Publications by authors named "Robert Rapaport"

90 Publications

Graves disease in infancy: a patient presentation and literature review.

Endocrinol Diabetes Metab Case Rep 2021 Jun 1;2021. Epub 2021 Jun 1.

Icahn School of Medicine, Mount Sinai Department of Pediatric Endocrinology, Kravis Children's Hospital, New York, NY, USA.

Summary: We describe a case of an infant who presented with clinical features of hyperthyroidism. The child was found to be tachycardic, hypertensive and diaphoretic, she was noted to have poor weight gain and difficulty in sleeping. The child was admitted to the pediatric intensive care unit for care. She was found to have biochemical evidence of hyperthyroidism with positive thyroid stimulating immunoglobulin. She responded well to methimazole and propranolol and had a remarkable recovery. She is the youngest patient to be diagnosed with Graves disease in the English literature, at 12 months of life.

Learning Points: Hyperthyroidism must always be considered even at very young age, for patient presenting with poor weight gain and hyperdynamic state. Autoimmune diseases are becoming more common in infancy. Craniosynostosis and increased height for age are well-documented consequences of untreated hyperthyroidism in developing children.
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http://dx.doi.org/10.1530/EDM-20-0162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240725PMC
June 2021

Treatment of Pediatric Growth Hormone Deficiency With Oral Secretagogues Revisited.

J Endocr Soc 2021 Jul 22;5(7):bvab096. Epub 2021 May 22.

Pediatrics, Division of Pediatric Endocrinology and Diabetes, Mount Sinai Kravis Children's Hospital, NY, USA.

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http://dx.doi.org/10.1210/jendso/bvab096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207831PMC
July 2021

Clinical findings influencing time to menarche post gonadotropin-releasing hormone agonist therapy in central precocious puberty.

Ann Pediatr Endocrinol Metab 2021 May 12. Epub 2021 May 12.

Department of Pediatric Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: This study aimed to evaluate the time interval to menarche after gonadotropin-releasing hormone agonist (GnRHa) treatment in females with central precocious puberty (CPP) and identify factors contributing to timing of menarche.

Methods: We retrospectively reviewed medical records of 39 females with CPP who reached menarche after GnRHa treatment (leuprolide or histrelin). CPP diagnostic criteria were: breast development <8 years, pubertal luteinizing hormone and/or estradiol concentrations, and bone age advancement. Indications to treat are advanced bone age and psychosocial concerns. Descriptive summaries were reported as frequency and proportion for categorical variables and mean and standard deviation for continuous measures. Linear regression models were performed to evaluate the association between clinical factors with the time interval to menarche.

Results: Mean age was 9.4±1.6 years at treatment onset and treatment duration was 2.2±1.4 years. Menarche occurred at 12.6±1.1 years, which was 1.04±0.5 years after treatment discontinuation. This was negatively associated with Tanner stage of breast development and bone age at treatment onset, and change in bone age during treatment. No association was seen between time interval to menarche and treatment duration, medication, or body mass index.

Conclusion: We found the average time interval to menarche after GnRHa treatment in our population of female patients with CPP was 1.04±0.5 years and this is in agreement with other reports. Tanner stage of breast development and bone age at treatment onset, and change in bone age were negatively associated with time interval to menarche. This data provide clinical correlates that assist providers during anticipatory guidance of patients with CPP after GnRHa treatment.
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http://dx.doi.org/10.6065/apem.2040220.110DOI Listing
May 2021

Diabetic ketoacidosis drives COVID-19 related hospitalizations in children with type 1 diabetes.

J Diabetes 2021 Aug 27;13(8):681-687. Epub 2021 Apr 27.

University of Florida College of Medicine, Gainesville, Florida, USA.

Background: Diabetes is a risk factor for poor COVID-19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies.

Methods: T1D Exchange coordinated a US type 1 diabetes COVID-19 registry. Forty-six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID-19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization.

