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
The FHS is caused by heterozygous mutations in exons 34 [4, 5, 6] and 33 [7, 8] of the
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
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, low-set 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. X-ray 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
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.
Hood
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
Comparison of clinical features reported in the literature (cases with a
Features | Literature | This Study | |||
---|---|---|---|---|---|
References | [4] | [5] | [6] | [8] | |
Facial gestalt | 13/13 | 6/6 | 52/52 | 5/5 | [+] |
Language delay | 13/13 | 6/6 | 52/52 | 5/5 | [+] |
Growth deficiency | 13/13 | 6/6 | 39/52 | 5/5 | [+] |
Delayed bone age | 13/13 | 6/6 | 23/25 | 4/5 The X-ray for bone age was not available in one case. | [+] |
Skeletal anomalies | 10/13 | 6/6 | [+] The authors report on different skeletal anomalies: broad thumb in 10/17 patients, broad toes, brachydactyly, broad fingertips (described as frequent), clavicular anomalies (six patients), hip dysplasia (four cases). | 5/5 | [+] |
Intellectual disability | 6/13 | 3/6 | 37/43 Patients with learning difficulties. | 4/5 | [+] |
Behavioral problems | NR | NR | [+] The authors report obsessive tendencies, rigid mannerisms (7/25) and ADHD (9/32). | 3/5 | [+] |
Eye anomalies | 4/13 | 2/6 | 13/43 | 0/5 | [–] |
Ear anomalies | 4/13 | 0/6 | 15/52 | 2/5 | [–] |
Dental issues | 4/13 Not reported in eight cases. | NR | 21/38 | 1/5 | [+] |
Genitourinary malformations | 8/13 | 1/6 | 5/24 | 0/5 | [+] |
Cardiac malformations | 3/13 | 3/6 | 3/52 | 0/5 | [–] |
Gastrointestinal malformations | 2/13 | 0/6 | 5/24 | 0/5 | [–] |
Seizures | 0/13 | 1/6 | 6/52 | 0/5 | [–] |
Hypothyroidism | NR | 0/6 | 2/52 | 0/5 | [–] |
NR: not reported; ADHD: attention deficit hyperactivity disorder.
Genetic testing of our patient detected the heterozygous mutation c.7330C>T in exon 34 of the
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
Checklist of Floating-Harbor syndrome clinical features to facilitate clinical diagnosis and management.
Features | Category |
---|---|
Characteristic face | mandatory Diagnosis of FHS requires meeting both mandatory criteria and at least one criterion from the frequent features category. |
Language delay | mandatory |
Short stature | frequent Diagnosis of FHS requires meeting both mandatory criteria and at least one criterion from the frequent features category. |
Delayed bone age | frequent |
Skeletal anomalies | frequent |
Intellectual disability | frequent |
Behavioral problems | recurrent Recurrent and infrequent categories include features that are not required for diagnosis, but further support FHS diagnosis and guide the clinical evaluation, planning and patient care, if present. |
Eye anomalies | recurrent |
Ear anomalies | recurrent |
Dental issues | recurrent |
Genitourinary malformations | infrequent Recurrent and infrequent categories include features that are not required for diagnosis, but further support FHS diagnosis and guide the clinical evaluation, planning and patient care, if present. |
Cardiac malformations | infrequent |
Gastrointestinal features | infrequent |
Seizures | infrequent |
Hypothyroidism | infrequent |
FHS: Floating-Harbor syndrome.
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.