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Review Pediatric Endocrinology
Key Developments in Pediatric
Endocrinology in 2015
Nazaneen Eshragh and Stephen H LaFranchi
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, US
T he year 2015 brought many exciting discoveries and key developments in the field of pediatric endocrinology. Examples range from reports
of a family with the first discovered insulin-like growth factor-2 gene mutation to a description of the first clinical trials of an ‘artificial
pancreas’ in children with diabetes mellitus, along with publication of important society guidelines, such as those for management of
thyroid nodules and cancer in children, the diagnosis of polycystic ovary syndrome in adolescents, and for neonatal hypoglycemia. This short
review will describe some of these key developments over the past year that we believe to be of interest to pediatric endocrinologists, organized
by endocrine categories.
Keywords Growth/growth hormone/insulin-like growth factors
Aggrecan, artificial pancreas, diabetes insipidus,
differentiated thyroid cancer, human growth
hormone, hypoglycemia, hypogonadism, insulin-
like growth factor-1 (IGF-1), insulin-like growth
factor-2 (IGF-2), polycystic ovary syndrome
Evidence has long supported insulin-like growth factor-2 (IGF-2) as an important fetal growth
factor. Begemann and co-workers from Germany and the Netherlands report four patients from a
multigenerational family with the combination of severe intrauterine and postnatal growth retardation,
relative macrocephaly, and Russell–Silver syndrome-like features, found to be caused by a paternally
inherited IGF2 nonsense mutation. 1 Neurodevelopment ranged from normal to modest impairment.
Skeletal maturation typically was delayed by a few years compared to chronological age. Endocrine
evaluation showed normal to elevated serum growth hormone (GH) and IGF-1 levels, while serum
IGF-2 levels were low for age (246–380 ng/mL). Adult height in three patients ranged from 148.0 to
170.0 cm (-4.0 to -1.6 standard deviation [SD]). GH treatment resulted in modest improvement in
height standard deviation score (SDS), with one patient reaching 170 cm.
Disclosure: Nazaneen Eshragh and Stephen H LaFranchi
have nothing to disclose in relation to this article. No
funding was received for the publication of this article.
Compliance with Ethics: This article involves a review
of the literature and did not involve any studies with human
or animal subjects performed by any of the authors.
Open Access: This article is published under the Creative
Commons Attribution Noncommercial License, which
permits any noncommercial use, distribution, adaptation,
and reproduction provided the original author(s) and source
are given appropriate credit.
Received: March 11, 2016
Accepted: April 21, 2016
Citation: US Endocrinology, 2016;12(2):87–9
Corresponding Author: Stephen H LaFranchi,
Department of Pediatrics, Oregon Health and Science
University, Portland, Oregon, 97239-3098, US.
Adding another piece to the ‘idiopathic’ short stature puzzle, Nilsson et al. describe 11 patients from
three families with autosomal dominant short stature. 2 Endocrine evaluation, including GH–IGF axis
function, was normal. They had features of a skeletal dysplasia, including brachydactyly, short thumbs,
and mid-face hypoplasia. Using whole exome sequencing, these patients were discovered to have a
heterozygous mutation in ACAN, a gene which codes for aggrecan, a proteoglycan in the extracelluar
matrix of the growth plate and other cartilaginous tissues. While most children with short stature have
delayed bone age, the unique feature in patients with aggrecan mutation is advanced bone age and
premature growth cessation.
Moving from new etiologies to unique treatment paradigms, Backeljauw et al. reported results from
the first study of combination GH/IGF-1 therapy in children with short stature. 3 In this randomized,
multicenter trial, enrolled children were below -2 SD in height, were GH sufficient, but had a serum
IGF-1 below -1 SD for age and gender. The rationale for combination therapy was that such children
might need an increase in both locally generated IGF-1 (from GH) and systemic IGF-1. In the first year,
children treated with GH/IGF-1 grew 9.7–11.2 cm/year (three groups, all receiving the same dose of
GH and incremental doses of IGF-1), compared to 9.3 cm/year in the GH alone group (highest IGF-1
dose significantly greater growth velocity vs. GH alone). Improved growth rate was sustained over three
years; the GH/IGF-1 group receiving the highest dose gained 1.9 SD in height, compared to 1.3 SD in the
GH-alone subjects. Adverse effects were similar in the GH/IGF-1 vs. GH alone, with the exception of a
higher frequency of lipohypertrophy and hypoglycemia in patients receiving the combination therapy,
perhaps because a significant proportion of these subjects had serum IGF-1 levels >+2 SD.
A potential adverse effect of GH treatment is the risk of neoplasia, either primary or secondary
malignancies in children with a history of prior cancer. This issue was explored in a PubMed search
carried out by the Pediatric Endocrine Society Drug and Therapeutics Committee. 4 In children without
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