Molecular Genetics and Pathogenesis of the Floating Harbor Syndrome: Case Report of Long-Term Growth Hormone Treatment and a Literature Review

Abstract

Introduction: Floating Harbor syndrome (FHS) is an extremely rare disorder, with slightly more than a hundred cases reported worldwide. FHS is caused by heterozygous mutations in the SRCAP gene; however, little is known about the pathogenesis of FHS or the effectiveness of its treatment.Methods: Whole-exome sequencing (WES) was performed for the definitive molecular diagnosis of the disease. Identified variants were validated using Sanger sequencing. In addition, systematic literature and public data on genetic variation in SRCAP and the effects of growth hormone (GH) treatment was conducted.Results: We herein report the first case of FHS in the Russian Federation. The male proband presented with most of the typical phenotypic features of FHS, including short stature, skeletal and facial features, delayed growth and bone age, high pitched voice, and intellectual impairment. The proband also had partial growth hormone deficiency. We report the history of treatment of the proband with GH, which resulted in modest improvement in growth prior to puberty. WES revealed a pathogenic c.7466C>G (p.Ser2489*) mutation in the last exon of the FHS-linked SRCAP gene. A systematic literature review and analysis of available genetic variation datasets highlighted an unusual distribution of pathogenic variants in SRCAP and confirmed the lack of pathogenicity for variants outside of exons 33 and 34. Finally, we suggested a new model of FHS pathogenesis which provides possible basis for the dominant negative nature of FHS-causing mutations and explains limited effects of GH treatment in FHS.Conclusion: Our findings expand the number of reported FHS cases and provide new insights into disease genetics and the efficiency of GH therapy for FHS patients.

A Case of Floating-Harbor Syndrome with “Growth and Language Development Delay” as Its Clinical Manifestation

“…Studies indicate that the syndrome may be caused by a defect in the downstream signaling pathway of IGF-1, as opposed to decreased secretion and/or activity of growth hormone or IGF-1. 8 Furthermore, studies have indicated that decreased growth hormone secretion or activity typically does not result in prenatal fetal growth restriction, whereas decreased IGF-1 secretion or activity is associated with prenatal fetal growth restriction or microcephaly. 1 In our case, the child has a growth hormone deficiency along with the normal range of birth length and weight, which is consistent with the study.…”

Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases

“…Importantly, our observations are in good concordance with several gene-level studies. One example is the SRCAP gene linked to Floating-Harbor syndrome (FHS, OMIM 136140), in which causal variants have been identified only in 33rd and 34th exons [28]. At the same time, pathogenic variants outside of this hotspot region have been described in association with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA, OMIM 619595) [29].…”

Human Exome Sequencing and Prospects for Predictive Medicine: Analysis of International Data and Own Experience

“…In male probands with delayed growth and bone age, intellectual impairment, skeletal and facial features, and partial responses to hormone treatment, we identified a c.7466C>G (p.Ser2489*) heterozygous pathogenic mutation in the last exon of the SRCAP (Snf2 related CREBBP activator protein) gene, thus suggesting a new model of floating harbor syndrome (FHS) pathogenesis. These genetic mutations have dominant-negative effects that explain the limited efficacy of growth hormone treatment in FHS [ 53 ].…”