Publications by authors named "Vivian Hwa"

101 Publications

Growth Hormone Receptor (GHR) 6Ω Pseudoexon Activation: a Novel Cause of Severe Growth Hormone Insensitivity.

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute, London EC1M 6BQ, UK.

Context: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.

Objective: This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals.

Methods: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute.

Context: Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.

Objective: Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.

Design: A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T>G, c.618 + 836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

Human growth disorders associated with impaired GH action: Defects in STAT5B and JAK2.

Authors:
Vivian Hwa

Mol Cell Endocrinol 2021 01 27;519:111063. Epub 2020 Oct 27.

Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, 45229, United States. Electronic address:

Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-JAK2-signal transducer and activator of transcription (STAT)-5B signaling pathway. Inactivating STAT5B mutations, both autosomal recessive (AR) and dominant-negative (DN), are causal of a spectrum of GH insensitivity (GHI) syndrome, IGF-I deficiency and postnatal growth failure. Only AR STAT5B defects, however, confer additional characteristics of immune dysfunction which can manifest as chronic, potentially fatal, pulmonary disease. Somatic activating STAT5B and JAK2 mutations are associated with a plethora of immune abnormalities but appear not to impact human linear growth. In this review, molecular defects associated with STAT5B deficiency is highlighted and insights towards understanding human growth and immunity is emphasized.
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http://dx.doi.org/10.1016/j.mce.2020.111063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736371PMC
January 2021

A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes.

Horm Res Paediatr 2020 28;93(5):322-334. Epub 2020 Oct 28.

Department of Pediatrics, University of Florida, Gainesville, Florida, USA,

Introduction: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery.

Case Presentation: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4+ Th-cell lineage commitment.

Discussion: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.
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http://dx.doi.org/10.1159/000510764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726096PMC
October 2020

Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings.

J Clin Immunol 2021 01 22;41(1):136-146. Epub 2020 Oct 22.

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Patients with rare homozygous mutations in signal transducer and activator of transcription 5B (STAT5B) develop immunodeficiency resulting in chronic eczema, chronic infections, autoimmunity, and chronic lung disease. STAT5B-deficient patients are typically diagnosed in the teenage years, limiting our understanding of the development of associated phenotypic immune abnormalities. We report the first detailed chronological account of post-natal immune dysfunction associated with STAT5B deficiency in humans. Annual immunophenotyping of three siblings carrying a novel homozygous nonsense mutation in STAT5B was carried out over 4 years between the ages of 7 months to 8 years. All three siblings demonstrated consistent B cell hyperactivity including elevated IgE levels and autoantibody production, associated with diagnoses of atopy and autoimmunity. Total T cell levels in each sibling remained normal, with regulatory T cells decreasing in the oldest sibling. Interestingly, a skewing toward memory T cells was identified, with the greatest changes in CD8 effector memory T cells. These results suggest an importance of STAT5B in B cell function and naïve versus memory T cell survival. Progressive dysregulation of FOXP3 regulatory T cells and CD8 memory T cell subsets reveal a crucial role of STAT5B in T cell homeostasis. The early diagnosis and focused immune evaluations of these three young STAT5B-deficient siblings support an important role of STAT5B in adaptive immune development and function.
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http://dx.doi.org/10.1007/s10875-020-00884-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854992PMC
January 2021

Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity.

Eur J Endocrinol 2020 Dec;183(6):581-595

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

Objective: Copy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS). It has not been extensively investigated in growth hormone insensitivity (GHI; short stature, IGF-1 deficiency and normal/high GH) or previously in IGF-1 insensitivity (short stature, high/normal GH and IGF-1).

Design And Methods: Array comparative genomic hybridisation was performed with ~60 000 probe oligonucleotide array in GHI (n = 53) and IGF-1 insensitivity (n = 10) subjects. Published literature, mouse models, DECIPHER CNV tracks, growth associated GWAS loci and pathway enrichment analyses were used to identify key biological pathways/novel candidate growth genes within the CNV regions.

