Ann Pediatr Endocrinol Metab.  2020 Dec;25(4):272-276. 10.6065/apem.1938198.099.

Identification of a heterozygous ACAN mutation in a 15-year-old boy with short stature who presented with advanced bone age: a case report and review of the literature

• Kim TY
• Jang KM
• Keum CW
• Oh SH
• Chung WY

• KMID: 2510899
• DOI: http://doi.org/10.6065/apem.1938198.099

Abstract

Longitudinal bone growth is primarily mediated by the growth plate, which is a specialized cartilaginous structure. Aggrecan, encoded by ACAN, is a primary proteoglycan component of the extracellular matrix in both the growth plate and articular cartilage. Aggrecanopathies have emerged as a phenotype of genetic skeletal disease in humans. A heterozygous ACAN mutation causes short stature, premature growth cessation, and accelerated bone age maturation. We report the case of a 15-year-old boy with familial short stature, with height of 149 cm (Korean standard deviation score [SDS] of -3.6) and weight of 50.5 kg (-1.48 SDS). He presented with mild midfacial hypoplasia, frontal bossing, a broad chest, and a short neck. The father's and mother's heights were 150 cm (-4.8 SDS) and 153 cm (-1.69 SDS), respectively. The patient's bone age was 2–3 years more advanced than his chronological age, and no endocrine abnormalities were detected. Wholeexome sequencing followed by Sanger sequencing revealed a heterozygous ACAN mutation, c.512C>T (p.Ala171Val), in both the proband and his father. Short stature is generally associated with a delayed bone age, and this case suggests that ACAN mutations may be the most likely etiology among patients with short stature and an advanced bone age and should warrant early treatment.

Keyword

ACAN; Aggrecan; Dysmorphism; Short stature

Figure

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  Fig. 1. The patient's height from 7–16 years of age was obtained from school physical examination records. The growth curve indicates a markedly short stature and a decreased height standard deviation score after puberty in a patient harboring an ACAN mutation.

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  Fig. 2. Clinical and radiographic characteristics of patients harboring heterozygous ACAN mutations. (A) The patient displayed mild midfacial hypoplasia, a flat nasal bridge, and frontal bossing and (B) brachydactyly and a broad thumb. (C) The left-hand anteroposterior view represents a bone age between 17 and 18 years in accordance with the standard Greulich-Pyle method. (D) The patient’s father had a short neck without midfacial hypoplasia.

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  Fig. 3. Genetic testing of the family members. (A) A pedigree of the family with familial short stature. Shaded symbols indicate patients with ACAN mutations; empty symbols with a slash represent deceased members; empty symbols with "WT" are family members without mutations; empty symbols indicate family members who have not undergone ACAN sequencing. (B) The patient harbored a c.512C>T(p.Ala171Val) mutation inherited from his father.

Reference

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