Zeina M. Nabhan

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.

A randomized prospective study of insulin pump vs. insulin injection therapy in very young children with type 1 diabetes: 12‐month glycemic, BMI, and neurocognitive outcomes

Objective:  To compare glycemic control, body mass index (BMI), neurocognitive function, and parenting stress for preschool‐aged diabetic children randomized to treatment either with continuous subcutaneous insulin infusion (CSII) or with intensive insulin injection therapy (IIT).

Newborn Screening Results in Children with Central Hypothyroidism

OBJECTIVE To investigate newborn screening results in children with congenital hypopituitarism, including central hypothyroidism, and to determine whether there were differences between children who had abnormal results and children with normal newborn screening results. STUDY DESIGN Medical records of children with central hypothyroidism observed in our pediatric endocrinology clinics from 1990 to 2006 were reviewed. RESULTS Forty-two subjects (22 boys) were identified. Eight children (19%) had a low total thyroxine level (<5.0 mcg/dL) on the newborn screening test. The average total thyroxine level in the remaining 34 subjects was 9.8 +/- 3.4 mcg/dL. Thyrotropin levels were within the reference range in all children. No differences were found in the 2 groups for birth history, jaundice (53% overall), hypoglycemia (36% overall), or micropenis (43% of boys). Fifty-seven percent of children had septo-optic dysplasia, and 98% had multiple pituitary hormone deficiencies. Children with an abnormal newborn screening results were initially examined by a pediatric endocrinologist at an average age of 4.6 +/- 5.0 months, and children with normal newborn screening results were initially examined at an average age of 16.9 +/- 26.7 months (P = .037). CONCLUSIONS Most children with congenital central hypothyroidism have normal thyroid function at birth. Normal newborn screening results can be falsely reassuring and may contribute to a delay in diagnosis of hypopituitarism despite classic clinical features.

Medical care of girls with Turner Syndrome: where are we lacking?

OBJECTIVE To characterize the medical care of a large cohort of girls with Turner syndrome with a focus on changes in management since establishment of international consensus guidelines in 2007. METHODS We reviewed medical records of patients followed up for Turner syndrome between 2000 and 2010. RESULTS A total of 128 girls aged 13.2 ± 0.5 years were identified. Average age at diagnosis was 4.1 ± 5.1 years. Overall, medical assessments performed included a hearing test in 56%, thyroid screening in 95%, renal ultrasonography in 100%, and echocardiography in 100%. Before 2007, none of the patients had screening performed for celiac disease, dyslipidemia, or liver dysfunction, and none had routine electrocardiography or cardiac magnetic resonance imaging. Since 2007, 63% were screened for celiac disease, 54% for liver abnormalities, and 38% for dyslipidemia. Electrocardiography was performed in 23%, while cardiac magnetic resonance imaging was performed in 39%. Although conjugated equine oral estrogen was the main mode of estrogen replacement, a significant increase was noted in the use of transdermal estrogen during the past 2 years compared with that observed in the earlier interval (78% vs 10%, respectively). CONCLUSIONS Although changes in medical practice have occurred since establishment of the international Turner syndrome guidelines, screening for associated comorbidities was deficient in greater than 50% of the patients in our study. This is the first study evaluating medical care in a large cohort of pediatric patients with Turner syndrome, and our findings emphasize the need for continual education of all physicians involved in the care of this population.

Upper-Tract Genitourinary Malformations in Girls With Congenital Adrenal Hyperplasia