Results: Both cohorts were enriched for class 3-5 CNVs (7/53 (13%) GHI and 3/10 (30%) IGF-1 insensitivity patients). Interestingly, 6/10 (60%) CNV subjects had diagnostic/associated clinical features of SRS. 5/10 subjects (50%) had CNVs previously reported in suspected SRS: 1q21 (n = 2), 12q14 (n = 1) deletions and Xp22 (n = 1), Xq26 (n = 1) duplications. A novel 15q11 deletion, previously associated with growth failure but not SRS/GHI was identified. Bioinformatic analysis identified 45 novel candidate growth genes, 15 being associated with growth in GWAS. The WNT canonical pathway was enriched in the GHI cohort and CLOCK was identified as an upstream regulator in the IGF-1 insensitivity cohorts.

Conclusions: Our cohort was enriched for low frequency CNVs. Our study emphasises the importance of CNV testing in GHI and IGF-1 insensitivity patients, particularly GHI subjects with SRS features. Functional experimental evidence is now required to validate the novel candidate growth genes, interactions and biological pathways identified.
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http://dx.doi.org/10.1530/EJE-20-0474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592635PMC
December 2020

Genetic causes of growth hormone insensitivity beyond GHR.

Rev Endocr Metab Disord 2021 03 8;22(1):43-58. Epub 2020 Oct 8.

Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA.

Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.
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http://dx.doi.org/10.1007/s11154-020-09603-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979432PMC
March 2021

Prenatal diagnosis of Proteus syndrome: Diagnosis of an AKT1 mutation from amniocytes.

Birth Defects Res 2020 11 15;112(19):1733-1737. Epub 2020 Sep 15.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activating mutation in AKT1. Rare prenatal presentations include segmental tissue overgrowth, and skeletal and CNS anomalies. We present the first report of prenatally diagnosed and molecularly confirmed Proteus syndrome. Prenatal imaging identified megalencephaly, brain and eye malformations, focal soft tissue enlargement, and ambiguous genitalia. Exome sequencing performed on cultured amniocytes demonstrated an AKT1 pathogenic variant consistent with Proteus syndrome, and postnatal examination confirmed the diagnosis. Postnatal Sanger sequencing could not identify the AKT1 pathogenic variant. This case underscores the importance of prenatal exome sequencing on cultured amniocytes for mosaic overgrowth disorders, as well as provides additional information on the prenatal phenotype of Proteus syndrome, and highlights the impact of prenatal diagnosis on postnatal management.
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http://dx.doi.org/10.1002/bdr2.1801DOI Listing
November 2020

Anthropometric and biochemical correlates of PAPP-A2, free IGF-I, and IGFBP-3 in childhood.

Eur J Endocrinol 2020 Mar;182(3):363-374

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Objective: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors.

Design: Cross-sectional study at a single center.

Methods: PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3-18 years old) and an evaluation of the relationship between these proteins and anthropometric factors.

Results: In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = -0.58, -0.65; P < 0.0001).

Conclusions: This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.
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http://dx.doi.org/10.1530/EJE-19-0859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238294PMC
March 2020

Severe growth failure associated with a novel heterozygous nonsense mutation in the GHR transmembrane domain leading to elevated growth hormone binding protein.

Clin Endocrinol (Oxf) 2020 04 22;92(4):331-337. Epub 2020 Jan 22.

Section of Diabetes and Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Objective: To report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity.

Context: Laron syndrome (LS) is a well-described disorder of growth hormone insensitivity due to mutations in the growth hormone receptor (GHR) that leads to short stature. Biochemically, LS patients classically have elevated levels of growth hormone (GH), but low levels of insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-3 and GH binding protein (GHBP).

Design: Case presentation with in vitro functional studies.

Patients: A young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP.

Measurements: Growth hormone stimulation tests revealed baseline GH level of 20.9 µg/L and maximum stimulated GH level of 52.7 µg/L and GHBP level of 4868 pmol/L. GHR gene sequencing revealed a novel heterozygous nonsense mutation (c.800G > A, p.Trp267*) in the transmembrane domain of the receptor. Immunoblot analysis of transfected GHR p.Trp267* in HEK293 revealed inhibition of GH-induced STAT5 signalling that was overcome with increasing doses of recombinant human GH.

Results: Using an in vitro model, we show that elevated levels of GHBP inhibit the action of GH. Furthermore, our studies demonstrate that this inhibition by GHBP can be overcome by increasing doses of recombinant human GH.

