Introduction
Floating-Harbor syndrome (FHS) is a known rare autosomal dominant disorder. The FHS was named after the two hospitals where the first two cases were described in the United States.2 It has clinical characteristics of shortened height, facial dysmorphia, skeletal abnormalities, a delayed bone age, speech and language difficulties, as well as intellectual disabilities.1
The cause of FHS has been identified as mutations in the SNF2-related CREBBP activator protein gene (SRCAP). This gene encodes the multiprotein chromatin remodeling SRCAP complex. Different phenotypes of FHS in patients have been reported, most are sporadic; however, some cases are autosomal dominant inherited. Growth hormone therapy is a treatment often used in patients with FHS to target short stature, the main clinical manifestations of FHS.1
Pathophysiology of floating harbor syndrome
This condition occurs due to a rare autosomal dominant trait as a result of heterozygous mutations on the SRCAP gene. Mutations in the terminal portion of the SRCAP gene in exon 34 result in the formation of a truncated variant of the SRCAP protein with missing domains. FSH is the result of the dominant negative effect of this encoding. At the moment, there are approximately 40 pathogenic variants of the SCRAP gene that have associations with FSH. The majority of these mutations occur between codons 2407 and 2527.
The SRCAP gene can be found on chromosome 16p11.2, which contains a 40,989-bp coding region. As well as 34 exons that encode a SNF2 related chromatin, remodeling the SRCAP protein (such as ATPase). This protein is abundant in the nuclei of cells in the human body. And performs an essential function in cellular pathways that include:
The SRCAP protein possesses various discrete functional domains such as SNF2. This is similar to the following:
The SRCAP protein can contribute to transcriptional regulation by activating CREBBP. This, in turn, activates several transcription factors and initiates gene expression. Therefore, as well as its role in chromatin remodeling, the SRCAP protein also has an effect on numerous signaling pathways (e.g. the Notch signaling pathway and steroid receptor-mediated transcriptional pathways).
There is an overlap in the clinical manifestations of FHS with Rubinstein-Taybi syndrome (RTS). This is due to mutations in the gene that encodes CREBBP. There are other structural domains that SRCAP carry that activate CREBBP. These structural domains contain sections of the AT-hook motif. Which is a small DNA-binding motif that consists of around nine amino acids. These proteins hold a key role in organising chromatin and the expression of genes that control cellular processes.
A non-sensor frame shift mutation on the exon 33 and 34 of the SRCAP gene produces a shortened protein that leads to a loss of the AT-hook structural domain. SRCAP proteins that have lost this structural domain are not able to activate the CREBBP gene effectively. This results in a stunted development and, ultimately FHS.2
Clinical manifestations
Phenotype variation is typical in FHS due to the multiple roles of SRCAP. To diagnose the condition, there are many clinical manifestations that are visible in individuals with FHS. These vary from facial features to gastrointestinal disorders and anxiety.
The main features visible in children with FHS are:
- Short stature
- Delayed bone age
- Delayed speech development
- Delayed expressive language
- Intellectual impairment
- High pitched voice
- High-pitched nasal tone
- Specific facial features
- Triangular face
- Long eyelashes
- Deep-set eyes
- A high nasal bridge
- A short philtrum
- Wide mouth
- Thin upper lip
- Low set ears
- Skeletal abnormalities
- Wide thumbs
- Short fingers
- Clavicle deformity
- Hip dysplasia
- Psycho-behavioral abnormalities
- Attention deficit hyperactivity disorder
- Obsessive compulsive disorder
- Anxiety
Growth hormone deficiency in FHS
The most distinctive feature of FHS is short stature in individuals. The exact mechanism of SRCAP mutations is under further evaluation to know the cause of short stature. Research by Bo and colleagues has discussed the skeletal growth plate that is responsible for bone elongation and height is impaired. Components in the bone cartilage require a process whereby new cartilage tissue is generated and remodeled into bone tissue. Leading to new bone gradually forming into the growth plate. This allows bones to become longer and ultimately adds height to children.
