Jennifer Harrington

Update on the Evaluation and Treatment of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that presents with a wide clinical phenotype spectrum: from perinatal lethality and severe deformities to very mild forms without fractures. Most cases of OI are due to autosomal dominant mutations of the type I collagen genes. A multidisciplinary approach with rehabilitation, orthopedic surgery, and consideration of medical therapy with bisphosphonates underpins current management. Greater understanding of the pathogenesis of OI may lead to novel, therapeutic approaches to help improve clinical symptoms of children with OI in the future.

Resting Energy Expenditure Is Decreased in Pseudohypoparathyroidism Type 1A.

CONTEXT Pseudohypoparathyroidism type 1A (PHP1A) is caused by loss-of-function mutations on the maternally inherited GNAS allele and is associated with early-onset obesity, neurocognitive defects, and resistance to multiple hormones. The role of energy intake vs central regulation of energy expenditure in the pathophysiology of obesity remains unclear. OBJECTIVE The aim of this study was to evaluate resting energy expenditure (REE) in participants with PHP1A. DESIGN We assessed REE, biochemical, endocrine, and auxological status of 12 participants with PHP1A who had normal or elevated body mass index; controls were a cohort of 156 obese participants. SETTING This study took place at Childrens Hospital in Philadelphia and Sick Childrens Hospital in Toronto. MAIN OUTCOME MEASURES REE as a percent of predicted REE was the outcome measure. RESULTS PHP1A participants had normal endocrine status while receiving appropriate hormone replacement therapy, but had significantly decreased REE as a percent of predicted REE (using the modified Schofield equation). CONCLUSION Our results are consistent with REE being the principal cause of obesity in PHP1A rather than it being caused by excessive energy intake or endocrine dysfunction.

Vitamin D and fetal–neonatal calcium homeostasis: findings from a randomized controlled trial of high-dose antenatal vitamin D supplementation

Background:There is current interest in the maternal–fetal effects of antenatal vitamin D supplementation, yet little data regarding vitamin D’s role in neonatal calcium homeostasis. We determined to assess the effect of high-dose antenatal vitamin D supplementation on fetal and neonatal calcium concentrations.Methods:In a double-blinded, placebo-controlled trial in Bangladesh, 160 pregnant women were randomized to oral vitamin D3 (35,000 IU/wk) or placebo from 26 to 29 wk of gestation.Results:Total serum calcium (Ca) was higher in cord blood of those supplemented vs. placebo (2.66 ± 0.1 vs. 2.61 ± 0.2 mmol/l; P = 0.04), but the difference in albumin-adjusted calcium was not statistically significant. Change in Ca concentration from birth to day 3 of life was attenuated by vitamin D (−0.10 ± 0.17) compared with placebo (−0.22 ± 0.18 mmol/l; P = 0.02). Maternal 25-hydroxyvitamin D (25(OH)D) (P = 0.04) and cord 25(OH)D (P < 0.01) were associated with day 3 infant Ca, suggesting that the effect of supplementation was mediated by change in maternal–infant vitamin D status. Six infants in each of the supplemented and placebo groups had transient hypercalcemia/hypercalcuria; in all the hypercalcemia/hypercalcuria was asymptomatic, spontaneously resolved, and unassociated with nephrocalcinosis at 1 mo of life.Conclusion:High-dose antenatal third-trimester vitamin D supplementation attenuated the early postnatal calcium nadir, without increasing the risk of postnatal hypercalcemia.Pediatric Research (2014); 76 3, 302–309. doi:10.1038/pr.2014.83

The Impact of Hypoparathyroidism Treatment on the Kidney in Children: Long-Term Retrospective Follow-Up Study

