FLOATING-HARBOR SYNDROME: PRESENTATION OF THE FIRST ROMANIAN PATIENT WITH A SRCAP MUTATION AND REVIEW OF THE LITERATURE
Budisteanu M, Bögershausen N, Papuc SM, Moosa S, Thoenes M, Riga D, Arghir A, Wollnik B
*Corresponding Author: Aurora Arghir, M.D., Ph.D., Victor Babes National Institute of Pathology, Medical Genetics Laboratory, 99-101 Splaiul Independentei, 050096 Bucharest, Romania. Tel/Fax: +40-21-319-27-32, ext. 207/+40-21-319-45-28. E-mail: aurora.arghir@ivb.ro
page: 83

DISCUSSION

Hood et al. [4] first demonstrated mutations in the SRCAP gene to be the cause of FHS in 2012. They reported a series of 13 patients who all carried truncating mutations within a small region of exon 34 (codons 2407 to 2517). Mutations could be proven to be de novo for all patients for whom parental DNA was available. In 2013, Le Goff et al. [5] published a cohort of nine patients. Six of them presented mutations of the SRCAP gene. The biggest cohort of patients with FHS yet reported was published by Nikkel et al. [6], who described 52 patients with mutations on the SRCAP gene, including the 13 patients previously reported by Hood et al. [4]. Nikkel et al. [6] refined the clinical spectrum of FHS and demonstrated autosomal-dominant inheritance in two mother/daughter pairs. They also extended the critical molecular region to between codons 2389 and 2748 [6]. The most recent series of five patients with FHS and mutations in the SRCAP gene was published in 2014 by Seifert et al. [8], who confirmed that exon 33 of the SRCAP gene can also be affected by pathogenic mutations, as previously reported by Kehrer et al. [7]. The main clinical features of FHS are the characteristic facial features (triangular face, long nose with narrow root and broad tip, low hanging columella, large nares, short philtrum, thin vermillion border of the lips, everted lower lip, a linear orientation of the mouth at rest or when smiling, deep set eyes, long eyelashes, low set, large ears), growth deficiency, language delay, skeletal anomalies (including brachydactyly, broad fingertips, short broad thumbs, big toes, clavicular anomalies, hip dysplasia), and delayed bone age. Intellectual disability was reported in many, but not in all patients, varying from mild to severe. Nikkel et al. [6] pointed out that language delay and sensory impairments might confound cognitive assessment in children with FHS. However, most patients did have schooling difficulties. Behavioral problems were noted in two studies (Nikkel et al. [6], Seifert et al. [8]) and included aggressive behavior, anxiety, rigid mannerisms, obsessions, and attention deficit hyperactivity disorder (ADHD). Other features, such as cardiac, gastrointestinal and genitourinary malformations, dental issues, eye and ear anomalies, seizures and hypothyroidism, were reported less frequently. Our patient presented all of the main clinical features in addition to mild intellectual disability, behavioral problems (ADHD), dental anomalies, and genital malformation. We summarize the published clinical data in comparison to the patient presented here in Table 1. Genetic testing of our patient detected the heterozygous mutation c.7330C>T in exon 34 of the SRCAP gene, which is a recurrent mutation in FHS patients; Hood et al. [4] identified the c.7330C>T mutation in six out of 13 patients and Nikkel et al. [6] found this mutation in 24/52 patients. Nikkel et al. [6] proposed that mutations in the last exons of the SRCAP gene should be considered mandatory for the diagnosis of FHS, in the presence of the classic phenotype. Thus, the patient presented here conforms to all of the published diagnostic criteria for FHS. A straightforward approach to clinical diagnosis of FHS is essential, especially in countries with limited resources. Therefore, we propose a checklist of clinical features suggestive of FHS (Table 2), based on the main clinical features defined by Nikkel et al. [6], to facilitate decision making with regard to molecular genetic testing and clinical evaluation planning. Floating-Harbor syndrome mandatory features are the characteristic facial gestalt and language delay, present in all patients reported and in the patient presented here. Growth retardation, skeletal anomalies and delayed bone age, as well as intellectual disability of varying degrees and behavioral problems, are quite frequently observed in FHS and we believe that at least one of these features should be present in addition to the mandatory features, as proposed in the checklist (Table 2). The other clinical findings (in the recurrent or infrequent categories in our checklist) are not required for a FHS diagnosis; however, their presence increase the confidence of FHS diagnosis and guide the clinical management. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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