OBJECTIVE. The objective of this study was to determine the incidence, specific abnormalities, and clinical significance of upper-tract genitourinary malformations in girls with congenital adrenal hyperplasia. METHODS. Medical charts of children who received a diagnosis of congenital adrenal hyperplasia between 1985 and 2005 were reviewed. RESULTS. Of 107 patients with congenital adrenal hyperplasia, 66 girls were identified. Of these, 14 were found to have upper-tract genitourinary abnormalities. The anomalies consisted of vesicoureteral reflux grades 1 to 3 (9), hydronephrosis (4), and duplicated collecting system (1). Two boys with congenital adrenal hyperplasia and known upper-tract genitourinary anomalies were also identified. One had ureteropelvic junction obstruction, and the other had a left malrotated kidney with hydronephrosis. Four patients (1 boy, 3 girls) underwent surgery that consisted of ureteral reimplantation (2) and ureteral stent placement (2). The reflux eventually resolved in 3 patients and worsened in 1. Hydronephrosis improved in 1 patient. None of the patients developed any impairment in renal function. CONCLUSION. The incidence of upper-tract genitourinary anomalies in girls with congenital adrenal hyperplasia is much higher in our cohort than in the general population (21.2% vs 2%–4%). This association represents a potentially significant medical issue because some patients may require surgical intervention and antibiotic prophylaxis to prevent urinary tract infections and impairment in renal function.

Urinary tract infections in children with congenital adrenal hyperplasia

OBJECTIVE To investigate the incidence of urinary tract infections (UTIs) in children with congenital adrenal hyperplasia (CAH), and to determine whether there was a correlation between UTIs and the timing and type of genital surgery in girls. STUDY DESIGN Medical records of patients with CAH < or = 15 years were reviewed. A parent questionnaire regarding history of UTIs was completed. RESULTS Seventy-one patients with classic CAH (41 girls, 30 boys) aged 8.3 +/- 4.2 years were identified. Thirty-five (85%) girls had undergone feminizing genitoplasty at 1.1 +/- 0.8 years, while six (15%) had not. History of UTI was reported in nine (12.6%) patients (one boy, eight girls). In seven of the eight girls, genital surgery had been performed and all UTIs occurred after surgery. One UTI was reported in a girl who had not undergone surgery. No correlation was found between UTIs and the type of genital surgery. CONCLUSION The incidence of UTIs in children with CAH is similar to that in the general population. Although preliminary, our results do not suggest an increased risk of UTIs if surgery is delayed.

A comparison of referral patterns to the pediatric endocrine clinic before and after FDA approval of growth hormone for idiopathic short stature.

Abstract Background: Short stature is a common reason for referral to the pediatric endocrine clinic. In 2003, the US Food and Drug Administration (FDA) approved the use of growth hormone (GH) for the treatment of children with idiopathic short stature (ISS). Objective: To explore if this indication changed referrals for short stature (SS). Design/Methods: A retrospective chart review of children seen for SS in the pediatric endocrine clinic between July 1998 and June 1999 (interval one, n=138) and July 2005–June 2006 (interval two, n=268) was performed. Variables collected included age, gender, height (h), and parental heights. Results: Average height standard deviation score (HT-SDS) was –2.11±0.9 in interval one and –2.14±0.83 in interval two (p=ns). No differences in age, gender distribution, relationship between child and parental heights, the proportion of subjects started on GH for ISS or in the HT-SDS of those treated between the two intervals were identified. Nearly half of all children referred in each interval did not meet the technical criteria for short stature. Conclusions: No differences in referral patterns for SS in our area following FDA approval of GH for ISS were identified. Although referrals appear unchanged, additional investigation of GH prescribing patterns before and after this new indication is needed. Continued education of primary care physicians and the general public regarding the definition of SS and the eligibility for GH therapy should be pursued.

