Endocrine Abstracts (2018) 57 032 | DOI: 10.1530/endoabs.57.032

Small stature with osteochondritis: a clinical report of a family with ACAN mutation and review of the literature

S Merckx1,2, S Moortgat3, T Mouraux1 & D Beckers1

1Endocrinology Unit, Pediatric department, CHU UCL Namur, Site Godinne, Avenue Docteur G. Thérasse, 1 - 5530 Yvoir, Belgium; 2Pediatrics Department, Cliniques Universitaires Saint Luc, Université catholique de Louvain, Brussels; 3Center of Human Genetics, IPG, Gosselies, Belgium.

Introduction: Thanks to advances in genetics, idiopatic short stature have, more frequently, a molecular diagnosis. Mutations in the ACAN gene are responsible for different forms of syndromic short stature but were also described in association with idiopathic short stature or with joint damage and advanced bone age. Transmission is autosomal dominant. Less than 25 mutations have been described since 2010 and are localized all along the protein. The ACAN gene located on chromosome 15q26 encodes a protein called the Aggrecan protein. It is a major component of the extra-cellular matrix of articular and growth cartilage. Some affected patients have been recently treated by growth hormone (GH) therapy and showed a variable increase in height. We report a 9-years-old girl with a familial history of autosomal dominant short stature and osteochondritis of the knee, where we found by clinical exome sequencing an heterozygous nonsense mutation c.2110 C> T (p.Gln704*) in the ACAN gene.

Case report: Lea consulted in 2013 for a short stature at 6 years old. She is the fourth in a family of four children from non-consanguinous parents. The father’s height is 156 cm (−3.4 SDS) and the mother’s heigt is 155 cm (−1.9 SDS). Her target height is therefore 150 cm (−2.8 SDS). Her 22 years old sister’s height is 145 cm (−3.6 SDS) with a normal endocrinological assessment (IgF1, cortisol, prolactin, TSH-T4, glucagon stimulation test). The 2 other sisters (19 and 18 year old) have a normal height (160 cm; −1.1 SDS). In the family history, there were several short stature in the father’s family associated with osteochondritis of the knee. Lea was born at term (39w) with a birth weight of 2680 gr (−1.7 SDS) and a birth length of 46 cm (−2 SDS). There was any neonatal problem. At the age of 6, her height was 100.8 cm (−3 SDS, −0.2 SDS below her target height) with a BMI of 0.7 SDS and a growth velocity of 6.5 cm per year (0.1 SDS). She had no symptoms, except transient knee pain without diagnose. The clinical examination was normal, prepuberal with normal proportion but a relative macrocrania (head circumference 52.8 cm +0.8 SDS). Endocrinological screening was normal (IGF-1 159 ng/ml – range 85–315 ng/ml), bone age (Greulich and Pyle) was 8 for a chronological age of 6 and genetic assessment was normal (CGH-array, SHOX and FGFR3 genes). In 2017, she start entry into puberty (Tanner P2M2) with a height of 115.7 cm (−3.1 SDS, −0.3 SDS below her target height) and a growth rate of 3.5 cm/year (−2.6 SDS). Bone age was 10 years old with a height prediction of ~ 147 cm. A mendelioma was done and showed a stop heterozygous C.2110 C> T mutation (p.Gln704 *) in the ACAN gene responsible for her familial short stature. GH treatment was started in combination with GH-RH analogs. Adult height is not yet reached.

Conclusion: We describe the case of a 9-year-old child with familial short stature associated with osteochondritis of the knee, advance bone age and the absence of growthspurt entering puberty in a context of heterozygous mutation in the ACAN gene. Paediatricians should accord importance to symptoms of osteochonditis associated with familial short stature as the association of small stature with advance bone age. According to some studies, GH treatment in this case could allow her to reach an adult height closer to her target height but more prospective studies are needed to clarify the height gain.


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