Publications by authors named "Anna Ryabets-Lienhard"

13 Publications

  • Page 1 of 1

Reversible severe ovarian enlargement in an infant with significant insulin resistance.

Radiol Case Rep 2021 Jul 1;16(7):1760-1765. Epub 2021 May 1.

Division of Endocrinology, Children's Hospital Los Angeles and University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.

The extent, severity, and radiological findings of ovarian growth in infants with genetic syndromes of insulin resistance have not been fully described. We report a rare case of reversible massive ovarian enlargement in a female infant with a congenital insulin resistance syndrome, likely Rabson-Mendenhall syndrome given the less clinically severe course. The patient presented with neonatal diabetes with hyperinsulinemia and hyperglycemia due to congenital insulin resistance. She developed increasing severe bilateral ovarian enlargement which peaked at 4 months of age, followed by gradual decrease in size of the ovaries following treatment with insulin-sensitizing drugs and improved hyperinsulinemia. The ovarian enlargement is postulated to be secondary to the trophic effects of insulin acting in a gonadotropin-independent mechanism. Hyperinsulinemia in congenital insulin resistance can also result in hypertrophy of other organs. Understanding the pathophysiology behind massive ovarian enlargement in the setting of congenital insulin resistance syndromes can help guide appropriate therapy.
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http://dx.doi.org/10.1016/j.radcr.2021.03.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111256PMC
July 2021

Quantifying RANKL and OPG levels in healthy children: A large cross-sectional analysis.

Bone 2019 10 15;127:215-219. Epub 2019 Jun 15.

Center For Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles (CHLA), United States of America.

Background: There have been new advances in understanding bone remodeling on a molecular level including the RANKL-OPG pathway, leading to advancements in targeted therapeutic intervention. There is however limited data in pediatrics with little known on normative values in healthy children. This is the largest cohort to quantify RANKL, OPG, and RANKL: OPG levels in healthy children as well as study the influence of age, gender, Tanner stage, and BMI in this population.

Methods: Healthy subjects, 1-21 years of age, were recruited from general pediatric clinics affiliated with CHLA and in collaboration with samples stored from a previously completed study. Healthy children were defined as those with no chronic disease, daily medication, or fractures in the past six months. Free soluble RANKL and OPG levels were quantified using a sandwich ELISA.

Results: Three hundred samples were collected with overall serum concentrations of RANKL, OPG and RANKL: OPG of 0.28 pmol/L, 3.56 pmol/L and 0.08 pmol/L, respectively. Serum RANKL and RANKL: OPG concentrations were significantly different by age (p = 0.0001 and 0.0027, respectively). There was an overall downward trend by age except in the 11-15-year age group where a slight increase was noted. RANKL concentrations were also significantly different between Tanner stages, with highest concentrations seen at Tanner 3 (p = 0.0481), and zBMI (p = 0.001). OPG was inversely correlated with zBMI, but not influenced by gender, age, or Tanner stage.

Conclusion: We showed significant difference in RANKL levels by age, Tanner stage, and zBMI. OPG was inversely correlated with zBMI. Insight into circulating levels of RANKL, OPG and RANKL: OPG in healthy children may be a potential tool to better understand disease states in pediatrics. Future studies are needed to evaluate the clinical significance of RANKL and OPG levels for diagnostic and therapeutic purposes in this population.
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http://dx.doi.org/10.1016/j.bone.2019.06.012DOI Listing
October 2019

Meeting Report: 2018 Annual Meeting of the Pediatric Endocrine Society, Toronto, Canada, May 5-8, 2018, Selected Highlights.

Pediatr Endocrinol Rev 2018 Dec;16(2):284-293

Children's Hospital Los Angeles, 4650 Sunset Blvd, MS #61, Los Angeles, CA 90027, USA, E-mail:

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http://dx.doi.org/10.17458/per.vol16.2018.lama.mr.pestorontoDOI Listing
December 2018

A case of severe TBCE-negative hypoparathyroidism-retardation-dysmorphism syndrome: Case report and literature review.

Am J Med Genet A 2018 08 28;176(8):1768-1772. Epub 2018 Jul 28.

Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California.

