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

INTRODUCTION

Floating-Harbor syndrome (FHS, MIM 136140) is a rare genetic condition characterized by proportionate short stature, delayed bone age, expressive language delay and distinctive facial features [1]. The syndrome was first described in two patients at the Boston Floating Hospital [2] and at the Harbor General Hospital in Torrance, CA, USA, respectively, hence the name [3]. Its prevalence is unknown; if we take into account only SRCAP mutated cases, around 65 individuals have been reported to date. The FHS is caused by heterozygous mutations in exons 34 [4-6] and 33 [7,8] of the SRCAP gene, on chromosome 16p11.2. The SRCAP gene mutations are de novo truncating mutations. The SRCAP protein activates the CREBBP gene that is involved in the regulation of cell growth and division. Growth deficiency in FHS becomes apparent in the first year of life, but it can occur before birth. Affected children have a short stature with an average height below the 5th percentile. Bone age is delayed in the first decade of life. Typical facial features in patients with FHS include a triangularly-shaped face, low-set ears, low hairline, deep-set eyes with abnormally long eyelashes, a long, triangular-shaped nose with a low hanging columella, a short philtrum, and a broad, linear mouth with thin lips [9]. Expressive language delay is a common feature, varying from mild to very severe. Most affected children show some degree of intellectual disability, ranging from mild to severe; some patients have behavioral troubles (hyperactivity, attention deficit, aggression, obsessive behavior). Patients with FHS tend to have an unusually high-pitched voice. Other symptoms reported in individuals with FHS include skeletal anomalies (brachydactyly, fifth finger clinodactyly, 11 pairs of ribs, kyphoscoliosis), congenital heart malformations (aortic coarctation, atrial septal defect, tetralogy of Fallot), gastrointestinal features (motility problems, celiac disease), genitourinary abnormalities (kidney agenesis, renal cysts, hydronephrosis, precocious puberty, cryptorchidism, hypospadias), dental anomalies (supernumerary teeth, microdontia, malocclusion, delayed loss of primary teeth), ear anomalies (recurrent otitis media, conductive hearing loss), ophthalmologic issues (hyperopia, refractive errors, strabismus), seizures and hypothyroidism [9]. Here, we report on a patient with growth deficiency, dysmorphic facial features, language delay, and mild intellectual disability, with a known pathogenic mutation c.7330C>T, p.(Arg2444*) in the SRCAP gene. To the best of our knowledge, this is the first case of molecularly proven FHS in Romania. Clinical Report. A 7-year-old Romanian boy was referred to the Pediatric Neurology Department, for speech delay. The boy is the second child of healthy, unrelated parents. The pregnancy was uncomplicated, fetal ultrasound revealed short humerus (at 5 months of gestation). The child was born at 40 weeks with a birth weight of 2800 g, 51 cm in length, and good postnatal adaptation. The child presented normal motor development, but delayed language development (he uttered first syllables at 27 months and first words at 4 years 6 months. Hypospadias was diagnosed at birth and surgically corrected at 1 year; the boy had frequent respiratory and middle ear infections. In the first year of life, he presented feeding difficulties and failure to thrive. Clinical examination at 7 years old revealed: a height of 107 cm [<2 standard deviation (SD), a weight of 17 kg (<2 SD), an occipito-frontal circumference (OFC) of 50 cm (10th percentile). He had dysmorphic facial features: a triangularly-shaped face, deep-set eyes, long eyelashes, lowset malformed ears (hypoplastic helix, small ear lobe), a long nose with narrow bridge, a short philtrum, thin lips, microdontia, malocclusion, and a low frontal hairline (Figure 1). He also had mild mental retardation (IQ 66), severe expressive language delay (few simple sentences), hyperkinesia and attention deficit, episodes of aggressiveness at minor frustrations. Skeletal anomalies (brachydactyly, broad finger tips) were noted at clinical investigation. Xray examination showed a bone age of 3 years at the age of 6. Cerebral magnetic resonance imaging (MRI) was normal, including normal pituitary anatomy, as were heart and abdominal ultrasound. Ophthalmologic evaluation was also normal. The levels of thyroid and growth hormones were within the normal range. Taking into account the association of growth deficiency with delayed bone age, expressive language delay and distinctive facial features, a clinical diagnosis of FHS was established. Written consent for publishing clinical data and images of the patient was obtained from the parents. Sanger sequencing of exons 33 and 34 of the SRCAP gene identified the heterozygous mutation c.7330C>T on exon 34. At the protein level, this sequence alteration leads to truncation of the protein at position 2444 (p.Arg2444*). This mutation is reported in the databases dbSNP (rs199469464; http://www.ncbi.nlm.nih.gov/ SNP/), Clin Var (RCV000023895; http://www.ncbi.nlm. nih.gov/clin var/) and HGMD (https://portal.biobaseinternational. com/ hgmd/pro/start.php) as a pathogenic variant. Segregation analysis revealed that both parents do not carry the mutation c.7330C>T, showing that it has occurred de novo in the patient. According to current recommendations, we instituted an intensive program of cognitive and speech stimulation, using picture exchange communication system (PECS), and behavioral therapy. Yearly neurological, psychological, ophthalmological, otorhinolaryngological, pediatric and endocrinological, monitoring of our patient was planned.



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