshall, Saroj Nimkarn, Jose B. Quintos, Svetlana Ten, Figen Ugrasbul, Laurie Vandermolen and Madeleine D. Harbison

Department of Pediatrics, Division of Pediatric Endocrinology, Weill Medical College of Cornell University, New York, New York 10021

Address correspondence and requests for reprints to: Maria I. New, M.D., Professor and Chairman, Department of Pediatrics, Chief, Division of Pediatric Endocrinology, Harold and Percy Uris Professor of Pediatric Endocrinology and Metabolism, New York–Presbyterian Hospital, 525 East 68th Street, Room M-622, New York, New York 10021. E-mail: minew{at}mail.med.cornell.edu


    Introduction
 Top
 Introduction
 Clinic Description
 Results
 Discussion
 Conclusion
 References
 
IN 1927, THE CORNELL University Medical College, now named The Weill Medical College of Cornell University, and The New York Hospital (which in 1998 became the Cornell campus of the merged New York–Presbyterian Hospitals) formally integrated their educational, research, and health care functions. The Medical College is also formally affiliated or closely associated with Memorial Sloan-Kettering Cancer Center, the Hospital for Special Surgery, and Rockefeller University, which are adjacent medical institutions. Together these institutions constitute one of the largest private centers of medical care, education, and research in the world.

In 1964, Dr. Maria I. New was appointed the first Director of the Division of Pediatric Endocrinology and established the university hospital’s first Pediatric Endocrine Clinic. In 1968, the National Institutes of Health funded a grant to the College for an inpatient and outpatient Pediatric Clinical Research Center, which has operated continuously to the present.

There has been no published comprehensive profile of a pediatric endocrine clinic profile since that in Lawson Wilkins’ (1) 1965 textbook on childhood and adolescent endocrine disorders. Hence, we thought it valuable to present a modern clinic profile in a major academic medical center, focusing on the past 5 years, which is the culmination of the clinic’s dynamic 35-yr history at The New York Hospital–Cornell Medical Center. In addition to the general endocrine clinic, we have had a particular focus on steroid disorders. Currently, our Division of Pediatric Endocrinology consists of the Director, six academic full-time faculty members, and eight clinical fellows. We shall review herein the philosophy, structure, and diagnostic patient profile of the outpatient pediatric endocrine service for the past 5 years, from 1994 to the present.


    Clinic Description
 Top
 Introduction
 Clinic Description
 Results
 Discussion
 Conclusion
 References
 
Operation of the clinic

Sixty-five percent of the endocrine service patients come from the five boroughs of the New York metropolitan area. Twenty-eight percent are referred from the remainder of New York State and the states of New Jersey and Connecticut. Five percent are patients from the rest of the United States, and 2% are referred from abroad.

The age distribution of our patients is shown in Fig. 1Go. The large number of patients in the newborn period reflects referrals from New York State Newborn Screening Laboratories. The patients over 20 yr of age represent the cohort of patients referred for abnormalities of androgen metabolism, relatives of congenital adrenal hyperplasia (CAH) patients, the patients Dr. New has continued to follow into adulthood, and adults with GH deficiency.



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Figure 1. Histogram showing the number of patients seen in each age category during the years of 1994–1999.

 
Our outpatient endocrine service sees patients daily. There are three formal clinics: the general Endocrine Clinic, Dr. New’s Steroid Clinic, and a Diabetes Clinic. Approximately 10% of outpatients are seen on the Children’s Clinical Research Center (CCRC). A total of about 70 patients are seen each week.

Our outpatient service follows a conference clinic format in which trainees—consisting of fellows, residents, and medical students—are supervised by a faculty member. Each patient on the service is followed by a specific fellow and has an attending-of-record. The patients’ clinical and laboratory data are logged in a computerized database, which was developed by the Informatics Section of the CCRC. The frequently used provocative tests are shown in Table 1Go.


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Table 1. Frequently used endocrine stimulation and suppression tests

 
In the Steroid Clinic, Dr. New sees her patients with disorders of steroid metabolism and sexual differentiation, many of whom she has followed since birth. She has developed a detailed form for following a patient with CAH, which enables accurate tracking of steroid levels, medication doses, linear growth, and bone age advancement (Fig. 2Go). These collected data points are entered into our informatics system.



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Figure 2. The form for ongoing care of patients with CAH.

