Long‐term follow‐up study for a patient with Floating–Harbor syndrome due to a hotspot SRCAP mutation

Abstract

Floating-Harbor syndrome (FHS) is a rare autosomal dominant disorder characterized by short stature, skeletal malformations, speech delay, and dysmorphic facial appearance. Recently, mutations in SRCAP encoding a coactivator for cAMP-response element binding protein (CREB)-binding protein have been identified in small number of patients with FHS. Here, we report on long-term follow-up data of a male patient with a SRCAP mutation. The patient presented with mild hypothyroidism and renal hypouricemia, in addition to several FHS-compatible features including growth impairment, cognitive disability, facial dysmorphisms, and hypertension. He showed delayed bone age from infancy to 9 years of age and markedly accelerated bone age with the formation of cone-shaped epiphyses and early epiphysial fusions after the onset of puberty. His pubertal sexual development was almost age appropriate. Two-year treatment with growth hormone (GH) did not significantly improve the growth velocity. Molecular analysis identified a de novo heterozygous nonsense mutation (p.R2444X) in the last exon of SRCAP, which has been most common mutation detected in patients from other ethnic groups. These results indicate that perturbed skeletal maturation from infancy through adolescence is a characteristic feature in patients with SRCAP mutations. Furthermore, our data imply that GH therapy exerted only a marginal effect on the growth of this patient, and that renal hypouricemia may be a novel complication of FHS.

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

“…According to these studies, the modalities of GH therapy, age of onset, dose, treatment period, and results have been inconsistent. 4,6,8,13) In our case, the patient had normal IGF-1 level and no GH deficiency. After 55 months of GH therapy, her height SDS increased from -3.33 to -2.70 SDS, and her growth velocity was 6.2 cm/yr.…”

“…White et al 6) Garcia et al 13) Nagasaki et al 4) Galli-tsinopoulou et al 8 www.e-apem.org 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.…”

“…Variable phenotypes of patients with FHS have been reported. [3][4][5][6] Most cases appear to be sporadic; however, autosomal dominant inheritance was reported in one familial case. 7) Although short stature is one of the main clinical manifestations, treatment with growth hormone (GH) therapy in patients with FHS is rare.…”

Floating Harbor Syndrome

“…Some developmental delay, especially in speech is common though great variability in intellect is reported. Additional features described in different reports include gluten intolerance, conductive hearing loss and polycystic kidney disease [3,4]. Most of the mutations described are truncating and appear to be clustered in the last (34th) exon as seen in this case also [2].…”

Diagnostic outcomes of exome gene panel sequencing in patients with unusual syndromic cleft lip/palate phenotypes

“…The majority of nonsense and frameshift SRCAP mutations that have 237 been identified in FLHS patients map to the exon 34 of the gene [32]. As exon 34 is the 238 last exon of the SRCAP gene, these mutations escape the nonsense-mediated mRNA 239 decay and lead to pathogenicity [33]. Given that identified mutation maps to the exon 240 34 of SRCAP and the extent of phenotypic similarity between the proband's phenotype 241 and FLHS features, the functional impact of the variant merits further investigation.…”