CONTEXT Adults with hypoparathyroidism have significant rates of nephrocalcinosis and impaired renal function. Little is known about the impact of hypoparathyroidism treatment on renal function in children. OBJECTIVES To determine the prevalence and predictors for renal abnormalities (nephrocalcinosis and decreased estimated glomerular filtration rate [eGFR]) in children with treated hypoparathyroidism. DESIGN AND SETTING A retrospective chart review of patients with permanent hypoparathyroidism at the Hospital for Sick Children, Toronto, between 1996 and 2013. PATIENTS Data of 29 patients (15 males) followed for at least 1 year with documented hypoparathyroidism were analyzed. Mean duration of follow up was 7.4 ± 5 years. MAIN OUTCOME MEASURES The presence or absence of nephrocalcinosis as detected on ultrasound and eGFR were evaluated. RESULTS Time-weighted average serum measurements were calculated for all biochemical variables. Mean total and ionized serum calcium were 8.9 ± 0.8 and 4.6 ± 0.5 mg/dL, respectively. Nephrocalcinosis was observed in 38% of the subjects, with the most significant predictors being the degree of relative hypercalcemia and hyperphosphatemia (R(2) = 0.47, P < .01). Although all patients had an eGFR greater than 60, in 45% of the children, the eGRF was between 60 and 90 mL/min per 1.73 m(2). Higher calcium concentrations (r = -0.42, P = .02) and a greater proportion of time with relative hypercalcemia (r = -0.41, P = .03) were associated with lower eGFR. CONCLUSIONS Our results establish that children with hypoparathyroidism treated with calcitriol and calcium supplements are at risk for nephrocalcinosis and decreased eGFR. Because hypoparathyroidism is most commonly a life-long condition, careful monitoring and management of calcium abnormalities has important future implications.

Use of local data to enhance uptake of published recommendations: an example from the diagnostic evaluation of precocious puberty

Background It has been recommended that basal luteinising hormone (LH) levels be used as the initial test to identify cases of central precocious puberty (CPP) in children. However, in clinical practice, gonadotropin-releasing hormone (GnRH) stimulation tests are frequently still used. Objective To assess the diagnostic utility of a single LH to identify CPP in girls, as a means to safely reduce GnRH stimulation testing rates. Design Retrospective analysis of patients referred for GnRH stimulation between August 2007 and December 2010, with prospective 12-month follow-up of GnRH stimulation testing rates post implementation of management algorithm. Patients 57 girls (6.2±2.1 years) with early signs of puberty. Main outcome measure Ability of basal LH to predict clinical pubertal progression, 6 months following the GnRH stimulation test. Results Pubertal progression occurred in 18 patients. All patients with a basal LH level ≥0.3 IU/L had subsequent pubertal progression, while 39 of 41 patients with a basal LH ≤0.2 IU/L did not progress, resulting in 100% specificity (95% CI 92% to 100%) and 90.5% sensitivity (69.6% to 98.8%). Using the locally derived algorithm, GnRH stimulation testing was redirected to patients with pubertal progression that was discordant with basal LH data. Post intervention, there was a 75% reduction in GnRH stimulation testing without comprising the rate of diagnosis of CPP. Conclusions Our results confirm the diagnostic utility of basal LH levels in the diagnosis of CPP and demonstrate that dissemination and interpretation of local data may facilitate change in clinical practice, resulting in streamlined patient care and cost savings.

The Child with Multiple Fractures, What Next?

Fractures are common during childhood; however, they can also be the presenting symptom of primary or secondary causes of bone fragility. The challenge is to identify those children who warrant further investigation. In children who present with multiple fractures that are not commonly associated with mild to moderate trauma or whose fracture count is greater than what is typically seen for their age, an initial evaluation, including history, physical examination, biochemistry, and spinal radiography, should be performed. In children with bone pain or evidence of more significant bone fragility, referral for specialist evaluation and consideration of pharmacologic treatment may be warranted.

Growth hormone secretion decreases with age in paediatric Prader‐Willi syndrome

Growth hormone deficiency is a common feature of Prader‐Willi syndrome; however, biochemical deficiency is not uniformly demonstrated. Criteria for GH treatment in paediatric PWS vary with some countries requiring documentation of biochemical GH deficiency. Data regarding the significance of age in the interpretation of GH stimulation test results, particularly in infants, are lacking. We aimed to assess age‐related trends in the prevalence of biochemical GH deficiency in infants and children with PWS.

TRPV6 Variants Interfere with Maternal-Fetal Calcium Transport through the Placenta and Cause Transient Neonatal Hyperparathyroidism