 
Steroid patients are generally seen at 3-month intervals, at which time an adrenal hormone profile is obtained. The Pediatric Steroid Laboratory measures the following steroids: deoxycorticosterone, corticosterone, cortisol, aldosterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate, {Delta}4-androstenedione, testosterone, dihydrotestosterone, estradiol, progesterone, 17-hydroxyprogesterone, 17-{Delta}5-pregnenolone. The molecular genetic laboratory conducts DNA analysis.

Weekly division conference—education and training

A weekly conference is chaired by Dr. New and attended by our entire Division, visiting scientists, residents, and medical students. Frequently other members of our scientific team, such as Dr. James German, geneticist and scholar in residence, and Dr. Leon Bradlow, steroid biochemist, also attend the conference. Interesting and/or enigmatic cases are presented to Dr. New and discussed in depth. Dr. Jean Wilson, the world-renowned endocrinologist from the University of Texas Southwestern Medical Center, attends on a regular basis. The conferences attended by Dr. Wilson are so interesting and educational that scientists come from many outside centers to participate. Guest speakers are invited at regular intervals to present relevant and novel research related to patients. Research-in-progress presentations are periodically scheduled during this conference, in which fellows or scientists in the department update the team on their research findings; these talks are usually preparation for presentations at national or international symposia and conferences.

Our Division has trained over 100 fellows since 1965, many of whom have gone on to distinguished careers. Over 30 are endocrine chiefs or heads of departments.


    Results
 Top
 Introduction
 Clinic Description
 Results
 Discussion
 Conclusion
 References
 
Frequency of diagnosis

Using the Accreditation Council for Graduate Medical Education categories for pediatric endocrinology patients, the most frequent diagnosis of the approximately 3800 patients seen since 1994 was growth abnormalities, followed by thyroid pathology, disorders of sexual development, and adrenal disorders (Table 2Go). Patients with carbohydrate, bone mineral, and anterior pituitary disorders made up a smaller group. Posterior pituitary cases were rare. When these categories were subdivided, the following pattern emerged (Table 3Go). In the growth abnormalities category, short stature was by far the leading diagnosis. Dysmorphic syndromes, failure-to-thrive, and delayed puberty followed in frequency. Only a very small number of patients were referred for tall stature. In the anterior pituitary category, hypopituitarism including isolated GH deficiency was the most frequent diagnosis. In the thyroid hormone category, referrals to rule out hypothyroidism increased markedly, owing to New York State laboratory newborn screening. Of these referrals, the diagnosis of hypothyroidism was confirmed in one third of the cases. Hyperthyroidism and goiter accounted for 10% of cases referred for thyroid pathology.


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Table 2. Number of patients in each of the major diagnostic categories

 

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Table 3. Diagnostic subdivisions

 
Among the patients evaluated for adrenal disorders, CAH, comprising various enzyme defects of steroid synthesis, was the most frequent diagnosis, followed by patients being tested for suspected CAH. Of the CAH patients, 92% had 21-hydroxylase deficiency.

Owing to our discovery of the disease, we are a major international referral center for apparent mineralocorticoid excess (AME), and we are one of the few centers in which an AME study population has been examined clinically, biochemically, and genetically. Remarkably, AME was diagnosed in 15 patients referred here out of about 40 known cases in the world. Twenty-seven family members of these patients were also studied.

The diagnoses falling into the category of disorders of sexual differentiation were more evenly distributed, with evaluations for precocious puberty, premature thelarche, and polycystic ovary disease being the most common.

Among the calcium/phosphate disorders, vitamin D deficiency and X-linked hypophosphatemic rickets were the main diagnoses.

Diabetes and obesity were frequent among the remaining endocrine patients, whereas all other diagnoses were relatively rare.

Treatment with human GH (hGH)

The total number of patients treated with hGH in the last 5 years was 347, with the number each year being similar (Table 4Go). Table 5Go shows the distribution of the number of GH-treated patients with different diagnoses.


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Table 4. Patients treated with recombinant hGH

 

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Table 5. Number of patients treated with recombinant hGH in each diagnostic category

 
Molecular genetic diagnosis

The number of 21-hydroxylase-deficient CAH patients and their families who have been genotyped by molecular genetic techniques was 152 since 1994. Since the molecular genetic laboratory was established in 1992, a total of 198 families followed here have had DNA analysis for 21-hydroxylase deficiency (Table 6Go). There are an additional 331 patients who are either probands in families referred for prenatal diagnosis or consultation cases. These patients also had molecular genetic analysis of CYP21. The most frequent mutations in the CYP21 gene are the intron 2 and deletion mutations (Table 7Go).


