Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations

Alexandra Gkourogianni, Melissa Andrew, Leah Tyzinski, Melissa Crocker, Jessica Douglas, Nancy Dunbar, Jan Fairchild, Mariana F A Funari, Karen E. Heath, Alexander A L Jorge, Tracey Kurtzman, Stephen Lafranchi, Seema Lalani, Jan Lebl, Yuezhen Lin, Evan Los, Dorothee Newbern, Catherine Nowak, Micah Olson, Jadranka PopovicStepanka Pruhova, Lenka Elblova, Jose Bernardo Quintos, Emma Segerlund, Lucia Sentchordi, Marwan Shinawi, Eva Lena Stattin, Jonathan Swartz, Ariadna Gonzalez Del Angel, Sinhue Diaz Cuellar, Hidekazu Hosono, Pedro A. Sanchez-Lara, Vivian Hwa, Jeffrey Baron, Ola Nilsson, Andrew Dauber

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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, 22.8 standard deviation score (SDS); range, 25.9 to 20.9] 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, 22.0 SDS; range, 24.2 to 20.6). Most children with ACAN mutations had advanced bone age (bone age 2 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.

Original languageEnglish (US)
Pages (from-to)460-469
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Aggrecans
Genes
Mutation
Cartilage
Osteoarthritis
Bone
Growth
Brachydactyly
Exome
Intervertebral Disc
Genetic Association Studies
Articular Cartilage
Growth Hormone
Medical Records
Therapeutics
Joints
Phenotype
Bone and Bones

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Gkourogianni, A., Andrew, M., Tyzinski, L., Crocker, M., Douglas, J., Dunbar, N., ... Dauber, A. (2017). Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. Journal of Clinical Endocrinology and Metabolism, 102(2), 460-469. https://doi.org/10.1210/jc.2016-3313

Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. / Gkourogianni, Alexandra; Andrew, Melissa; Tyzinski, Leah; Crocker, Melissa; Douglas, Jessica; Dunbar, Nancy; Fairchild, Jan; Funari, Mariana F A; Heath, Karen E.; Jorge, Alexander A L; Kurtzman, Tracey; Lafranchi, Stephen; Lalani, Seema; Lebl, Jan; Lin, Yuezhen; Los, Evan; Newbern, Dorothee; Nowak, Catherine; Olson, Micah; Popovic, Jadranka; Pruhova, Stepanka; Elblova, Lenka; Quintos, Jose Bernardo; Segerlund, Emma; Sentchordi, Lucia; Shinawi, Marwan; Stattin, Eva Lena; Swartz, Jonathan; Del Angel, Ariadna Gonzalez; Cuellar, Sinhue Diaz; Hosono, Hidekazu; Sanchez-Lara, Pedro A.; Hwa, Vivian; Baron, Jeffrey; Nilsson, Ola; Dauber, Andrew.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 102, No. 2, 01.02.2017, p. 460-469.

Research output: Contribution to journalArticle

Gkourogianni, A, Andrew, M, Tyzinski, L, Crocker, M, Douglas, J, Dunbar, N, Fairchild, J, Funari, MFA, Heath, KE, Jorge, AAL, Kurtzman, T, Lafranchi, S, Lalani, S, Lebl, J, Lin, Y, Los, E, Newbern, D, Nowak, C, Olson, M, Popovic, J, Pruhova, S, Elblova, L, Quintos, JB, Segerlund, E, Sentchordi, L, Shinawi, M, Stattin, EL, Swartz, J, Del Angel, AG, Cuellar, SD, Hosono, H, Sanchez-Lara, PA, Hwa, V, Baron, J, Nilsson, O & Dauber, A 2017, 'Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 2, pp. 460-469. https://doi.org/10.1210/jc.2016-3313
Gkourogianni, Alexandra ; Andrew, Melissa ; Tyzinski, Leah ; Crocker, Melissa ; Douglas, Jessica ; Dunbar, Nancy ; Fairchild, Jan ; Funari, Mariana F A ; Heath, Karen E. ; Jorge, Alexander A L ; Kurtzman, Tracey ; Lafranchi, Stephen ; Lalani, Seema ; Lebl, Jan ; Lin, Yuezhen ; Los, Evan ; Newbern, Dorothee ; Nowak, Catherine ; Olson, Micah ; Popovic, Jadranka ; Pruhova, Stepanka ; Elblova, Lenka ; Quintos, Jose Bernardo ; Segerlund, Emma ; Sentchordi, Lucia ; Shinawi, Marwan ; Stattin, Eva Lena ; Swartz, Jonathan ; Del Angel, Ariadna Gonzalez ; Cuellar, Sinhue Diaz ; Hosono, Hidekazu ; Sanchez-Lara, Pedro A. ; Hwa, Vivian ; Baron, Jeffrey ; Nilsson, Ola ; Dauber, Andrew. / Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. In: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, No. 2. pp. 460-469.
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abstract = "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, 22.8 standard deviation score (SDS); range, 25.9 to 20.9] 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, 22.0 SDS; range, 24.2 to 20.6). Most children with ACAN mutations had advanced bone age (bone age 2 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.",
author = "Alexandra Gkourogianni and Melissa Andrew and Leah Tyzinski and Melissa Crocker and Jessica Douglas and Nancy Dunbar and Jan Fairchild and Funari, {Mariana F A} and Heath, {Karen E.} and Jorge, {Alexander A L} and Tracey Kurtzman and Stephen Lafranchi and Seema Lalani and Jan Lebl and Yuezhen Lin and Evan Los and Dorothee Newbern and Catherine Nowak and Micah Olson and Jadranka Popovic and Stepanka Pruhova and Lenka Elblova and Quintos, {Jose Bernardo} and Emma Segerlund and Lucia Sentchordi and Marwan Shinawi and Stattin, {Eva Lena} and Jonathan Swartz and {Del Angel}, {Ariadna Gonzalez} and Cuellar, {Sinhue Diaz} and Hidekazu Hosono and Sanchez-Lara, {Pedro A.} and Vivian Hwa and Jeffrey Baron and Ola Nilsson and Andrew Dauber",
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T1 - Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations

AU - Gkourogianni, Alexandra

AU - Andrew, Melissa

AU - Tyzinski, Leah

AU - Crocker, Melissa

AU - Douglas, Jessica

AU - Dunbar, Nancy

AU - Fairchild, Jan

AU - Funari, Mariana F A

AU - Heath, Karen E.

AU - Jorge, Alexander A L

AU - Kurtzman, Tracey

AU - Lafranchi, Stephen

AU - Lalani, Seema

AU - Lebl, Jan

AU - Lin, Yuezhen

AU - Los, Evan

AU - Newbern, Dorothee

AU - Nowak, Catherine

AU - Olson, Micah

AU - Popovic, Jadranka

AU - Pruhova, Stepanka

AU - Elblova, Lenka

AU - Quintos, Jose Bernardo

AU - Segerlund, Emma

AU - Sentchordi, Lucia

AU - Shinawi, Marwan

AU - Stattin, Eva Lena

AU - Swartz, Jonathan

AU - Del Angel, Ariadna Gonzalez

AU - Cuellar, Sinhue Diaz

AU - Hosono, Hidekazu

AU - Sanchez-Lara, Pedro A.

AU - Hwa, Vivian

AU - Baron, Jeffrey

AU - Nilsson, Ola

AU - Dauber, Andrew

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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, 22.8 standard deviation score (SDS); range, 25.9 to 20.9] 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, 22.0 SDS; range, 24.2 to 20.6). Most children with ACAN mutations had advanced bone age (bone age 2 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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