CHARACTERIZATION OF SPONTANEOUS AND INDUCED PUBERTY IN GIRLS WITH TURNER SYNDROME

OBJECTIVE To characterize puberty in girls with Turner syndrome (TS) and determine whether specific patient characteristics are associated with the timing of menarche. We also sought to compare spontaneous versus induced puberty in these patients. METHODS Medical records of girls followed in our Pediatric Endocrine clinic for TS from 2007 to 2015 were reviewed. RESULTS Fifty-three girls were included, of whom 10 (19%) achieved menarche spontaneously and 43 (81%) received hormone replacement therapy (HRT). Of girls receiving HRT, a younger age at estrogen initiation correlated with a longer time to menarche (P = .02), and a mosaic karyotype was associated with a shorter time to menarche (P = .02), whereas no relationship was seen for body mass index, estrogen regimen, or maternal age at menarche. Nineteen girls (44%) receiving HRT had bleeding on estrogen alone at a wide dose range and were more likely to be on transdermal than oral preparations (P = .01). Girls with spontaneous puberty achieved menarche at a younger age (P<.01) and were more likely to have mosaic TS (P = .02). CONCLUSION Significant variability in the timing of menarche exists among girls with TS. However, age at pubertal induction and karyotype were significantly correlated with age at menarche in our patients. A wide range of estrogen doses is seen in girls who bleed prior to progesterone, suggesting extreme variability in estrogen sensitivity among patients with TS. Girls achieving spontaneous menarche are younger and more likely to have a mosaic karyotype than those with induced menarche. Large-scale prospective studies are needed to confirm these results. ABBREVIATIONS BMI = body mass index; HRT = hormone replacement therapy; TS = Turner syndrome.

Hormone replacement therapy in children with hypogonadotropic hypogonadism: Where do we stand?

OBJECTIVE To characterize hormone replacement therapy in a cohort of adolescent males and females with hypogonadotropic hypogonadism (HH) with a focus on changes in management during the past 10 years. METHODS Medical records of patients followed for HH during the past 10 years were reviewed. RESULTS A total of 45 patients (22 female: 23 male) with HH were identified. The average age at HH diagnosis was 14.48 ± 2.02 years in females and 14.89 ± 1.64 years in males (P = .53). In females, the average age of pubertal induction was 14.53 ± 1.86 years. Conjugated equine estrogen was used in 54.5%, transdermal estradiol in 41%, and oral estradiol in 4.5%. The average duration to cycling was 1.96 ± 0.78 years. A progressive increase in the use of transdermal estradiol was noted over time, with 100% of females being started on this regimen since 2008. In males, the average age of induction was 15.22 ± 1.41 years. All were started on intramuscular testosterone cypionate at various doses. The average duration to full adult replacement was 1.95 ± 0.51 years. CONCLUSION There is no current standard of care to guide pubertal induction in adolescents with HH. However, a significant increase in the use of transdermal estrogen was noted in females during the past 10 years. While much less variability in pubertal induction was seen in males, wide disparities in doses and escalation schedules were found. Prospective studies aimed at elucidating optimal strategies for sex steroid replacement in this pediatric population are badly needed.

The Relationship Between Components of the Metabolic Syndrome and Bone Health

Childhood obesity has become a global epidemic in the past decade. It is now estimated that more than 17% of the US children and adolescents are obese. The effects of childhood obesity on overall health are multiple and involve various organ systems including the musculoskeletal system. Increased fat mass is associated with increased bone mineral density in adults; however, studies regarding obesity’s effects on bone mass in children have been conflicting. Some pediatric studies have demonstrated increased bone mass in overweight children compared to healthy weight peers, while others have shown that overweight youth have decreased bone mass relative to bone size and body weight and thus are at increased risk for fracture. Childhood obesity is associated with high fracture rates due to a combination of biologic and biomechanical factors. Childhood obesity has also been linked to multiple orthopedic complications. Reports indicate increased prevalence of musculoskeletal pain, lower extremity malalignment, slipped capital femoral epiphysis, genu valgum, Blount’s disease, and foot structure abnormalities in obese children compared to normal-weight counterparts. Increased physical activity is a cornerstone for treatment of childhood obesity; however, obese children often lead a more sedentary lifestyle than normal-weight peers, which in part results from musculoskeletal pain in the back, knees, and feet. In conclusion, while the full impact of obesity on the overall function and development of the growing child has not been studied completely, it is well established that obesity adversely affects the musculoskeletal system. More research is needed to better understand the full impact of obesity on bone accrual, fracture rates, and physical function in children.