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Table 6. Patients with molecular genetic diagnosis for 21-hydroxylase deficiency

 

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Table 7. Allelic frequency of mutations in 21-hydroxylase deficient patients

 
Prenatal diagnosis and treatment

The molecular genetic laboratory made possible the prenatal diagnosis of 21-hydroxylase deficiency, 11ß-hydroxylase deficiency, and AME. Since 1994, 241 fetuses and their families have had DNA analysis of the 21-hydroxylase gene (CYP21). Altogether since 1989, 330 fetuses have been tested for 21-hydroxylase deficiency by molecular genetic techniques (Table 8Go). Of these, 70 have been identified as affected. Molecular genetic diagnoses have been used in two pregnancies at-risk for 11ß-hydroxylase deficiency.


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Table 8. Molecular genetic diagnoses in fetuses at risk for 21-hydroxylase deficiency

 
Patients never seen

As evidence that pediatric endocrinology has become a biochemical and molecular genetic discipline, we receive two to three requests monthly for consultation in which only blood or DNA is evaluated for diagnosis.

CCRC

We owe the discovery of several diseases and advances in therapy to our 32-yr-old federally funded CCRC. It has allowed us to integrate clinical, biochemical, and genetic data in a controlled setting and has permitted us to assemble statistically significant numbers of patients of rare diseases. Furthermore, the data from these patients have been logged into the CCRC informatics system.


    Discussion
 Top
 Introduction
 Clinic Description
 Results
 Discussion
 Conclusion
 References
 
The profile of the Clinic reported in the 1965 edition of the Lawson Wilkins (1) textbook indicates the referrals to the best-known pediatric endocrinologist of his time: 3190 cases in 27 years. This contrasts with 3778 patients seen by this clinic in 5 years. Although the distribution of diagnoses has not changed significantly, the great increase in the number of patients seen in today’s Pediatric Endocrine Clinic reflects the heightened awareness of the role of hormones in health and disease in children. Several other factors may account for the increase in the number of patients referred to our clinic. For example, the development of bioengineered GH has resulted in the availability and clinical use of GH in the treatment of children. The impact of the advances in molecular genetic analysis plus the interest of the director of the clinic in steroid disorders probably account for the marked increase in the patients seen with CAH. Thyroid screening in the state of New York has been responsible for the increase in patients seen with hypothyroidism. The marked increase in childhood obesity in the United States is also paralleled in the Pediatric Endocrine Clinic.

Another change from the time of Lawson Wilkins is the marked increase in the use of provocative tests. These tests are evidence of the more biochemical approach to diagnosis. This has made possible the diagnosis of the large number of patients never seen whose biological samples are evaluated by biochemical or genetic tests.

The international character of our Clinic is reflected in the trainees, the visiting scientists, and the patients. Referrals from abroad are no longer rare. Fellows from 1991–1999 have originated from all over the world, including Argentina, Iran, Brazil, the Philippines, India, the Dominican Republic, Greece, Bangladesh, Egypt, Thailand, Croatia, Turkey, and Russia. International visiting scientists (1994–1999), bringing a world view to our clinic, and returning home with an intimate awareness of our medical and scientific advances, have come from Egypt, China, Iran, Brazil, Greece, Italy, and Germany.


    Conclusion
 Top
 Introduction
 Clinic Description
 Results
 Discussion
 Conclusion
 References
 
Molecular genetic techniques and provocative endocrine testing have changed the practice of pediatric endocrinology. However, in the end, our patients remain our most important teachers. The rare and complicated cases provide an arena for our trainees to learn physiologic mechanisms and therapeutics. Our Division members are taught to consider the ethical, social, and legal issues as vital to the medical care of their patients. Unusual patients have become "prismatic cases," leading to the discovery of diseases such as AME (11ß-hydroxysteroid dehydrogenase type 2 deficiency) and the mechanism of resistance to several steroids. Furthermore, by inviting collaboration from our colleagues worldwide, we provide our patients with cutting edge diagnostic and therapeutic techniques.


    Footnotes
 
1 Significant sections of the work on which the data are reported herein were supported by USPHS-NIH Grants HD-00072 and RR-06020. Back

Received October 13, 1999.

Accepted October 15, 1999.


    References
 Top
 Introduction
 Clinic Description
 Results
 Discussion
 Conclusion
 References
 

  1. Wilkins L. 1965 The relation of extrinsic genetic and endocrine factors to growth and development. In: Blizzard RM, Migeon CJ, eds. The diagnosis and treatment of endocrine disorders in childhood and adolescence, 3rd ed. Springfield, IL: Charles C. Thomas; 3–11.