Hypoparathyroidism-retardation-dysmorphism syndrome (HRD) is a rare autosomal recessive disorder attributed to the mutations in the tubulin-specific chaperone E (TBCE) gene, which is vital for microtubule function during mitosis, organelle positioning, and neuronal cytokinesis. HRD is a congenital syndromic hypoparathyroidism associated with growth deficiency, microcephaly, intellectual disability, ocular anomalies, and facial dysmorphism. To our knowledge, there is only one published case of mild HRD-like syndrome with no identifiable genetic etiology. We report a case of severe TBCE-negative phenotypic HRD in a 4-year-old female from India presenting with hypocalcemic seizures due to congenital hypoparathyroidism, extreme microcephaly, growth deficiency, ocular anomalies, and facial dysmorphism. SNP microarray and whole exome sequencing (WES) did not detect any abnormalities in TBCE or other genes of interest. WES revealed two variants of unknown clinical significance in CASC5 gene, which codes for a protein in the kinetochore and, interestingly similar to TBCE, is essential for proper microtubule function during mitosis and cell proliferation and has been implicated in primary microcephaly disorders. However, further targeted sequencing in the parents revealed both variants inherited from the unaffected mother. Significant copy number variant noise in the proband and her parents limited further analysis. At this time the role of variants in the CASC5 gene is unclear and cannot explain our patient's phenotype. In conclusion, we report a severe case of phenotypic HRD syndrome, in which extensive genetic evaluation failed to reveal an etiology. Our case demonstrates that the pathogenesis of HRD may be genetically heterogenous, meriting further genetic investigations.
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http://dx.doi.org/10.1002/ajmg.a.38851DOI Listing
August 2018

The Optic Nerve Hypoplasia Spectrum: Review of the Literature and Clinical Guidelines.

Adv Pediatr 2016 08;63(1):127-46

Center for Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA; The Saban Research Institute, Children's Hospital Los Angeles, 4661 Sunset Boulevard, Los Angeles, CA 90027, USA.

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http://dx.doi.org/10.1016/j.yapd.2016.04.009DOI Listing
August 2016

Efficacy of growth hormone replacement on anthropometric outcomes, obesity, and lipids in children with optic nerve hypoplasia and growth hormone deficiency.

Int J Pediatr Endocrinol 2016 2;2016. Epub 2016 Mar 2.

The Vision Center, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027 USA ; The Saban Research Institute, Children's Hospital Los Angeles, 4661 Sunset Boulevard, Los Angeles, CA 90027 USA.

Background: Hypopituitarism and obesity are causes of major lifelong morbidity in patients with optic nerve hypoplasia (ONH). Growth hormone deficiency (GHD) affects the majority of children with ONH, though the degree of deficiency and variability of early growth patterns range from early severe retardation to normal initial growth. The utility of early GH replacement for improving anthropometric, body composition, and lipid outcomes in patients with ONH and GHD, especially those with normal initial height velocity, is unknown. This study examines the effects of GH replacement in a cohort of children with ONH and GHD.

Methods: Controlled clinical trial from 2005-2014. The study included 17 children with ONH and untreated GHD. Those meeting criteria for growth deceleration were assigned to treatment with recombinant human growth hormone (n = 5) while those with normal height velocity were randomized either to treatment (n = 5) or to observation (no intervention, n = 7). Study duration was 3 years. Primary outcome measures included stature, weight, weight-for-stature, and BMI standard deviation score (SDS) at study completion.

Results: Subjects on GH, irrespective of entry growth trajectory, grew more on average in stature than controls by a difference of 0.98 SDS by study end; this effect persisted after adjusting for baseline overweight status. Treatment had an effect on weight SDS only after adjusting for initial overweight status, resulting in an average increase of 0.83 SDS more than controls. Subjects who were overweight at the outset experienced greater gains in both weight and stature SDS. Treatment had no statistically significant impact on weight-for-stature or BMI SDS. A reduction in body fat percentage was observed in those treated, both before (-6.1 %) and after (-4.3 %) adjustment for initial overweight status.

Conclusion: Early GH replacement has a positive effect on short-term statural outcomes in children with ONH and GHD, even in those exhibiting normal initial linear growth. Results were less conclusive regarding treatment effects on body composition and lipids.
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http://dx.doi.org/10.1186/s13633-016-0023-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774157PMC
March 2016

Carotid Intima-Media Thickness Is Associated with Increased Androgens in Adolescents and Young Adults with Classical Congenital Adrenal Hyperplasia.