Results: Data from 266 patients with previously established type 1 diabetes aged <19 years with COVID-19 were reported. Diabetic ketoacidosis (DKA) was the most common adverse outcome (n = 44, 72% of hospitalized patients). There were four hospitalizations for severe hypoglycemia, three hospitalizations requiring respiratory support (one of whom was intubated and mechanically ventilated), one case of multisystem inflammatory syndrome in children, and 10 patients who were hospitalized for reasons unrelated to COVID-19 or diabetes. Hospitalized patients (n = 61) were more likely than nonhospitalized patients (n = 205) to have minority race/ethnicity (67% vs 39%, P < 0.001), public insurance (64% vs 41%, P < 0.001), higher A1c (11% [97 mmol/mol] vs 8.2% [66 mmol/mol], P < 0.001), and lower insulin pump and lower continuous glucose monitoring use (26% vs 54%, P < 0.001; 39% vs 75%, P < 0.001). Age and gender were not associated with risk of hospitalization. Higher A1c was significantly associated with hospitalization, with an odds ratio of 1.56 (1.34-1.84) after adjusting for age, gender, insurance, and race/ethnicity.

Conclusions: Higher A1c remained the only predictor for hospitalization with COVID-19. Diabetic ketoacidosis is the primary concern among this group.
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http://dx.doi.org/10.1111/1753-0407.13184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251108PMC
August 2021

Celiac disease: A global survey.

J Diabetes 2021 Jun 30;13(6):446-447. Epub 2021 Mar 30.

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http://dx.doi.org/10.1111/1753-0407.13178DOI Listing
June 2021

Screening for celiac disease in youth with type 1 diabetes: Are current recommendations adequate?

J Diabetes 2021 Jun 23;13(6):525-526. Epub 2021 Mar 23.

Department of Pediatrics, Division of Pediatric Endocrinology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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http://dx.doi.org/10.1111/1753-0407.13177DOI Listing
June 2021

SARS-CoV-2 infection-related diabetes mellitus.

J Diabetes 2021 Jun 19;13(6):523-524. Epub 2021 Mar 19.

Department of Pediatric Endocrinology, Mount Sinai Medical Center, New York, New York, USA.

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http://dx.doi.org/10.1111/1753-0407.13173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013172PMC
June 2021

Growth failure: 'idiopathic' only after a detailed diagnostic evaluation.

Endocr Connect 2021 Mar;10(3):R125-R138

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, UK.

The terms 'idiopathic short stature' (ISS) and 'small for gestational age' (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term 'SGA' was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms 'SGA' and 'ISS' as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.
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http://dx.doi.org/10.1530/EC-20-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052574PMC
March 2021

Increased DKA at presentation among newly diagnosed type 1 diabetes patients with or without COVID-19: Data from a multi-site surveillance registry.

J Diabetes 2021 Mar 24;13(3):270-272. Epub 2020 Dec 24.

Mount Sinai Kravis Children's Hospital, Icahn School of Medicine, New York, New York, USA.

Highlights Our multicenter study reports a higher proportion of diabetic ketoacidosis presentation of over 60% in newly diagnosed patients with type 1 diabetes with or without confirmed coronavirus disease 2019 (COVID-19) at diagnosis. This finding is suggestive of delays in seeking care during the COVID-19 pandemic.
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http://dx.doi.org/10.1111/1753-0407.13141DOI Listing
March 2021

Brain injury in children with diabetic ketoacidosis: Review of the literature and a proposed pathophysiologic pathway for the development of cerebral edema.

Pediatr Diabetes 2021 03 3;22(2):148-160. Epub 2020 Dec 3.

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.

Cerebral edema (CE) is a potentially devastating complication of diabetic ketoacidosis (DKA) that almost exclusively occurs in children. Since its first description in 1936, numerous risk factors have been identified; however, there continues to be uncertainty concerning the mechanisms that lead to its development. Currently, the most widely accepted hypothesis posits that CE occurs as a result of ischemia-reperfusion injury, with inflammation and impaired cerebrovascular autoregulation contributing to its pathogenesis. The role of specific aspects of DKA treatment in the development of CE continues to be controversial. This review critically examines the literature on the pathophysiology of CE and attempts to categorize the findings by types of brain injury that contribute to its development: cytotoxic, vasogenic, and osmotic. Utilizing this scheme, we propose a multifactorial pathway for the development of CE in patients with DKA.
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http://dx.doi.org/10.1111/pedi.13152DOI Listing
March 2021

Undervirilized male infant with in utero exposure to maternal use of high dose antifungal therapy.

Int J Pediatr Endocrinol 2020 9;2020:16. Epub 2020 Sep 9.

Division of Pediatric Endocrinology and Diabetes, Kravis Children's Hospital, Icahn School of Medicine at Mount Sinai, New York, NY USA.

