IGF1 Haploinsufficiency in Children with Short Stature: A Case Series

Context: Short stature in children is a common reason for referral to pediatric endocrinologists. The underlying cause of short stature remains unclear in many cases and patients often receive unsatisfactory, descriptive diagnoses. While textbooks underline the rarity of genetic causes of growth hormone (GH) insensitivity and the severity of its associated growth failure, increased genetic testing in patients with short stature of unclear origin has revealed gene defects in the GH/ insulin-like growth factor (IGF-I) axis associated with milder phenotypes. As such, heterozygous IGF1 gene defects have been reported as a cause of mild and severe short stature. Here, we aimed to describe the clinical and hormonal profile of children with IGF1 haploinsufficiency and their short-term response to growth hormone treatment (GHT). Case descriptions: We describe five patients presenting with short stature, microcephaly, and in 4 out of 5 born small for gestational age diagnosed with IGF1 haploinsufficiency. The phenotype of these patients resembles that of previously described cases with similar gene defects. In our series, segregation of the short stature with the IGF1 deletion is evident from the pedigrees and our data suggests a modest response to GHT. Conclusions: This study is the first case series of complete heterozygous IGF1 deletions in children. The specific genetic defects provide a clear image of the phenotype of IGF1 haploinsufficiency - unbiased by heterozygous mutations with possible dominant negative effects on IGF-I function. We increase the evidence for IGF1 haploinsufficiency as a cause of short stature, microcephaly, and SGA.

Download Full-text

Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency

Journal of the Endocrine Society ◽

10.1210/js.2016-1119 ◽

2017 ◽

Vol 1 (4) ◽

pp. 345-358 ◽

Cited By ~ 13

Author(s):

Kanimozhi Vairamani ◽

Lina Merjaneh ◽

Paula Casano-Sancho ◽

Merve Emecen Sanli ◽

Alessia David ◽

...

Keyword(s):

Growth Hormone ◽

Combination Therapy ◽

Short Stature ◽

Growth Hormone Receptor ◽

Recombinant Human Growth Hormone ◽

Dominant Negative ◽

Negative Effects ◽

Intracellular Domain ◽

Early Protein ◽

Igf I

Abstract Context: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. Objective: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. Results: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. Conclusion: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.

Download Full-text

Idiopathic short stature: will genetics influence the choice between GH and IGF-I therapy?

Acta Endocrinologica ◽

10.1530/eje-07-0292 ◽

2007 ◽

Vol 157 (suppl_1) ◽

pp. S33-S37 ◽

Cited By ~ 14

Author(s):

Martin O Savage ◽

Cecilia Camacho-Hübner ◽

Alessia David ◽

Louise A Metherell ◽

Vivian Hwa ◽

...

Keyword(s):

Short Stature ◽

Growth Regulation ◽

Single Gene ◽

Idiopathic Short Stature ◽

Dominant Negative ◽

Growth Responses ◽

Igf I ◽

The Usa ◽

Gene Defects ◽

Gh Resistance

Background: Idiopathic short stature (ISS) includes a range of conditions. Some are caused by defects in the GH–IGF-I axis. ISS is an approved indication for GH therapy in the USA and a similar approval in Europe may be imminent. Genetic analysis for single-gene defects has made enormous contributions to understanding the physiology of growth regulation. Can this type of investigation help in predicting growth responses to GH or IGF-I therapy? Methods: The rationale for choice of GH or IGF-I therapy in ISS is reviewed. Many ISS patients have low IGF-I, but most can generate IGF-I levels in response to short-term GH administration. Some GH resistance seems to be present. Mutation analysis in several cohorts of GHIS and ISS patients is reviewed. Results: Low IGF-I levels suggest either unrecognised GH deficiency or GH resistance. In classical GHIS patients, there was a positive relationship between IGFBP-3 levels and height SDS. No relationship exists between mutations and phenotype. There is a wide variability of phenotype in patients carrying identical mutations. Heterozygous GH receptor (GHR) mutations were present in <5% of ISS patients and their role in causing growth defects is questionable. Exceptions are dominant negative mutations that have been shown to disturb growth. Conclusions: Analysis for single-gene defects does not give sensitive predictions of phenotype and cannot predict responses to GH or IGF-I therapy. Endocrine abnormalities have closer correlations with phenotype and may thus be a better guide to therapeutic responsiveness.