Conclusions: To our knowledge, this is the first study to demonstrate in vitro that elevated levels of GHBP attenuate the effect of GH and inhibit GH-induced signalling, thereby leading to short stature. Though this inhibition was overcome in vitro with supraphysiologic doses of GH, significantly above endogenously available GH, it remains to be seen whether such an effect can be replicated in vivo.
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http://dx.doi.org/10.1111/cen.14148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172700PMC
April 2020

Targeted Searches of the Electronic Health Record and Genomics Identify an Etiology in Three Patients with Short Stature and High IGF-I Levels.

Horm Res Paediatr 2019 20;92(3):186-195. Epub 2019 Dec 20.

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA,

Introduction: Short stature is one of the most common reasons for referral to a pediatric endocrinologist and can result from many etiologies. However, many patients with short stature do not receive a definitive diagnosis.

Objective: To ascertain whether integrating targeted bioinformatics searches of electronic health records (EHRs) combined with genomic studies could identify patients with previously undiagnosed rare genetic etiologies of short stature. We focused on a specific rare phenotypic subgroup: patients with short stature and elevated IGF-I levels.

Methods: We performed a cross-sectional cohort study at three large academic pediatric healthcare networks. Eligible subjects included children with heights below -2 SD, IGF-I levels >90th percentile, and no known etiology for short stature. We performed a search of the EHRs to identify eligible patients. Patients were then recruited for phenotyping followed by exome sequencing and in vitro assays of IGF1R function.

Results: A total of 234 patients were identified by the bioinformatics algorithm with 39 deemed eligible after manual review (17%). Of those, 9 were successfully recruited. A genetic etiology was identified in 3 of the 9 patients including 2 novel variants in IGF1R and a de novo variant in CHD2. In vitro studies supported the pathogenicity of the IGF1R variants.

Conclusions: This study provides proof of principle that patients with rare phenotypic subgroups can be identified based on discrete data elements in the EHRs. Although limitations exist to fully automating this approach, these searches may help find patients with previously unidentified rare genetic disorders.
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http://dx.doi.org/10.1159/000504884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173346PMC
May 2020

Low IGF-I Bioavailability Impairs Growth and Glucose Metabolism in a Mouse Model of Human PAPPA2 p.Ala1033Val Mutation.

Endocrinology 2019 06;160(6):1363-1376

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Bioactive free IGF-I is critically important for growth. The bioavailability of IGF-I is modulated by the IGF-binding proteins (IGFBPs) and their proteases, such as pregnancy-associated plasma protein-A2 (PAPP-A2). We have created a mouse model with a specific mutation in PAPPA2 identified in a human with PAPP-A2 deficiency. The human mutation was introduced to the mouse genome via a knock-in strategy, creating knock-in mice with detectable protein levels of Papp-a2 but without protease activities. We found that the Pappa2 mutation led to significant reductions in body length (10%), body weight (10% and 20% in males and females, respectively), and relative lean mass in mice. Micro-CT analyses of Pappa2 knock-in femurs from adult mice showed inhibited periosteal bone expansion leading to more slender bones in both male and female mice. Furthermore, in the Pappa2 knock-in mice, insulin resistance correlated with decreased serum free IGF-I and increased intact IGFBP-3 concentrations. Interestingly, mice heterozygous for the knock-in mutation demonstrated a growth rate for body weight and length as well as a biochemical phenotype that was intermediate between wild-type and homozygous mice. This study models a human PAPPA2 mutation in mice. The mouse phenotype closely resembles that of the human patients, and it provides further evidence that the regulation of IGF-I bioavailability by PAPP-A2 is critical for human growth and for glucose and bone metabolism.
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http://dx.doi.org/10.1210/en.2018-00755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507901PMC
June 2019

De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism.

Am J Hum Genet 2019 04 28;104(4):758-766. Epub 2019 Mar 28.

Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, 6525GA Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202AZ Maastricht, the Netherlands.

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451728PMC
April 2019

Laron syndrome related to homozygous growth hormone receptor c.784>C mutation in a patient with hypoplastic pulmonary arteries.

Cardiovasc J Afr 2019 Mar/Apr 23;30(2):e7-e8. Epub 2019 Jan 22.

Department of Paediatric Endocrinology, Faculty of Medicine, Inonu University, Malatya, Turkey.

