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Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations.

ABSTRACT: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.The aim was to identify underlying genetic causes of short stature with advanced bone age.We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function.Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation.

SUBMITTER: Nilsson O

PROVIDER: S-EPMC4121031 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations.

Nilsson Ola O Guo Michael H MH Dunbar Nancy N Popovic Jadranka J Flynn Daniel D Jacobsen Christina C Lui Julian C JC Hirschhorn Joel N JN Baron Jeffrey J Dauber Andrew A

The Journal of clinical endocrinology and metabolism 20140424 8

<h4>Context</h4>Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.<h4>Objective</h4>The aim was to identify underlying genetic causes of short stature with advanced bone age.<h4>Setting and design</h4>We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.<h4>Results</h4>Affected individuals presented with short stature [ad ...[more]

PMID: 24762113

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Project description:BackgroundLinear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature.Case presentationWe report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient's phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient's father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature.ConclusionWe investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

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Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations.

Publications

Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations.

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