Download Full-text

First report on growth hormone treatment response in a patient with spondylodysplastic type of Ehlers-Danlos syndrome with normal growth hormone secretion

Zdravstvena zastita ◽

10.5937/zdravzast50-30794 ◽

2021 ◽

Vol 50 (1) ◽

pp. 47-56

Author(s):

Katarina Božić ◽

Tatjana Milenković ◽

Srđan Pašić ◽

Katarina Mitrović ◽

Slađana Todorović ◽

...

Keyword(s):

Growth Hormone ◽

Case Report ◽

Short Stature ◽

Treatment Response ◽

Growth Hormone Treatment ◽

Hormone Treatment ◽

Gh Treatment ◽

Ehlers Danlos Syndrome ◽

Gh Secretion ◽

First Case

Introduction/Aim: Spondylodysplastic Ehlers-Danlos Syndrome (sdEDS) is a rare genetic disorder of collagen synthesis, caused by a mutation in the B4GALT7, B3GALT6, or SLC39A13 gene. Features of this very rare disorder are short stature, hypotonia, hyperflexible joints, soft, thin, and overly stretchable skin, sparse hair and eyebrows, elderly face, wide forehead and prolonged wound healing. Molecular genetic analysis is needed for definite confirmation of the diagnosis. So far, only three case reports describing growth hormone treatment response in patients with sdEDS have been published. All of these patients had growth hormone (GH) deficiency. We present the first case report regarding growth hormone treatment response in a patient with sdEDS and normal GH secretion (without GH deficiency). Case report: Patient was a girl with short stature and normal GH secretion. Having in mind that the girl was born small for the gestational age, due to her short stature, she started using HR, before the diagnosis of sdEDS was made. Based on the lack of improvement in growth velocity as well as the girl's phenotype, genetic analyses were performed and the diagnosis of sdEDS due to biallelic mutations of the B4GALT7 gene was established. After the diagnosis of sdEDS was made and due to suboptimal response in growth velocity to the GH treatment, the GH therapy was stopped at the age of 11 years. Conclusion: This is a first case report regarding GH treatment in a child with sdEDS and normal GH secretion, demonstrating a very limited therapeutic effect of GH on linear growth in the presented patient.

Download Full-text

Growth Hormone Treatment of Children with Idiopathic Short Stature or Growth Hormone Sufficient Growth Failure

Pediatric Endocrinology ◽

10.1385/1-59259-336-4:067 ◽

2003 ◽

pp. 067-077

Author(s):

Jean-Claude Desmangles ◽

John Buchlis ◽

Margaret H. MacGillivray

Keyword(s):

Growth Hormone ◽

Short Stature ◽

Growth Hormone Treatment ◽

Growth Failure ◽

Hormone Treatment ◽

Idiopathic Short Stature

Download Full-text

MANAGEMENT OF ENDOCRINE DISEASE: Growth and growth hormone therapy in short children born preterm

Acta Endocrinologica ◽

10.1530/eje-16-0482 ◽

2017 ◽

Vol 176 (3) ◽

pp. R111-R122 ◽

Cited By ~ 5

Author(s):

Margaret Cristina da Silva Boguszewski ◽

Adriane de Andre Cardoso-Demartini

Keyword(s):

Growth Hormone ◽

Short Stature ◽

Survival Rates ◽

Adult Life ◽

Growth Failure ◽

Hormone Treatment ◽

Postnatal Growth ◽

Childhood Growth ◽

Short Children ◽

Postnatal Growth Failure

Approximately 15 million babies are born preterm across the world every year, with less than 37 completed weeks of gestation. Survival rates increased during the last decades with the improvement of neonatal care. With premature birth, babies are deprived of the intense intrauterine growth phase, and postnatal growth failure might occur. Some children born prematurely will remain short at later ages and adult life. The risk of short stature increases if the child is also born small for gestational age. In this review, the effects of being born preterm on childhood growth and adult height and the hormonal abnormalities possibly associated with growth restriction are discussed, followed by a review of current information on growth hormone treatment for those who remain with short stature during infancy and childhood.

Download Full-text