Background: Antifungals act on fungal sterols structurally similar to human cholesterol. Ketoconazole reversibly suppresses steroidogenesis by inhibiting cytochrome P450 enzymes and interferes with dihydrotestosterone (DHT) activity by binding to the androgen receptor. Hypospadias was reported in infants exposed to nystatin in utero.

Case Presentation: A male infant exposed to antepartum nystatin presented with severe under-undervirilization and transient adrenal corticosteroid abnormalities. He was born in USA at 31 weeks gestation to a mother treated with vaginal Polygynax capsules (nystatin-100,000 international units, neomycin sulphate-35,000 international units and polymyxin B-35,000 international units) for vaginal discharge in the Ivory Coast. She used approximately 60 capsules between the first trimester until delivery. The infant was born with micropenis, chordee, perineo-scrotal hypospadias and bifid scrotum with bilaterally palpable gonads. The karyotype was 46,XY. No Mullerian structures were seen on ultrasound. Serum 17-hydroxyprogesterone (17 OHP) on newborn screening was high (304 ng/ml, normal < 35). Cortisol response to cosyntropin on the 3rd day of life (DOL) was 10 mcg/ml; the subnormal cortisol response may have resulted from prematurity and the predelivery treatment with betamethasone. The elevation of several adrenal corticosteroids was not consistent with any specific enzymatic defect. Hydrocortisone and fludrocortisone were initiated at another hospital for suspected mild glucocorticoid and mineralocorticoid deficiencies. Genetic screening for adrenal and gonadal developmental defects performed when transferred to our care were normal. All medications were gradually discontinued over 5-8 months. Adrenal and testicular responses to cosyntropin and human chorionic gonadotropin (hCG) were normal at 8 months.

Conclusions: We report severe undervirilization in a 46,XY infant born to a mother treated with prolonged and high dose nystatin during pregnancy. This presentation suggests that prolonged antepartum use of high dose nystatin could lead to severe but transient defects in androgen synthesis and/or action possibly by acting as an endocrine disruptor. Further studies are warranted to confirm this finding. Thus, endocrine disruptors should be considered in male newborns with atypical genitalia not explained by common pathologies.
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http://dx.doi.org/10.1186/s13633-020-00087-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488073PMC
September 2020

Update: Pediatric Diabetes.

J Diabetes 2020 Oct 13;12(10):769-771. Epub 2020 Mar 13.

Division of Pediatric Endocrinology & Diabetes, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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http://dx.doi.org/10.1111/1753-0407.13033DOI Listing
October 2020

Update: Pediatric Diabetes.

J Diabetes 2020 03 13;12(3):262-264. Epub 2019 Dec 13.

Division of Pediatric Endocrinology & Diabetes, Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1111/1753-0407.13012DOI Listing
March 2020

Peak Growth Hormone Response to Combined Stimulation Test in 315 Children and Correlations with Metabolic Parameters.

Horm Res Paediatr 2019 28;92(1):36-44. Epub 2019 Aug 28.

Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background/aims: Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH.

Methods: During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as &#x3c;10 ng/mL. IGF-1, IGF BP3, BMI, and metabolic parameters were obtained in a fasting state at baseline.

Results: In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol.

Conclusion: We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of &#x3c; 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.
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http://dx.doi.org/10.1159/000502308DOI Listing
April 2020

Update: Pediatric diabetes.

J Diabetes 2019 09 27;11(9):771-772. Epub 2019 May 27.

Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1111/1753-0407.12939DOI Listing
September 2019

Primary Cortisol Deficiency and Growth Hormone Deficiency in a Neonate With Hypoglycemia: Coincidence or Consequence?

J Endocr Soc 2019 Apr 20;3(4):838-846. Epub 2019 Feb 20.

Division of Pediatric Endocrinology and Diabetes, Mount Sinai Kravis Children's Hospital, Icahn School of Medicine at Mount Sinai, New York, New York.

