Erica A. Eugster

Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children

OBJECTIVE. Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents. PARTICIPANTS. When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise. EVIDENCE. Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion. CONSENSUS PROCESS. Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement. CONCLUSIONS. The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.

Summary of Consensus Statement on Intersex Disorders and Their Management

Advances in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital repair, and the persistent controversies inherent to clinical management were all compelling factors that led to the organization of an international consensus conference. The goals were to acknowledge and discuss the more controversial issues in intersex management, provide management guidelines for intersex patients, and identify and prioritize questions that need additional investigation. This is a summary statement. Advances in molecular genetic causes of abnormal sexual development and heightened awareness of the ethical and patient-advocacy issues mandate reexamination of existing nomenclature for patients with intersex.1 Terminology such as “pseudohermaphroditism” is controversial, potentially pejorative to patients,2 and inherently confusing. Therefore, the term “disorders of sex development” (DSD) is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex. Additional rationale for new classification is the need for modern categorization to integrate the modern molecular genetic aspects, to maximize precision when applying definitions and diagnostic labels,3 and to meet the need for psychologically sensitive yet descriptive medical terminology. Nomenclature should be flexible enough to incorporate new information, robust enough to maintain a consistent framework, use descriptive terms, reflect genetic etiology, accommodate phenotypic variation spectrum, and be useful for clinicians, scientists, patients, and families. Hence, we propose a new classification (see “Consensus Statement on Management of Intersex Disorders”4 in this months issue of Pediatrics Electronic Edition ). Three traditionally conceptualized domains of psychosexual development are gender identity (ones self-representation [ie, male or female]), gender role (sexually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic interest). Gender dissatisfaction denotes unhappiness with assigned sex and may result in gender self-reassignment. Psychosexual developmental factors relate to parental psychopathology, parent-child … Address correspondence to Peter A. Lee, MD, PhD, Department of Pediatrics, MC-H085, Penn State College of Medicine, Milton S. Hershey Medical Center, Box 850, 500 University Dr, Hershey, PA 17033-0850. E-mail: plee{at}psu.edu

McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia

Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of café-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, Gsα, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues.The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD.

Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial.

OBJECTIVE We undertook a 1-year multicenter trial of tamoxifen treatment for precocious puberty in girls with McCune-Albright syndrome (MAS). STUDY DESIGN Girls < or =10 years with classic or atypical MAS were recruited. Pretreatment history was collected for 6 months. Patients received 20 mg tamoxifen daily. Diaries were used to record bleeding. Evaluations included physical examination, bone age, pelvic ultrasound, hormone levels, and safety assessments. RESULTS A total of 28 girls (2.9-10.9 years of age) were enrolled from 20 centers, of whom 25 completed 12 months of tamoxifen treatment. Compared with before the study, vaginal bleeding episodes decreased (3.42+/-3.36/year vs 1.17+/-1.41/year), growth velocity slowed (SDS 1.22+/-2.65 vs -0.59+/-3.06, P=.005), and rate of bone maturation decreased (1.21+/-0.78 vs 0.72+/-0.36, P=.02). Ovarian volumes were enlarged and asymmetric throughout the study, and uterine volumes were increased. No adverse events occurred. CONCLUSIONS Tamoxifen treatment of precocious puberty in MAS results in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation.

Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: A pilot comparative study

BACKGROUND The optimal route of estrogen replacement in Turner syndrome (TS) is unknown. OBJECTIVE The objective of the study was to compare conjugated oral vs. transdermal estrogen (TD E2) on bone accrual, uterine growth, pubertal development, IGF-I, and lipids in girls with TS. METHODS Prepubertal GH-treated girls aged 10 yr or older with TS were eligible. Subjects were randomized to conjugated oral estrogen or TD E2 for 1 yr. Assessments included dual-emission x-ray absorptiometry, pelvic ultrasound, Tanner staging, growth velocity, IGF-I, and lipid profile. RESULTS Twelve girls (14.0 +/- 1.7 yr) were enrolled. TD E2 resulted in a significantly greater change in spine bone density at 12 months compared with conjugated oral estrogen (bone mineral content 9.0 +/- 0.9 vs. 5.8 +/- 0.9 g, P = 0.04; bone mineral density 0.12 +/- 0.01 vs. 0.06 +/- 0.01 g/cm2, P = 0.004; Z-score 0.7 +/- 0.1 vs. 0.3 +/- 0.1, P = 0.03). Greater increases in uterine length (4.13 +/- 0.39 vs. 1.98 +/- 0.39 cm, P = 0.003) and volume (22.2 +/- 4.4 vs. 4.0 +/- 4.4 ml, P = 0.02) were also found in the TD vs. the oral group at 1 yr. At study end, 66% of subjects in the TD group had a mature uterus vs. 0% in the oral group. No significant differences in other parameters examined were seen. CONCLUSION In girls with TS, TD E2 resulted in faster bone accrual at the spine and increased uterine growth compared with conjugated oral estrogen. This pilot study provides preliminary information for optimizing estrogen replacement in this population.