Transient neonatal hyperparathyroidism (TNHP) is etiologically a heterogeneous condition. One of the etiologies is an insufficient maternal-fetal calcium transport through the placenta. We report six subjects with homozygous and/or compound-heterozygous mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6), an epithelial Ca2+-selective channel associated with this condition. Exome sequencing on two neonates with skeletal findings consistent with neonatal hyperparathyroidism identified homozygous frameshift mutations before the first transmembrane domain in a subject born to first-cousins parents of Pakistani descent as well as compound-heterozygous mutations (a combination of a frameshift mutation and an intronic mutation that alters mRNA splicing) in an individual born to a non-consanguineous couple of African descent. Subsequently, targeted mutation analysis of TRPV6 performed on four other individuals (born to non-consanguineous Japanese parents) with similar X-rays findings identified compound-heterozygous mutations. The skeletal findings improved or resolved in most subjects during the first few months of life. We identified three missense variants (at the outer edges of the second and third transmembrane domains) that alter the localization of the TRPV6: one recurrent variant at the S2-S3 loop and two recurrent variants (in the fourth ankyrin repeat domain) that impair TRPV6 stability. Compound heterozygous loss-of-function mutations for the pathogenic frameshift allele and the allele with an intronic c.607+5G>A mutation resulted in the most severe phenotype. These results suggest that TNHP is an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport.

Annual Conference 2014 Highlights

Jamie Wooda, Elisa Gianib, Jennifer Harringtonc, Shideh Majidid, Vanita Paisc, Katrin Nagle, Elwaseila Hamdounf and Sabine Hoferg aDivision of Endocrinology, Diabetes and Metabolism, Department of Pediatrics, Children’s Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA; bPediatric, Adolescent and Young Adult Section, Joslin Diabetes Center, Harvard Medical School, Boston, MA; cDivision of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada; dBarbara Davis Center for Childhood Diabetes, Children’s Hospital Colorado, University of Colorado, Aurora, CO; eDepartment of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; fDivision of Pediatric Endocrinology, Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, University of Minnesota, Minneapolis, Minnesota and gDepartment of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria

Are elevated androgens a cause of discordant pubertal development? Evidence from a case of adrenocortical carcinoma

We present a case of an adolescent with an adrenocortical carcinoma that demonstrates the potential inhibitory effects of androgens on breast and endometrial development. A previously well 141⁄2-year-old girl presented with a 2-year history of worsening hirsutism and abdominal pain. She had onset of pubarche at 11 years, but had not yet had breast development or menarche. In contrast, her mother and sister had menarche at 12 and 11 years of age, respectively. On examination, her height was 150 4 cm (3rd percentile) and weight 57 3 kg (50th percentile). She had a deep voice, muscular build, and hirsutism involving her upper lip, chin, chest and lower back. There were no features suggestive of glucocorticoid excess. She was Tanner stage 1 for breast and 5 for pubic hair. The remainder of the examination was unremarkable. Investigations revealed significantly elevated androgens, with no evidence of glucocorticoid or mineralocorticoid excess (Table 1). Despite the lack of breast development, the gonadotropins and estradiol were in the pubertal range, and bone age was significantly advanced at 18 years. Imaging demonstrated a large left-sided retroperitoneal mass arising from the adrenal gland, consistent with an adrenocortical carcinoma, with no evidence of metastatic spread. On ultrasound, the uterus was peri-pubertal in size, but without a defined endometrial stripe. The patient proceeded to have an open trans-abdominal left adrenalectomy, with pathological confirmation of adrenocortical carcinoma. Postoperatively she had biochemical resolution of the hyperandrogenism (Table 1) and was monitored for pubertal progression. She had a menstrual bleed 2 months postoperatively and subsequently had regular monthly menses. Breast development also occurred postoperatively with progression from Tanner stage 1–5 within 15 months. Adrenocortical carcinomas are rare tumours, presenting in children most commonly with virilization. Our patient with an adrenocortical carcinoma presented with an unusual pubertal picture: complete lack of breast development and no increase in the endometrium, despite evidence of pubertal activation of the hypothalamic–pituitary–gonadal axis. We hypothesize that excessively high androgen levels interfered with breast and endometrial development. Pubertal mammary gland development is primarily initiated and driven by the presence of increasing oestrogen levels. The effect of androgens on breast tissue has been more controversial. By providing increased precursor supplies of oestrogen through aromatization, elevated androgen levels have been theorized to lead to stimulation of breast tissue. However, increasing evidence from in vitro and animal studies has shown that androgens, by down-regulating oestrogen receptor gene expression, can instead reduce proliferation and increase apoptosis in cultured human breast tissue. This has led to interest regarding the potential protective role of androgens in the development of breast cancer. Epidemiological studies have shown a reduced risk of breast cancer in women with polycystic ovarian syndrome. Postmenopausal women treated with trans-dermal testosterone and hormone replacement therapy demonstrate less breast cell proliferation on needle aspiration biopsy than those on hormone therapy alone. In addition, remission rates of breast cancer were doubled in a