Cortisol and growth hormone (GH) deficiencies are causes of neonatal hypoglycemia. When they coexist, a pituitary disorder is suspected. We present an infant with hypoglycemia in whom an ACTH receptor defect was associated with transient GH deficiency. A full-term boy with consanguineous parents presented with hypoglycemia (serum glucose 18 mg/dL) at 4 hours of life with undetectable serum cortisol (<1 μg/dL). Examination showed diffuse hyperpigmentation with normal male genitalia. Patient developed hyperbilirubinemia and elevated transaminase levels. GH levels of 6.8 ng/mL and 7.48 ng/mL during episodes of hypoglycemia, peak of 9.2 ng/mL with glucagon stimulation, and undetectable IGF-1 suggested GH deficiency. Thyroid function, prolactin, and gonadotropins were normal. Baseline ACTH was elevated at 4868 pg/mL, whereas serum cortisol remained undetectable with ACTH stimulation. Hydrocortisone replacement resulted in normalization of blood glucose and cholestasis with decline in ACTH level. GH therapy was not initiated, given improvement in cholestasis and euglycemia. An ACTH receptor defect was confirmed with molecular genetic testing that revealed homozygosity for a known mutation of the melanocortin 2 receptor () gene. At 12 weeks, a random GH level was 10 ng/mL. IGF-1 was 75 ng/mL and 101 ng/mL at 7 and 9 months, respectively. This report describes glucocorticoid deficiency from an mutation associated with GH deficiency. With glucocorticoid replacement, GH secretion normalized. Our findings are consistent with a previously stated hypothesis that physiologic glucocorticoid levels may be required for optimal GH secretion [1].
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http://dx.doi.org/10.1210/js.2018-00386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447946PMC
April 2019

Growth hormone therapy in children born small for gestational age: results from the ANSWER program.

Endocr Connect 2018 Aug 23. Epub 2018 Aug 23.

G Piccoli , Novo Nordisk Inc, Plainsboro, United States.

Growth hormone (GH) is used to treat short stature and growth failure associated with growth disorders. Birth size and GH status variably modulate response to GH therapy. The aim of this study was to determine the effect of birth size on response to GH therapy, and to determine the impact of GH status in patients born small for gestational age (SGA) on response to GH therapy. Data from the prospective, non-interventional American Norditropin® Studies: Web-Enabled Research (ANSWER) Program were analyzed for several growth outcomes in response to GH therapy over 3 years. GH-naïve children from the ANSWER Program were included in this analysis: SGA with peak GH ≥10 ng/mL (20 mIU/l), SGA with peak GH <10 ng/mL (20 mIU/l), isolated growth hormone deficiency (IGHD) born SGA, IGHD not born SGA, and idiopathic short stature. For patients with IGHD, those who did not meet criteria for SGA at birth showed greater improvements in height SDS and BMI SDS than patients with IGHD who met criteria for SGA at birth. For patients born SGA, response to GH therapy varied with GH status. Therefore, unlike previous guidelines, we recommend that GH status be established in patients born SGA to optimize GH therapy.
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http://dx.doi.org/10.1530/EC-18-0286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198185PMC
August 2018

Thyroid Ultrasound: More Sensitive than Radioactive Iodine Imaging in Detecting Recurrence of Papillary Thyroid Cancer in Two Pediatric Patients.

Horm Res Paediatr 2018 25;90(1):66-72. Epub 2018 May 25.

Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Papillary thyroid cancer (PTC) is an uncommon pediatric disease with an excellent prognosis. In follow-up surveillance, neck ultrasound (US), basal and thyroid-stimulating hormone-stimulated serum thyroglobulin (Tg) levels, and diagnostic whole-body radioactive iodine scans (DxWBS) have been traditionally used in both adults and children for the detection of recurrence or metastases of PTC.

Methods: Two pediatric patients with metastatic PTC were followed after standard ablative treatment with routine neck US and serum Tg levels, as well as periodic DxWBS.

Results: Neck US identified recurrent and metastatic PTC which DxWBS failed to detect.

Conclusion: Neck US was superior to DxWBS in the detection of recurrent PTC in these 2 pediatric patients. These findings are consistent with the 2015 American Thyroid Association (ATA) Guidelines that neck US is an ideal imaging modality in pediatric patients for the surveillance of PTC local recurrence or lymph node metastases.
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http://dx.doi.org/10.1159/000487436DOI Listing
December 2018

Ezh2 Mutations Found in the Weaver Overgrowth Syndrome Cause a Partial Loss of H3K27 Histone Methyltransferase Activity.

J Clin Endocrinol Metab 2018 04;103(4):1470-1478

Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.

Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function.

Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.

Results: A de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.

Conclusion: We generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.
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http://dx.doi.org/10.1210/jc.2017-01948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276576PMC
April 2018

Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome.

J Clin Endocrinol Metab 2017 07;102(7):2501-2507

Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.

