What is the diagnosis?

The clinical features of this child (short stature, global developmental delay, delayed bone age, brachydactyly, typical facial features including triangular face, bitemporal narrowing, midface hypoplasia, prominent eyes, epicanthic fold, long nose with broad tip and short philtrum and thin lips) were suggestive of Floating Harbor Syndrome (FHS). FHS is a rare genetic disorder characterised by distinctive craniofacial features, short stature, delayed bone age, variable skeletal anomalies, expressive and receptive language delay and mild to moderate grade intellectual disability.¹

Molecular testing by Next Generation Sequencing (NGS) on extracted DNA from proband's peripheral blood detected a heterozygous pathogenic variant c.7330C>T in exon 34 of the SRCAP gene. This is a de novo nonsense mutation that changes the 2444th codon from Arginine to STOP. This variant has been reported multiple times in literatures as disease causing. The molecular diagnosis of FHS (OMIM#136140) was substantiated.

The exact prevalence of FHS is unknown. Over 100 cases have been reported worldwide.²

How is the clinical diagnosis established in FHS?

FHS should be suspected in individuals with the following clinical and radiographic features.³

Characteristic craniofacial features include triangular face, deep-set eyes, short philtrum, wide mouth with thin lip, long nose with broad base and tip, low-hanging columella and low-set ears. Variable skeletal anomalies include brachydactyly, broad fingertips that give the appearance of clubbing, clinodactyly, prominent joints and clavicular abnormalities. Speech and language delay are commonly presented features. Severe receptive and expressive language impairment can be across all domains of function. Patients with FHS may also have dysarthria, verbal dyspraxia with phoneme imprecision, hypernasality and high-pitched voice.

Other features such as hyperopia, strabismus, conductive hearing loss, seizures, gastroesophageal reflux, renal anomalies (e.g., hydronephrosis. cysts, renal agenesis) and genital anomalies (e.g., hypospadias, micropenis, undescended testes) can also be present in FHS patients.

Molecular diagnosis of FHS and Genetic counselling

The diagnosis of FHS is established in a proband with aforementioned suggestive findings by identification of a heterozygous pathogenic variant in SCRAP on molecular genetic testing.

The SRCAP gene (OMIM*611421), located on chromosome 16p11.2, encodes an SNF2-related chromatin-remodelling ATPase which serves as a transcriptional activator via binding to CREB-binding protein. It is believed that the truncated SRCAP variant disrupts the binding of wild-type SRCAP to both DNA and chromatin targets, thus affecting gene expression that controls the onset of differentiation and developmental processes.⁴

Nearly all reported pathogenic variants were located in exons 33 and 34 of SRCAP that are predicted to cause truncation of the protein resulted in the FHS. FHS is inherited in an autosomal dominant manner, although most cases are sporadic. The offspring of an affected individual is at a 50% risk of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk are possible. There are no silent carriers of FHS.

What are the management issues for FHS?

Management of FHS requires a multi-disciplinary approach. Depending on the clinical manifestations, paediatricians, endocrinologist, ophthalmologists, ENT specialists, audiologists, dental surgeons, urologists, clinical geneticists, speech therapists, clinical psychologists' inputs are important.

Treatment and surveillance are suggested as follows.³

To date, over 100 FHS cases have been reported worldwide, and only a few of these patients were GH deficient. Short stature is the core feature of FHS; however, there are limited data on the GH-IGF-1 axis in FHS. It was suggested that FHS may lead to impaired IGF-1 signalling 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). For use of GH treatment in FHS, a few case reports have shown improvement in growth velocity and height. However, caution is indicated since further studies are necessary to clarify the real effectiveness and safety.⁵

Acknowledgement

We would like to thank the patient and his family for their contribution.

References

1. McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:136140; Last Update: 08/22/2014. Available at: http://omim.org/entry/136140. Accessed September 24, 2014.

2. Zhang S, Chen S, Qin H, et al. Novel genotypes and phenotypes among Chinese patients with Floating-Harbor syndrome. Orphanet J Rare Dis 2019;14:144.

3. Nowaczyk MJM, Nikkel SM, White SM. Floating-Harbor Syndrome. 2012 Nov 29 [Updated 2019 May 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK114458/. Accessed August 16, 2021.

4. Messina G, Atterrato M, Dimitri P. When chromatin organisation floats astray: The Srcap gene and Floating-Harbor syndrome. JJ Med Genet 2016;53:793-7.

5. Homma T, Freire B, Honjo R, et al. Growth and Clinical Characteristics of Children with Floating-Harbor Syndrome: Analysis of Current Original Data and a Review of the Literature. Horm Res Paediatr 2019;92:115-23.