Novel GPC3 Gene Mutation in Simpson-Golabi-Behmel Syndrome with Endocrine Anomalies: A Case Report

Simpson-Golabi-Behmel syndrome (SGBS) represents a rare X-linked recessive inherited overgrowth syndrome caused by GPC3 gene mutations [1]. The phenotype is highly heterogeneous in patients, including prenatal and postnatal overgrowth, particular craniofacial characteristics, supernumerary nipples, organomegaly, heart or renal defects, gastrointestinal and genitourinary malformations, skeletal or hand abnormalities and tumor predisposition [2,3]. Here, we describe a novel GPC3 gene mutation in a Chinese SGBS patient, who presented with endocrine anomalies.

A 12-year-old boy was hospitalized at our institution for developmental abnormalities. His family history revealed that he was born to non consanguineous parents [Figure 1(A)], and had macrosomia, with a birth weight 5.80 kg (>97th percentile) height 56.2 cm (>97th percentile) and head circumference 37.6 cm (>97th percentile). At the time of admission, his weight was 50.5 kg (75th–90th percentile), height 165 cm (>97th percentile) and head circumference 59.6 cm (>97th percentile). Physical examination revealed facial dysmorphism with coarse face, lip thickening, macroglossia with a midline furrow, pectus excavatum, supernumerary nipples, a broad nape and upper back, winged scapula, bilateral large hands and fingertips and nail dysplasia, predominately on the forefinger [Figure 1(B), 1(C), 1(D), 1(E) and (F)]. There was no intellectual disability and mental retardation.

Figure 1

Because of these developmental anomalies, he underwent serum endocrine hormone assessment (Table 1). As for the hypothalamic-pituitary-gonadal axis, he had high prolactin (PRL), high testosterone and low estradiol levels. Meanwhile, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and progesterone levels were normal. High thyroid-stimulating hormone (TSH) levels were detected, whereas free triiodothyronine (FT3) and free thyroxine (FT4) levels were normal. The adrenal axis evaluation showed normal adrenocorticotropic hormone (ACTH) and random cortisol levels. Growth hormone (GH) levels were also normal. His 24-hour dynamic ECG revealed sinus rhythm and incomplete right bundle branch block. Echocardiography showed no signs of heart malformation and brain magnetic resonance imaging (MRI) revealed a normal-appearing pituitary.

DNA extraction was carried out from the peripheral blood samples collected from the proband, his mother and father after informed consent was obtained. The high-throughput sequencing technology was employed to assess the proband's whole exome. A specific GPC3 gene mutation was verified by Sanger sequencing in all participants. By sequencing, a hemizygous mutation, c.185delT, p.(Leu62Cysfs*22), was detected in exon 2 of the GPC3 gene in the proband. The mother was a heterozygous carrier [Figure 2(A), 2(B), 2(C)]. The mutation has not previously been reported. It was also not listed in the major databases including the gnomAD, Clinvar, dbSNP, HGMD pro and LOVD. The parents of the patient provided written informed consent for publication of the case details and analyses. This study was approved by the Ethics Committee of Shandong First Medical University, Jinan, Shandong, People's Republic of China..

Figure 2

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-year-old 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 poly-peptide 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].

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.