Novel genotypes and phenotypes among Chinese patients with Floating-Harbor syndrome

Abstract

Background Floating-Harbor syndrome (FHS) is a rare syndromic short stature disorder caused by truncating variants in SRCAP . Few Chinese FHS patients had been reported so far and limited knowledge regarding the benefit of growth hormone treatment existed. Methods We ascertained 12 short stature patients with molecularly confirmed diagnosis of FHS by whole exome sequencing. We performed a comprehensive clinical evaluation for all patients and assessed the responsiveness of growth hormone treatment in a subset of the patients. Results Five distinct pathogenic/likely pathogenic variants were identified in 12 independent FHS patients including two previously reported variants (c.7303C > T/p.Arg2435Ter and c.7330C > T/p.Arg2444Ter) and three novel variants (c.7189G > T/p.Glu2397Ter, c.7245_7246delAT/p.Ser2416ArgfsTer26 and c.7466C > G/p.Ser2489Ter). The c.7303C > T/p.Arg2435Ter mutation appears more common in Chinese FHS patients. The clinical presentations of Chinese FHS patients are very similar to those of previously reported patients of different ethnicities. Yet we noticed micropenis and ear abnormalities in multiple patients, suggesting that these may be novel phenotypes of Floating-Harbor syndrome. Eight patients (one with GH deficiency, one with undetermined GH level, six without GH deficiency) underwent growth hormone treatment, 3 patients had good responses, one with modest and two with poor responses. Conclusion We described novel genotypes and phenotypes in a Chinese FHS patient cohort. We showed that about half of FHS patients exhibited modest to good response to GH treatment regardless of their respective GH deficiency status. We didn’t find any correlation between different mutations and response to GH treatment. Electronic supplementary material The online version of this article (10.1186/s13023-019-1111-8) contains supplementary material, which is available to authorized users.

Floating-Harbor Syndrome Treated With Recombinant Human Growth Hormone: A Case Report and Literature Review

“…The dominant-negative effect of the truncated protein variant encoded by the SRCAP gene is FHS (14). Currently, more than 40 pathogenic variants of the SRCAP gene associated with FHS have been reported (mainly nonsense or frameshift mutations in exon 34), and most of these mutations occur between codons 2407 and 2517, while only two variants are nonsense mutations in exon 33. c.7330C>T (p.Arg2444Ter) is the most common variant, while c.7303C>T (p.Arg2435Ter) is the second most common variant (2). The heterozygous mutation (c.7401delC; p.Ile2468Phefs * 7) in the SRCAP gene of our patient was a de novo frameshift mutation in exon 34, with the mutation site located between codons 2407 and 2517, which is consistent with the previous description.…”

“…The SRCAP gene is located on chromosome 16p11.2, which contains a 40,989-bp coding region and 34 exons encoding a SNF2-related chromatin remodeling ATPase (the SRCAP protein), which is abundant in the nuclei of human cells (2). The SRCAP protein plays a crucial role in essential cellular pathways, such as chromatin remodeling, gene expression, DNA damage response, and cell division (4).…”

“…FHS is caused by heterozygous mutations in the SNF2-related cAMP response element-binding protein (CREBBP) activator protein (SRCAP) gene (OMIM: 611421). Most mutations are spontaneous mutations; however, there are occasional reports of autosomal dominant familial inheritance (2). In this paper, we retrospectively analyzed the clinical data of a child with FHS who was treated with recombinant human growth hormone (rhGH) for a short stature.…”

Effects of long-term growth hormone therapy in a girl with Floating-Harbor syndrome

“…Garcia et al [ 13 ] suggested that FHS may lead to impaired IGF-1 signaling because of the discrepancy between the modest growth response to GH therapy and serum IGF-1 level (upper limit of the normal level during therapy). To date, over 100 FHS cases have been reported worldwide, and only a few of these patients were GH deficient [ 8 , 14 ]. Table 2 summarizes the results of previous studies on GH therapy in FHS patients.…”

“…To date, over 100 FHS cases have been reported worldwide, and only a few of these patients were GH deficient. 8,14) Table 2 summarizes the results of previous studies on GH therapy in FHS patients. According to these studies, the modalities of GH therapy, age of onset, dose, treatment period, and results have been inconsistent.…”