Evaluation of Pediatric Cases with ACAN Gene Variants

Aysun Ata; Nihal Hatipoğlu; Arzu Jalilova; Şiraz Ülkü Gül; Semra Çetinkaya; Şahin Nursel Muratoğlu; Ayça Altıncık; Sütçü Zümrüt Kocabey; Mehmet Eltan; Ayşe Karadağ; Tahir Atik; Şükran Darcan

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ESPE Abstracts (2024) 98 P2-47

ESPE2024 Poster Category 2 Bone, Growth Plate and Mineral Metabolism (31 abstracts)

Evaluation of Pediatric Cases with ACAN Gene Variants

Aysun Ata ¹ , Nihal Hatipoğlu ² , Arzu Jalilova ³ , Ülkü Gül Şiraz ² , Semra Çetinkaya ⁴ , Nursel Muratoğlu Şahin ⁴ , Ayça Altıncık ⁵ , Zümrüt Kocabey Sütçü ⁶ , Mehmet Eltan ⁷ , Ayşe Karadağ ² , Tahir Atik ⁸ & Şükran Darcan ³

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¹Afyonkarahisar Health Sciences University Faculty of Medicine, Department of Pediatric Endocrinology, Afyonkarahisar, Turkey. ²Erciyes University Faculty of Medicine, Department of Pediatric Endocrinology, Kayseri, Turkey. ³Ege University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey. ⁴Dr Sami Ulus Child Health and Diseases Health Application and Research Center, Department of Pediatric Endocrinology, Ankara, Turkey. ⁵Pamukkale University Faculty of Medicine, Department of Pediatric Endocrinology, Denizli, Turkey. ⁶Başakşehir Çam and Sakura City Hospital, Department of Pediatric Endocrinology, İstanbul, Turkey. ⁷Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital, Department of Pediatric Endocrinology, İstanbul, Turkey. ⁸Ege University Faculty of Medicine, Department of Pediatric Genetics, İzmir, Turkey

Introduction-Aim: Aggrecan, encoded by the ACAN gene; is a cartilage- specific proteoglycan- containing protein that is densely found in the growth plate and intervertebral discs. Heterozygous variants have been reported in cases with short stature, mild skeletal dysplasia, and advanced bone age. The Aim of this study is to examine the phenotypic characteristics of pediatric cases with ACAN gene variants in Turkey.

Material-Method: Children who applied with complaints of short stature and whose ACAN gene variant was detected in genetic analysis were included retrospectively. Anthropometric data, dysmorphic findings, bone age and genetic analysis results of the cases were examined.

Results: A total of 15 pediatric cases from 6 centers participating in the study were evaluated. Eight (53.3%) of the cases were female and 7 (46.7%) were male. The median age at presentation was 4 (0.5;11) years. While the median admission height SDS of the cases was -2.6 (-6.3; -1.1), one case was pubertal and 14 cases were prepubertal. When accompanying dysmorphic findings are examined; frontal prominence, flattened nasal root, low nuchal hairline, nipple separation, brachydactyly, anteverted ears and pectus excavatum was detected (Table-1). Advanced bone age at presentation was detected in 8 (53.3%) cases. There was a family history of short stature in 13 (86.6%) cases, but segregation was performed in 5 of these cases. When the variant analyzes were examined, the variant detected in one case was homozygous, while the other cases were heterozygous (Table-2). Homozygous variant was shown in the case with the most severe short stature (-6.3 SDS).


Number	Age (years)	Bone age (years)	Height SDS
1	4.2	7.9	-2.79
2	5.7	7	-2.4
3	3.9	4	-2.7
4	9.2	8	-2.6
5	5.2	5	-6.34
6	3.2	4	-2.98
7	5.4	5	-3.33
8	5	5.5	-1.6
9	1.9	2.5	-3.6
10	11.9	13.5	-1.14
11	1.9	2.5	-3.38
12	7.6	8.5	-2.03
13	8.7	10.5	-1.21
14	5.3	4.5	-1.94
15	3.4	3.5	-1.76

Conclusion: Aggrecanopathy/aggrecan related dysplasias are one of the skeletal dysplasias that cause short stature. In these cases, height is variable and there is usually a family history. Contrary to popular belief, advanced bone age and osteoarticular complications are not mandatory and cannot be demonstrated in every case. ACAN gene mutations should also be considered in the differential diagnosis of cases with familial short stature. Detailed genetic studies are needed to elucidate the pathogenic mechanisms of these variants.