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
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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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