Position Statement: Continuous Subcutaneous Insulin Infusion in Very Young Children With Type 1 Diabetes

Insulin pump therapy has become increasingly popular for the treatment of type 1 diabetes in pediatric patients. Although significant experience has accrued with the use of this modality in older children and adolescents, much less data are available regarding continuous subcutaneous insulin infusion in the very young. Policies of individual physician practices and insurance companies vary widely, and there is currently no consensus regarding the appropriateness of insulin pump therapy in the under 6 age group. However, we have witnessed in recent years a significant increase in the number of clinical trials investigating the use of continuous subcutaneous insulin infusion in young patients, and reports of >100 preschool-aged diabetic children treated with insulin pumps are available in the literature. Although these studies have been of relatively short duration (≤12 months), the results are remarkably consistent. Although there is no evidence that insulin pump therapy results in a sustained improvement in glycemic control in this age group, risks associated with these devices in the hands of reliable adults who are managing diabetes in very young children are low. Parental satisfaction related to the increased flexibility that continuous subcutaneous insulin infusion affords anecdotally seems to be high, although formal examination of parental stress and health-related quality of life in this setting has been minimal. Important questions remain regarding selection of appropriate candidates for insulin pump therapy, whether benefits of continuous subcutaneous insulin infusion outweigh the costs, and what eventual outcomes will be in children treated with pumps from a very young age. Long-term follow-up of medical, psychological, and neurocognitive parameters in these young patients will be paramount. Our goal with this review is to summarize efficacy and safety of continuous subcutaneous insulin infusion in children ≤6 years of age, present potential pros and cons of using insulin pumps in this population, and propose clinical management guidelines that could be useful for both practitioners and third-party payers alike.

Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development.

Although treatment of children and adolescents who have disorders of growth and adolescent development with aromatase inhibitors is increasingly common, data for or against their use are extremely limited. Precocious puberty, short stature, and gynecomastia are conditions for which inhibition of the enzyme aromatase might prove beneficial to reduce clinical signs of estrogenization and/or estrogen-mediated skeletal maturation. In this report, we summarize the published data regarding the use of aromatase inhibitors in these conditions, and review known and potential benefits, safety concerns, and shortcomings of the available information.

Ascertainment Bias in Turner Syndrome: New Insights From Girls Who Were Diagnosed Incidentally in Prenatal Life

Objective. To evaluate differences in phenotype and other clinical features between patients who have Turner syndrome diagnosed incidentally (on the basis of a prenatal karyotype performed for reasons unrelated to suspicion of Turner syndrome, eg, advanced maternal age) or traditionally (on the basis of either a prenatal karyotype performed for abnormal ultrasound findings or a postnatal karyotype performed for clinical findings suggesting Turner syndrome). Methods. Analysis was performed on baseline data from 88 girls, aged 9 months to 4 years, who were randomized into a multicenter growth hormone intervention trial. Baseline information included a detailed medical history (especially of cardiac and renal anomalies), examination for presence of phenotypic features characteristic of Turner syndrome, length or height (depending on age) expressed as a standard deviation score, and weight standard deviation score. Patients were classified to either the “incidental” (N = 16) or the “traditional” (N = 72) diagnosis group as described above. Results. The incidental group had significantly fewer total phenotypic features of Turner syndrome than the traditional group (3.6 ± 2.9 vs 6.7 ± 2.9). When subgrouped by karyotype, the proportion of patients who manifested phenotypic features was greatest in patients with a 45,X nonmosaic karyotype, lowest in the patients with 45,X/46,XX mosaicism, and intermediate in those with “other” karyotypes. Fewer congenital cardiac defects were observed in the incidental group (31%) compared with the traditional group (64%), but there was no difference between the groups in the prevalence of renal defects. Karyotype distribution differed significantly between the traditional and incidental groups: 74% versus 19% had the nonmosaic 45,X karyotype in the traditional group and 7% versus 56% had the mosaic 45,X/46,XX karyotype. Conclusions. Patients whose Turner syndrome was diagnosed incidentally had significantly fewer phenotypic features and cardiac defects, as well as a greater proportion of mosaic karyotypes, compared with patients whose Turner syndrome was diagnosed clinically. These results support the theory that significant ascertainment bias exists in our understanding Turner syndrome, with important implications for prenatal counseling.

