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

Abstract

Context: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.

Objective: The aim was to identify underlying genetic causes of short stature with advanced bone age.

Setting and design: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.

Results: 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.

Conclusions: 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.

Figure 1.

Pedigrees of the families studied: A) Family 1; B) Family 2; C) Family 3. The arrows indicate the proband. Individuals carrying heterozygous ACAN mutations are indicated by solid symbols whereas unaffected individuals are indicated as open symbols. The age (years) and adult height SDS is indicated for all affected individuals that have reached adult height and age (years:months), bone age (BA; years:months), and height SDS at most recent visit for all affected children who are still growing.

Figure 2.

Growth charts of patients with heterozygous ACAN mutations. A) Proband of family 1 (II:1); B) Younger brother of proband Family 1 (II:2); C) Proband of Family 2 (III:1); D) Proband of Family 3 (III:5). Bone age assessments are indicated by triangles (A, B).

Figure 3.

Patients with short stature, advanced bone age, and/or history of early growth cessation. A and B) Proband of Family 1 at 9 years 3 months of age; C and D) Younger brother of Family 1 proband at 6 years 8 months of age; E and F) Proband of Family 2 at 15 years of age; G and H) Proband of Family 3 at 15 years of age. Affected individuals of Family 3 has short thumbs and distal phalanges (H).

Figure 4.

Structure of the ACAN gene and aggrecan protein and the locations of current and previously reported mutations. A, Top panel shows the gene structure (RefSeq NM_013227.3) of ACAN and the locations of the variants identified in Families 1, 2, and 3, as well as the previously identified pathogenic variants (SEDK, spondyloepiphyseal dysplasia type Kimberly; SEMD, spondyloepimetaphyseal dysplasia; OD, osteochondritis Dissecans); B) Organization of the aggrecan proteoglycan (G1, 2, 3, globular domain 1, 2, 3; IGD, interglobular domain; KS, keratan sulfate; CS1, 2, chondroitin sulfate 1, 2; CLD, C-type lectin domain; CRP, complement regulatory like domain; EGF1, 2, epidermal growth factor–like domain 1, 2). Protein coordinates are based on RefSeq NP_037359.3. Figures are modified from (29) and are drawn approximately to scale.