Horm Res Paediatr 2016 3;85(4):242-9. Epub 2016 Mar 3.

Division of Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, Calif., USA.

Background/aims: Youth with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency develop cardiovascular disease (CVD) risk factors of obesity and hypertension. Carotid intima-media thickness (CIMT), a marker of CVD risk, is increased in CAH young adults. We examined CIMT and its relationship with androgens and obesity in adolescents/young adults with CAH.

Methods: Twenty CAH subjects (age 16 ± 3.3 years, 50% female) and 20 matched controls were studied cross-sectionally. Eight additional obese patients with CAH were included in within-group comparisons. CIMT by high-resolution ultrasound, androgens, anthropometry, bone age (BA), and metabolic/inflammatory markers were assessed.

Results: Within the CAH group, CIMT correlated with 17-hydroxyprogesterone (r = 0.48, p < 0.05) and androstenedione (r = 0.46, p < 0.05), and was greater in obese subjects. CIMT was greater in CAH males than females, but similar among CAH females with advanced BA, CAH males with normal BA, and control males. There was no difference in CIMT between CAH and controls, although high-density lipoprotein was inversely correlated with CIMT in both groups.

Conclusion: CIMT is associated with increased androgens in CAH adolescents and young adults, with loss of sex differences in CAH females with excess androgen exposure. Our findings highlight the importance of hormonal control for CVD prevention in CAH.
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http://dx.doi.org/10.1159/000444169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865455PMC
April 2017

Increased Abdominal Adiposity in Adolescents and Young Adults With Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency.

J Clin Endocrinol Metab 2015 Aug 10;100(8):E1153-9. Epub 2015 Jun 10.

Children's Hospital Los Angeles (M.S.K., A.R.-L., A.D.-T., S.D.M., V.G., S.M.S., M.E.G.); Division of Endocrinology (M.S.K., A.R.-L., A.D.-T., S.D.M., M.E.G.) and Hospital Medicine (S.M.S.); and Department of Radiology (V.G.), Los Angeles, California 90027; and The Saban Research Institute and the University of Southern California (M.S.K., S.D.M., V.G., M.E.G.), Los Angeles, California 90027.

Context: Childhood obesity rates in congenital adrenal hyperplasia (CAH) exceed the high rates seen in normal children, potentially increasing their risk of cardiovascular disease (CVD). Abdominal adiposity, in particular visceral adipose tissue (VAT), is strongly associated with metabolic syndrome and CVD. However, it remains unknown whether VAT is increased in CAH.

Objective: The objective of the study was to determine whether adolescents and young adults with classical CAH have more VAT and sc adipose tissue (SAT) than matched controls and whether VAT and SAT are associated with biomarkers of metabolic syndrome, inflammation, and hyperandrogenism in CAH.

Design/setting: This was a cross-sectional study at a tertiary center.

Participants: CAH subjects (n = 28; 15.6 ± 3.2 y; 15 females) were matched for age, sex, ethnicity, and body mass index to healthy controls (n = 28; 16.7 ± 2.3 y; 15 females).

Main Outcome Measures: VAT and SAT, using computed tomography imaging and serum biomarkers associated with CVD risk, were measured. Data are reported as mean ± SD.

Results: Both VAT (43.8 ± 45.5 cm(2)) and SAT (288.1 ± 206.5 cm(2)) were higher in CAH subjects than controls (VAT 26.4 ± 29.6 cm(2) and SAT 226.3 ± 157.5 cm(2); both P < .001). The VAT to SAT ratio was also higher in CAH subjects (0.15 ± 0.07) than controls (0.12 ± 0.06; P < .05). Within CAH, measures of obesity (waist to height ratio, fat mass) and inflammation (plasminogen activator inhibitor-1, high-sensitivity C-reactive protein, leptin) correlated strongly with VAT and SAT. In addition, homeostasis model assessment of insulin resistance, and low-density lipoprotein correlated with abdominal adiposity. There were no sex differences for VAT or SAT in CAH subjects.