Context: Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland characterized by the triad of a very thin/interrupted pituitary stalk, an ectopic (or absent) posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland. Complex genetic patterns of inheritance of this disorder are increasingly recognized.

Objective: The objective of this study was to identify a genetic cause of PSIS in an affected child.

Methods: Whole exome sequencing (WES) was performed by using standard techniques, with prioritized genetic variants confirmed via Sanger sequencing. To investigate the effects of one candidate variant on mutant WDR11 function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization.

Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus.

Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered.
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http://dx.doi.org/10.1210/jc.2017-00332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505202PMC
July 2017

Small at Birth, but How Small? The Definition of SGA Revisited.

Horm Res Paediatr 2016 30;86(5):357-360. Epub 2016 Sep 30.

Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA.

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http://dx.doi.org/10.1159/000449275DOI Listing
April 2017

Focus on Pediatric Endocrinology: Time to Revisit Some Established Challenges and Explore New Ones.

Authors:
Robert Rapaport

Endocrinol Metab Clin North Am 2016 06;45(2):xvii-xviii

Icahn School of Medicine at Mount Sinai, Division of Pediatric Endocrinology and Diabetes, Kravis Children's Hospital at Mount Sinai, One Gustave L. Levy Place, Box 1616, New York, NY 10029, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2016.04.001DOI Listing
June 2016

Genetic Techniques in the Evaluation of Short Stature.

Endocrinol Metab Clin North Am 2016 06;45(2):345-58

Division of Pediatric Endocrinology and Diabetes, Kravis Children's Hospital at Mount Sinai, One Gustave L. Levy Place, Box 1616, New York, NY 10029, USA; Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1616, New York, NY 10029, USA.

Normal growth is a complex dynamic process dependent on the coordination of multiple factors including genetics, nutrition and hormones that are all working in balance. This chapter will review selected features of commonly utilized genetic techniques such as chromosomal analysis, microarray analysis, targeted gene screening and whole exome sequencing that are being used to identify genes influencing growth. As genetic technologies continue to improve and become more accessible many of these techniques will help to provide a better understanding of mechanisms underlying abnormal growth and will eventually lead to novel management approaches for abnormal growth.
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http://dx.doi.org/10.1016/j.ecl.2016.02.006DOI Listing
June 2016

Thyroid Imaging in Infants.

Endocrinol Metab Clin North Am 2016 06;45(2):255-66

Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Radiology and Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Kravis Children's Hospital at Mount Sinai.

Congenital hypothyroidism is the most common preventable cause of mental retardation. It is important to know the cause of each patient's thyroid dysfunction to foresee the course of therapy and outcomes. Imaging methods, such as ultrasound and thyroid scan, help determine the anatomy and function of the thyroid gland. Although thyroid scan is considered superior in detecting ectopic thyroid tissue, ultrasound is able to detect the presence of thyroid tissue not otherwise visualized in 15% of patients.
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http://dx.doi.org/10.1016/j.ecl.2016.02.005DOI Listing
June 2016

Growth and growth hormone: An overview.

Growth Horm IGF Res 2016 06 23;28:3-5. Epub 2016 Feb 23.

Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sina, 1 Gustave L. Levy Place, NY, USA.

Growth is a good indicator of a child's health. Growth disturbances, including short stature or growth failure, could be indications of illnesses such as chronic disease, nutritional deficits, celiac disease or hormonal abnormalities. Therefore, a careful assessment of the various requirements for normal growth needs to be done by history, physical examination, and screening laboratory tests. More details will be reviewed about the GH-IGF axis, its abnormalities with special emphasis on GH deficiency, its diagnosis and treatment. GH treatment indications in the US will be reviewed and a few only will be highlighted. They will include GH deficiency, as well as the treatment of children born SGA, including the results of a US study using FDA approved dose of 0.48mg/kg/week. GH deficiency in adults will also be briefly reviewed. Treatment of patients with SHOX deficiency will also be discussed. Possible side effects of GH treatment and the importance of monitoring safety will be highlighted.
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http://dx.doi.org/10.1016/j.ghir.2016.02.004DOI Listing
June 2016

Erratum: A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome.