Laron syndrome, also known as growth hormone insensitivity, is an autosomal recessive disorder characterised by short stature due to mutations or deletions in the growth hormone receptor (GHR), leading to congenital insulin-like growth factor 1 (IGF1) deficiency. Cardiac abnormalities, such as patent ductus arteriosus or peripheral vascular disease are rare in patients with Laron syndrome, but cardiac hypertrophy has been observed after IGF1 therapy. In this report, we present a 10-year-and-5-month-old girl with severe peripheral-type pulmonary artery hypoplasia and Laron syndrome related to homozygous GHR c.784>C mutation.
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http://dx.doi.org/10.5830/CVJA-2019-002DOI Listing
February 2020

A Novel Homozygous Mutation of the Acid-Labile Subunit Gene in a Male Adolescent

J Clin Res Pediatr Endocrinol 2019 11 5;11(4):432-438. Epub 2019 Feb 5.

İstanbul University İstanbul Faculty of Medicine, Unit of Pediatric Endocrinology, İstanbul, Turkey

Acid-labile subunit (ALS) forms ternary complexes with insulin like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and is essential for normal circulating IGF-1 levels. The gene encodes the ALS and mutations in cause ALS deficiency. We describe a patient with ALS deficiency with a novel homozygous frameshift mutation in presenting with short stature and delayed puberty but ultimately achieving an adult height (AH) comparable to his target height (TH). A 15.25 year old boy presented with short stature (149.9 cm, -3.04 standard deviation score). The patient had a low circulating IGF-1 concentration, extremely low IGFBP-3 concentration, insulin resistance and osteopenia. The peak growth hormone (GH) response to GH stimulation test was high (31.6 ng/mL). Sequencing of revealed a novel, homozygous, frameshift mutation (p.Ser555Thrfs.19). His mother and elder sister were heterozygous carriers. Although he had delayed puberty and short stature at the onset of puberty, he reached his TH and an AH similar to those of his heterozygous mother and sister. The heterozygous carriers had normal or low IGF-1 concentrations and low IGFBP-3 concentrations but not as markedly low as that of the patient. They had normally timed puberty, insulin metabolism and bone mineral density (BMD). The phenotype of ALS deficiency is quite variable. Despite short stature and delayed puberty, patients can achieve normal pubertal growth and AH. ALS deficiency may cause osteopenia and hyperinsulinemia. Heterozygous carriers may have normal prenatal growth, puberty, insulin metabolism and BMD.
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http://dx.doi.org/10.4274/jcrpe.galenos.2019.2018.0301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878349PMC
November 2019

Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.

Nat Genet 2019 01 26;51(1):96-105. Epub 2018 Nov 26.

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.

DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a pluripotent cells in vitro, and is also evident in Dnmt3a dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.
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http://dx.doi.org/10.1038/s41588-018-0274-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520989PMC
January 2019

Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action.

Endocr Rev 2019 04;40(2):476-505

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature and dysmorphic and metabolic abnormalities. In recent years, the clinical, biochemical, and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders. We review this important spectrum of defects, which present with phenotypes at the milder end of the GHI continuum. We discuss their clinical, biochemical, and genetic characteristics. The objective of this review is to clarify the definition, identification, and investigation of this clinically relevant group of growth defects. We also review the therapeutic challenges of mild GHI.
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http://dx.doi.org/10.1210/er.2018-00146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607971PMC
April 2019

PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: and Evidence.

J Endocr Soc 2018 Jul 28;2(7):646-656. Epub 2018 May 28.

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Context: Pregnancy-associated plasma protein A2 (PAPPA2) is a protease that cleaves IGF-binding protein (IGFBP)-3 and IGFBP-5, liberating free IGF-I. Five patients from two families with genetic mutations in presented with growth retardation, elevated total IGF-I, and IGFBP-3 but decreased free IGF-I.

Objective: To determine whether plasma transfusion or recombinant human (rh)PAPPA2 could increase free IGF-I in patients with PAPPA2 deficiency or idiopathic short stature (ISS).

Design: Single patient interventional study combined with experimentation.

Setting: Academic medical center.

Patients: Three siblings with PAPPA2 deficiency and four patients with ISS.

Interventions: An adult female with PAPPA2 deficiency received a 20 mL/kg plasma transfusion. PAPPA2, intact IGFBP-3, and free and total IGF-I levels were monitored during 2 weeks. rhPAPPA2 was added to serum from patients with PAPPA2 deficiency and ISS for 4 hours. Intact IGFBP-3 and free IGF-I levels were assayed via ELISA.