The aromatase inhibitor anastrozole is ineffective in the treatment of precocious puberty in girls with McCune-Albright syndrome.

CONTEXT Precocious puberty (PP) in girls with McCune-Albright syndrome (MAS) is characterized by episodic development of large unilateral ovarian cysts followed by sudden onset of vaginal bleeding. Some patients experience frequent bleeding as well as accelerated linear growth and advanced skeletal maturation. The use of anastrozole for the treatment of PP in this condition has not been well studied. OBJECTIVE The objective of the study was to determine the safety and efficacy of the aromatase inhibitor anastrozole for the treatment of PP in girls with MAS. DESIGN AND SETTINGS This was a prospective international multicenter study in which subjects received anastrozole 1 mg daily for 1 yr. PATIENTS Twenty-eight girls 10 years of age or younger with MAS and progressive PP were enrolled. MAIN OUTCOME MEASURES Vaginal bleeding, rate of skeletal maturation (change in bone age over change in chronological age), growth velocity, and uterine/ovarian volumes were measured. These indices were compared with a 6-month pretreatment interval. RESULTS No difference in vaginal bleeding (mean number of days per year) was noted. Mean change in DeltaBA/DeltaCA, which was 1.25 +/- 0.77 at baseline, was -0.25 +/- 1.02 at study end (P = 0.22). Average growth velocity z score was 1.40 +/- 3.15 at study entry and 0.26 +/- 2.71 at 12 months (P = 0.10). Mean ovarian/uterine volumes were unaffected by anastrozole, and no significant adverse events occurred. CONCLUSIONS Although it appears safe, anastrozole for 1 yr was ineffective in halting vaginal bleeding, attenuating rates of skeletal maturation, and linear growth in girls with MAS. Pharmacological strategies other than anastrozole should be pursued for the treatment of PP in this population.

Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system structural defects in children with optic nerve hypoplasia.

OBJECTIVE Optic nerve hypoplasia (ONH) is a heterogeneous disease with variable findings of pituitary insufficiency, CNS and neurodevelopmental abnormalities. We characterized the spectrum of endocrinopathy in a cohort of children with ONH and attempted to correlate the presence of different midline CNS findings with the degree of hypopituitarism. The correlation of variable CNS abnormalities with the presence of a seizure disorder and neurodevelopmental delay was also examined. METHODS Charts of 56 patients with ONH referred to our endocrine clinics between 1990 and 2000 were reviewed. Neurodevelopmental assessment was based on questionnaires sent to families during the study period. RESULTS Forty-six patients (82%) had hypopituitarism, with growth hormone deficiency being the most common endocrinopathy. All patients with diabetes insipidus, hypocortisolism, and hypogonadotropin hypogonadism also had combined pituitary hormone deficiency. Evolving pituitary hormone deficiency was observed in two of 37 patients diagnosed with hypopituitarism in the first 3 years of life. No single midline CNS finding correlated with the presence of hypopituitarism or a seizure disorder. However, hydrocephalus or a seizure disorder was more commonly seen in patients with developmental delay. CONCLUSION ONH is a heterogeneous disorder with possible multifactorial etiologies. All patients with this diagnosis deserve a comprehensive endocrine and neurodevelopmental evaluation.