Conclusions: CAH adolescents and young adults have increased abdominal adiposity, with a higher proportion of proinflammatory VAT than SAT. An improved understanding of the mechanism of obesity in CAH may lead to targeted prevention and therapeutics in this high-risk population.
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http://dx.doi.org/10.1210/jc.2014-4033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524992PMC
August 2015

Endocrine Society 96th Annual Meeting & EXPO Chicago, IL USA (June 20-24, 2014) selected highlights.

Pediatr Endocrinol Rev 2014 Dec;12(2):239-55

Children's Hospital Los Angeles, Keck School of Medicine of USC, CA, USA.

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December 2014

Decreased adrenomedullary function in infants with classical congenital adrenal hyperplasia.

J Clin Endocrinol Metab 2014 Aug 30;99(8):E1597-601. Epub 2014 May 30.

Division of Endocrinology (M.S.K., A.R.-L., B.B., A.H.P., S.H., M.E.G.), Children's Hospital Los Angeles, The Saban Research Institute (M.S.K., M.E.G.), and the University of Southern California (M.S.K., C.J.L., M.E.G.), Los Angeles, California 90027.

Context: Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can cause life-threatening adrenal crises as well as severe hypoglycemia, especially in very young children. Studies of CAH patients 4 years old or older have found abnormal morphology and function of the adrenal medulla and lower levels of epinephrine and glucose in response to stress than in controls. However, it is unknown whether such adrenomedullary abnormalities develop in utero and/or exist during the clinically high-risk period of infancy and early childhood.

Objective: The objective of the study was to characterize adrenomedullary function in infants with CAH by comparing their catecholamine levels with controls. Design/Settings: This was a prospective cross-sectional study in a pediatric tertiary care center.

Main Outcome Measures: Plasma epinephrine and norepinephrine levels were measured by HPLC.

Results: Infants with CAH (n = 9, aged 9.6 ± 11.4 d) had significantly lower epinephrine levels than controls [n = 12, aged 7.2 ± 3.2 d: median 84 [(25th; 75th) 51; 87] vs 114.5 (86; 175.8) pg/mL, respectively (P = .02)]. Norepinephrine to epinephrine ratios were also significantly higher in CAH patients than controls (P = .01). The control infants had primary hypothyroidism, but pre- and posttreatment analyses revealed no confounding effects on catecholamine levels.

Conclusions: This study demonstrates for the first time that infants with classical CAH due to 21-hydroxylase deficiency have significantly lower plasma epinephrine levels than controls, indicating that impaired adrenomedullary function may occur during fetal development and be present from birth. A longitudinal study of adrenomedullary function in CAH patients from infancy through early childhood is warranted.
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http://dx.doi.org/10.1210/jc.2014-1274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121032PMC
August 2014

2012 annual meeting of the Endocrine Society, Houston, Texas (June 23-26 2012) selected highlights.

Pediatr Endocrinol Rev 2012 Dec-2013 Jan;10(2):246-59

University of California, San Francisco, San Francisco, CA 94143-0434, USA.

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May 2013

Management of congenital adrenal hyperplasia in childhood.

Curr Opin Endocrinol Diabetes Obes 2012 Dec;19(6):483-8

Center for Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, Los Angeles, California 90027, USA.

Purpose Of Review: Congenital adrenal hyperplasia (CAH) can present management challenges to the pediatric clinician. Glucocorticoid replacement remains the cornerstone of treatment; however, there are new formulations and delivery mechanisms being studied. Clinicians continue to discuss the optimal treatment of patients from the prenatal stage, through infancy to adulthood. As well, the role of genetics in the clinical care of patients with CAH, and screening for complications, remain topics of discussion. This review will highlight advances made in the past year, as they pertain to the management of pediatric patients with CAH.

Recent Findings: This article covers recent studies pertaining to optimal medication regimens, including prenatal dexamethasone treatment; medication delivery; monitoring of hormonal control; and the role of genotyping and genetics in the management of children with CAH.

Summary: Much remains to be learned about the optimal management of children with CAH, including fludrocortisone replacement in simple-virilizing patients, frequency of specific monitoring strategies (e.g., electrolytes, bone age), catecholamine status, stress-dosing in nonclassical adrenal hyperplasia, and early screening for complications or metabolic sequelae. Further randomized and prospective studies are needed to address these issues.
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http://dx.doi.org/10.1097/MED.0b013e32835a1a1bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584711PMC
December 2012
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