Main Outcome Measures: Free IGF-I concentrations.

Results: Plasma transfusion resulted in a 2.5-fold increase of free IGF-I levels on day 1 posttransfusion with a return to baseline during a 2-week period. studies demonstrated a dose-dependent increase in free IGF-I and decrease in intact IGFBP-3 after the addition of rhPAPPA2. The increase in free IGF-I was more pronounced in patients with PAPPA2 deficiency compared with those with ISS.

Conclusions: PAPPA2 plays a key role in regulation of IGF-I bioavailability. rhPAPPA2 is a promising therapy to increase free IGF-I levels both in patients with PAPPA2 deficiency as well as in patients with ISS.
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http://dx.doi.org/10.1210/js.2018-00106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009608PMC
July 2018

Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation.

Nat Commun 2018 05 29;9(1):2105. Epub 2018 May 29.

Division of Endocrinology, 240 Albert Sabin Way, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA.

Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.
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http://dx.doi.org/10.1038/s41467-018-04521-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974024PMC
May 2018

Adrenal Insufficiency, Sex Reversal, and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1.

Horm Res Paediatr 2018 22;89(3):205-210. Epub 2018 Mar 22.

Background/aims: Cholesterol side-chain cleavage enzyme (P450scc) deficiency is a rare genetic disorder causing primary adrenal insufficiency with or without a 46,XY disorder of sexual development (DSD). Herein, we report a case of the combination of primary adrenal insufficiency, a DSD (testes with female external genitalia in a setting of a 47,XXY karyotype), and Angelman syndrome.

Methods: Comprehensive genetic analyses were performed, including a single nucleotide polymorphism microarray and whole-exome sequencing. In vitro studies were performed to evaluate the pathogenicity of the novel mutation that was identified by whole-exome sequencing.

Results: The patient was found to have segmental uniparental disomy (UPD) of chromosome 15 explaining her diagnosis of Angelman syndrome. Whole-exome sequencing further revealed a novel homozygous intronic variant in CYP11A1, the gene encoding P450scc, found within the region of UPD. In vitro studies confirmed that this variant led to decreased efficiency of CYP11A1 splicing.

Conclusion: We report the first case of the combination of 2 rare genetic disorders, Angelman syndrome, and P450scc deficiency. After 20 years of diagnostic efforts, significant advances in genetic diagnostic technology allowed us to determine that these 2 disorders originate from a unified genetic etiology, segmental UPD unmasking a novel recessive mutation in CYP11A1.
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http://dx.doi.org/10.1159/000487638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906135PMC
September 2018

Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations.

Mol Cell Endocrinol 2018 09 3;473:166-177. Epub 2018 Feb 3.

Centro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina. Electronic address:

Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They presented differences in their dephosphorylation kinetics and transcriptional activities under interleukin-6 stimulation. Both variants increased their transcriptional activities in response to growth hormone (GH) treatment. Nonetheless, STAT5b transcriptional activity was diminished in the presence of STAT3 GOF variants, suggesting a disruptive role of STAT3 GOF variants in the GH signaling pathway. This study highlights the broad clinical spectrum of patients presenting activating STAT3 mutations and explores the underlying molecular pathway responsible for this condition, suggesting that different mutations may drive increased activity by slightly different mechanisms.
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http://dx.doi.org/10.1016/j.mce.2018.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143347PMC
September 2018

Novel Modulators of the Growth Hormone - Insulin-Like Growth Factor Axis: Pregnancy-Associated Plasma Protein-A2 and Stanniocalcin-2.

J Clin Res Pediatr Endocrinol 2017 Dec 27;9(Suppl 2):1-8. Epub 2017 Dec 27.

Cincinnati Children's Hospital Medical Center, Cincinnati Center for Growth Disorders, Clinic of Endocrinology, Cincinnati, Ohio, USA.

Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), play a critical role in human growth. In circulation, IGF-1 is found in a ternary complex with IGF binding proteins (IGFBPs) and acid labile subunit (ALS) but little attention has been paid to the regulation of IGF-1 bioavailability. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) were identified as novel modulators of IGF-I bioavailability. PAPP-A2 is a protease which cleaves IGFBP-3 and -5, while STC2 inhibits PAPP-A and PAPP-A2 activity. In collaboration with a group in Madrid, we reported the first human cases carrying mutations in the PAPPA2 gene who presented with short stature, elevated total IGF-1, IGFBP-3, IGFBP-5 and ALS, but low free IGF-1. Additionally, the patients demonstrated insulin resistance and below average bone mineral density (BMD). The PAPP-A2 deficient patients were treated with recombinant human IGF-1, resulting in improvements in growth velocity, insulin resistance, and BMD. These findings suggested that the bioactive, free IGF-1 liberated from IGFBPs by PAPP-A2 is important for human growth. Mouse models of PAPP-A2 and STC2 provide further insights into their roles in growth physiology. This review will summarize new insights into PAPP-A2 and STC2 and their role in the GH-IGF axis, thereby highlighting the importance of the regulation of IGF-1 bioavailability in human health and disease.
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http://dx.doi.org/10.4274/jcrpe.2017.S001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790331PMC
December 2017

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

J Endocr Soc 2017 Apr 8;1(4):345-358. Epub 2017 Mar 8.

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.

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 causing a nonclassical GHI phenotype.

Objective: To determine if the identified heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients.

Results: All three mutations (c, and >C) are predicted to result in frameshift and early protein termination. functional analysis of variants c and suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type 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 () mutation.

Conclusion: Dominant-negative mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of 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.
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http://dx.doi.org/10.1210/js.2016-1119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686656PMC
April 2017

Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density.

J Clin Endocrinol Metab 2017 12;102(12):4568-4577

Division of Endocrinology, Cincinnati Children's Hospital Medical Center.

Context: The pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulinlike growth factor binding proteins 3 and 5, releasing free insulinlike growth factor 1 (IGF-1). Homozygous mutations in PAPP-A2 result in growth failure with elevated total but low free IGF-1.

Objective: To determine the 24-hour pharmacokinetic (PK) profile of free and total IGF-1 after a dose of recombinant human insulinlike growth factor 1 (rhIGF-1). We describe the growth response and effects on glucose metabolism and bone mineral density (BMD) after 1 year of rhIGF-1 therapy.

Design And Patients: Three affected siblings, their heterozygous parents, and two healthy controls participated. The subjects received a dose of rhIGF-1, followed by serial blood samples collected over 24 hours. The two younger siblings were started on rhIGF-1 treatment. An oral glucose tolerance test and dual-energy X-ray absorptiometry scans were obtained at baseline and after 1 year of treatment.

Results: Subcutaneous administration of rhIGF-1 increased the concentration of free and total IGF-1 in patients with PAPP-A2 deficiency. The PK profile was comparable in all participants. At baseline, all three subjects demonstrated insulin resistance and below-average BMD. Treatment with rhIGF-1 is ongoing in the youngest patient but was discontinued in his brother because of the development of pseudotumor cerebri. The treated patient had an increase in height velocity from 3.0 to 6.2 cm/y, resolution of insulin resistance, and an increase in total body BMD.

Conclusions: rhIGF-1 at standard dosages resulted in similar PK characteristics in patients with PAPP-A2 deficiency, heterozygous relatives, and healthy controls. The youngest affected patient experienced a modest growth response to therapy with rhIGF-1, as well as beneficial effects on glucose metabolism and bone mass.
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http://dx.doi.org/10.1210/jc.2017-01411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718699PMC
December 2017

Two Siblings with a Mutation in CCDC8 Presenting with Mild Short Stature: A Case of 3-M Syndrome.

Horm Res Paediatr 2017 4;88(5):364-370. Epub 2017 Jul 4.

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background: Short stature can be caused by mutations in a multitude of different genes. 3-M syndrome is a rare growth disorder marked by severe pre- and postnatal growth retardation along with subtle dysmorphic features. There have only been 2 prior reports of mutations in CCDC8 causing 3-M syndrome.

Methods: Two patients presenting with mild short stature underwent whole exome sequencing. The mutation was confirmed via Sanger sequencing. We compare the clinical characteristics of our 2 patients to patients previously reported with mutations in the same gene.

Results: Exome sequencing identified a homozygous frameshift mutation in CCDC8 in both patients. They presented with a much milder phenotype than previously described patients with the same mutation.

