Balkan Journal of Medical Genetics

NOVEL GPC3 GENE MUTATION IN SIMPSON-GOLABIBEHMEL SYNDROME WITH ENDOCRINE ANOMALIES: A CASE REPORT
Bu W, Zhu M, Li S, Liu H, Liu X,
*Corresponding Author: Xiaomin Liu, M.D., Department of Neurology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Road, Jinan 250014, Shandong, People’s Republic of China. Tel: +86-531-89269012. Fax: +86-531- 82967114. E-mail: bosucn@163.com
page: 95

DISCUSSION

The current patient displayed some typical clinical features of SGBS, including macrosomia at birth, distinctive craniofacial features, supernumerary nipples, chest deformity, heart conduction defects and hand anomalies. In addition, the patient had hypothalamic-pituitary-gonadal axis dysfunction and thyroid impairment, which have rarely been described in SGBS. In 2008, Pénisson- Besnier et al. [4] described a 44-year-old male with SGBS, presenting with endocrine anomalies, including reduced LH and testosterone levels, while normal FSH, estradiol, TSH, and GH levels. In 2013, a patient with SGBS was reported with reduced morning random cortisol levels and an improper normal ACTH levels, low testosterone levels, and decreased sex hormone-binding globulin levels [5]. Recently, Zhang et al. [6] described a neonate of an SGBS patient, presenting with subclinical hypothyroidism, which is consistent with the patient in our study. These cases raise the question of putative endocrine problems in this disease. However, Cottereau et al. [2] described the clinical findings of 42 SGBS patients in their study and reviewed the data of 63 SGBS patients from the literature, all with a GPC3 gene mutation. Although some patients had genitourinary malformations, among them 21 patients having cryptorchidism, and five patients had central nervous system malformations, none of the above endocrine anomalies have been reported. In addition, in 2019, Andrysiak-Mamos et al. [7] reported a 39-yearold male SGBS patient with suspected acromegaly. His MRI focusing on the pituitary gland revealed a series of abnormalities of median line structures, including a sellar-suprasellar cyst, persistent craniopharyngeal canal, a dysmorphic pituitary gland and a cyst of the septum pellucidum. However, his hormonal tests, including IGF1, GH, ACTH at 8:00 a.m., cortisol at 8:00 a.m., DHEAS, TSH, FT3, FT4, LH, FSH, testosterone and PRL, were not significant deviations. Thus, the association of endocrine anomalies and SGBS in our study may be merely coincidental. A novel mutation, c.185delT, p.(Leu62Cysfs*22), was detected on the GPC3 gene in the current family with SGBS. This mutation causes a Leu62Cys substitution. A concomitant frameshift maybe occur that introduces a new stop codon at 22 amino acid residues downstream to the new reading frame. This is predicted to lead to a polypeptide reduced by 498 amino acids compared with the wild type protein. Recently, Vuillaume et al. [3] reviewed 57 GPC3 gene mutations reported in previous studies, and detected 29 novel mutations, most of which were large deletions (34.9%), frameshift (24.4%) and nonsense (16.3%) mutations. To date, at least 105 pathogenic mutations have been identified on the GPC3 gene, including the one in our study and those listed in the professional version of the Human Gene Mutation Database. The GPC3 gene encodes the 580 amino acid long glypican-3 protein, which is a heparan sulfate proteoglycan and cell surface oncofetal protein covalently binding to the exocytoplasmic surface of the cytoplasmic membrane. Glypicans can regulate multiple pathways, including the canonical Wnt/- catenin, Hedgehog and fibroblast growth factor signaling, and have critical roles in cell proliferation and differentiation [8]. The majority of GPC3 gene mutations are large deletions or truncations, suggesting that loss-of-function is the mechanism responsible for SGBS [3]. Conclusions. We describe a novel GPC3 gene mutation in a Chinese patient with SGBS who presented with endocrine anomalies. This report broadens the GPC3 gene mutation spectrum, and provides novel insights into the clinical variability of SGBS. Further investigations are required to determine the genetic pathogenesis of SGBS. Acknowledgments. We are deeply grateful to the family members for their participation in this study. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This study was supported by in part by the Natural Scientific Foundation of Shandong Province [ZR2013HQ016], and the Key Research and Development Project of Shandong Province [2015GGH318011].

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