Mol Autism 2015 2;6:31. Epub 2015 Jun 2.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1230, New York, NY 10029 USA ; Icahn School of Medicine at Mount Sinai, New York, NY USA ; Friedman Brain Institute, New York, NY USA ; Mindich Child Health Institute, New York, NY USA ; Departments of Psychiatry, New York, NY USA ; Departments of Neuroscience, New York, NY USA ; Departments of Genetics and Genomic Sciences, New York, NY USA.

[This corrects the article DOI: 10.1186/2040-2392-5-54.].
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http://dx.doi.org/10.1186/s13229-015-0025-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450831PMC
June 2015

A 4-Year, Open-Label, Multicenter, Randomized Trial of Genotropin® Growth Hormone in Patients with Idiopathic Short Stature: Analysis of 4-Year Data Comparing Efficacy, Efficiency, and Safety between an Individualized, Target-Driven Regimen and Standard Dosing.

Horm Res Paediatr 2015 1;84(2):79-87. Epub 2015 May 1.

University of Maryland School of Medicine, Baltimore, Md., USA.

Background/aims: Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short stature (ISS) have not been optimized. To compare the efficacy, efficiency, and safety of an individualized, target-driven GH regimen with standard weight-based dosing after 4 years of treatment.

Methods: This is a 4-year, open-label, multicenter, randomized trial comparing individualized, formula-based dosing of Genotropin® versus a widely used ISS dose of Genotropin®. Subjects were prepubertal, had a bone age of 3-10 years for males and 3-9 years for females, were naive to GH treatment, and had a height standard deviation score (Ht SDS) of -3 to -2.25, a height velocity <25th percentile for their bone age, and peak stimulated GH >10 ng/ml. After the first 2 years, the individualized-dosing group was further randomized to either 0.18 or 0.24 mg/kg/week.

Results: At 4 years, subjects in all treatment regimens achieved similar average height gains of +1.3 SDS; however, the individualized dosing regimen utilized less GH to achieve an equivalent height gain.

Conclusion: Individualized, formula-based GH dosing, followed by a dose reduction after 2 years, provides a more cost-effective growth improvement in patients with ISS than currently employed weight-based regimens.
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http://dx.doi.org/10.1159/000381642DOI Listing
May 2016

A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome.

Mol Autism 2014 12;5(1):54. Epub 2014 Dec 12.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1230, New York, NY 10029 USA ; Friedman Brain Institute, New York, NY USA ; Mindich Child Health Institute, New York, NY USA ; Departments of Psychiatry, New York, NY USA ; Departments of Neuroscience, New York, NY USA ; Departments of Genetics and Genomic Sciences, New York, NY USA ; Icahn School of Medicine at Mount Sinai, New York, NY USA.

Background: Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.

Methods: Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.

Results: Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.

Conclusions: This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.
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http://dx.doi.org/10.1186/2040-2392-5-54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326443PMC
February 2015

SHOX gene variants: growth hormone/insulin-like growth factor-1 status and response to growth hormone treatment.

Horm Res Paediatr 2015 31;83(1):26-35. Epub 2015 Jan 31.

Division of Pediatric Endocrinology and Diabetes, Mount Sinai School of Medicine, New York, N.Y., USA.

Context: Short stature homeobox-containing gene (SHOX) variants of unknown clinical significance occur frequently among children with short stature, yet their growth hormone (GH)/insulin-like growth factor-1 (IGF-1) status and response to GH have not been studied.

Objective: To define GH and IGF-1 status in children with SHOX variants and assess their response to GH.

Patients And Methods: This is a retrospective review of children with short stature. Children with SHOX variants were compared to those with no variants. Height standard deviation scores (SDS) and IGF-1 SDS at baseline and during GH treatment at 6, 12, and 24 months were analyzed. Growth velocity (GV), maximum GH dose, IGF-BP3, and changes in height SDS, IGF-1 SDS, and GV were compared.

Results: Among 355 children, 83 (23%) had SHOX variants. Nineteen different SHOX variants were detected. There was no difference in age, height SDS, IGF-1 SDS, or IGF-BP3 between children with SHOX variants and those with normal SHOX. Height SDS, IGF-1 SDS, IGF-BP3, GV, and GH dose were not different between patients with SHOX variants and those without.

Conclusions: The GH and IGF-1 characteristics of children with short stature were not different between children with SHOX+ variants and children with no variants. Although these findings suggest that SHOX variants are polymorphisms, studies prospectively comparing individual SHOX variants are needed.
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http://dx.doi.org/10.1159/000365507DOI Listing
December 2015