Conclusion: In this study, we report a case of 2 sisters with relatively mild short stature who were found via exome sequencing to carry a previously reported homozygous mutation in CCDC8. These patients expand the anthropometric phenotype of 3-M syndrome and demonstrate the power of exome sequencing in the diagnosis of children with short stature. 3-M syndrome should be considered in children with mild skeletal abnormalities, normal/high growth hormone-IGF axis parameters, and normal intelligence.
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http://dx.doi.org/10.1159/000477907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261367PMC
July 2018

Isolated growth hormone deficiency due to the R183H mutation in GH1: Clinical analysis of a four-generation family.

Clin Endocrinol (Oxf) 2017 12 21;87(6):874-876. Epub 2017 Jul 21.

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

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http://dx.doi.org/10.1111/cen.13400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698139PMC
December 2017

IMAGe and Related Undergrowth Syndromes: The Complex Spectrum of Gain-of-Function CDKN1C Mutations.

Pediatr Endocrinol Rev 2017 Mar;14(3):289-297

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center. Cincinnati, OH, USA.

CDKN1C is a cyclin-dependent kinase Inhibitor and negative regulator of cellular proliferation. Recently, gain-of-function mutations in the PCNA domain of CDKN1C have been reported as the genetic basis of various growth-retarded syndromes including IMAGe syndrome, Russell Silver syndrome as well as a novel undergrowth syndrome that additionally exhibited early adulthood onset diabetes. This review summarizes the key clinical features and the molecular advances that have contributed to our understanding of this complex phenotypic spectrum.
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http://dx.doi.org/10.17458/per.vol14.2017.SKHD.imageandrelatedundergrowthDOI Listing
March 2017

Biology of the somatotroph axis (after the pituitary).

Ann Endocrinol (Paris) 2017 Jun 8;78(2):80-82. Epub 2017 May 8.

Cincinnati Center for Growth Disorders, Cincinnati, Ohio, United States; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.

Normal growth requires that pituitary-secreted growth hormone (GH) bind to its specific receptor and activate a complex signaling cascade, leaving to production of insulin-like growth factor-I (IGF-I), which, in turn, activates its own receptor (IGF1R). The GH receptor (GHR) is preformed as a dimer and is transported in a nonligand bound state to the cell surface. Binding of GH to the GHR dimer, results in a conformational change of the dimer, activation of the intracellular Janus Kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 5B. Phosphorylated STAT5B dimers are then translocated to the nucleus, where they transcriptionally activate multiple genes, including those for IGF-I, IGF binding protein-3 and the acid-labile subunit (ALS).
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http://dx.doi.org/10.1016/j.ando.2017.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239688PMC
June 2017

Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies.

Horm Res Paediatr 2017 10;87(6):412-422. Epub 2017 Apr 10.

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background: The growth-promoting effects of IGF-I is mediated through the IGF-I receptor (IGF1R), a widely expressed cell-surface tyrosine kinase receptor. IGF1R copy number variants (CNV) can cause pre- and postnatal growth restriction or overgrowth.

Methods: Whole exome sequence (WES), chromosomal microarray, and targeted IGF1R gene analyses were performed on 3 unrelated children who share features of small for gestational age, short stature, and elevated serum IGF-I, but otherwise had clinical heterogeneity. Fluorescence-activated cell sorting (FACS) analysis of cell-surface IGF1R was performed on live primary cells derived from the patients.

Results: Two novel IGF1R CNV and a heterozygous IGF1R nonsense variant were identified in the 3 patients. One CNV (4.492 Mb) was successfully called from WES, utilizing eXome-Hidden Markov Model (XHMM) analysis. FACS analysis of cell-surface IGF1R on live primary cells derived from the patients demonstrated a ∼50% reduction in IGF1R availability associated with the haploinsufficiency state.

Conclusion: In addition to conventional methods, IGF1R CNV can be identified from WES data. FACS analysis of live primary cells is a promising method for efficiently evaluating and screening for IGF1R haploinsufficiency. Further investigations are necessary to delineate how comparable IGF1R availability leads to the wide spectrum of clinical phenotypes and variable responsiveness to rhGH therapy.
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http://dx.doi.org/10.1159/000464143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509495PMC
April 2018

Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations.

J Clin Endocrinol Metab 2017 Feb;102(2):460-469

Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Insurgentes-Cuicuilco, Coyoacán 04530, México.

Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation.

Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies.

Patients And Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records.

Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity.

Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
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http://dx.doi.org/10.1210/jc.2016-3313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413162PMC
February 2017
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