Abnormalities in the signaling pathways of bone elongation can contribute to skeletal deformity, for example, short fingers. FSH in children commonly experience severe delay in bone development until six years. Followed by bone age delay or normal in individuals aged six until 12, and significantly accelerated. The process of suddenly accelerated growing cartilage suggests delayed bone age. This does not express room for height growth, suggesting impaired signaling pathways in cartilage tissue formation.
Short stature in children with FSH has been associated with growth hormone deficiency. As well as neurosecretory dysfunction and IGF-1 signaling defects. Most cases of FSH have reports of growth hormone deficiency. Research has suggested that impaired IGF-1 signaling may lead to FSH. Which has an effect on height due to the difference between growth response to rhGH and serum IGF-1.
Increasing growth rate and height in children with dwarfism has risen with rhGH treatment. In rhGH treatment, IGF-1 levels are maintained at high rates. This stimulates hypertrophy of growth plates in bones and ultimately accelerates overall linear growth.
Clinical evidence for GH therapy in FHS
Innovative research in Frontiers in Pediatrics presented a case of a height increase of 6.3cm after six months of receiving rhGH treatment. However, IGF-1 levels fluctuated between -1 and +1 standard deviation. It was recommended that a longer treatment period was needed as well as potentially the effects of late treatment.
On the contrary, the research study also discussed that the mean adult height of children treated with the growth hormone therapy were significantly greater in comparison to those who received no treatment. This suggests that rhGH treatment may hold a good opportunity to enhance children's height with FSH. There was also a potential association between spinal cord embolism and rhGH therapy in individuals with FSH. These findings recommended patients whilst undergoing the treatment on a clinical basis undergo lower limb neurological examinations regularly.
In another case, it was revealed that a child had developed nephrotic syndrome during growth hormone therapy. For this reason, the treatment was discontinued.
In a different study, four cases of FHS developed cerebrovascular disease, which included three cases of hypertension. Clinical measures are recommended to monitor FHS. However, Bo and colleagues reviewed data from 22 children who were treated with rhGH. No side effects were reported.2
For example, children with FHS should undergo routine monitoring for:
- Growth
- Bone age
- Blood pressure
- Renal function tests
- Urinary ultrasound
- Auditory screening
- Dental evaluation
- Neurological disease screening
- Ophthalmologic evaluation2
Summary
To summarise, clinically, FSH is a complex genetic condition. The main features are specific facial features, delayed language development, and a short stature. A timely and accurate diagnosis is crucial for early intervention and clinical management. Individuals’ short height can be treated with at least six months of rhGH treatment. However, the backbone of growth disorders in children with FSH remains unclear. The effectiveness and safety of receiving growth hormone therapy needs to be monitored in a larger sample size, particularly over a longer timeframe.
FAQS
What is floating harbour syndrome?
Floating-Harbor syndrome (FHS) is an extremely rare genetic disorder, with multiple characteristics, such as facial dysmorphism, various skeletal malformations and expressive and receptive language delays.
How common is FSH?
The prevalence and incidence of FSH are typically unknown. However, approximately 100 cases have been reported in scientific literature to date.
How much does growth hormone cost in the UK?
The average annual cost of growth hormone treatment is around £3350 per individual. However, the cost of the treatment reduces due to age. This is because the growth hormone requirement decreases as individuals age.
What are the risks of growth hormone therapy in children?
- Allergic reaction, e.g rash and hives
- Swelling at the injection site, where the treatment was injected
- Joint pain, e.g hip or knee pain
- Headache
- Progression of spine curvature in patients with scoliosis
- Increase in blood sugar levels (temporary), however, this stops when the growth hormone treatment stops
References
- Son, HW., Lee, J., Oh, SH., Keum, C and Chung, WY ‘Effects of long-term growth hormone therapy in a girl with Floating-Harbor syndrome’ Annals of Pediatric Endocrinology & Metabolism, vol. 25 (2), June 2020 pp. 126-131, Accessible at https://doi.org/10.6065/apem.1938144.072.
- Bo, H., Jiang, L., Zhaeng, J and Sun, J ‘Floating-Harbour Syndrome Treated With Recombinant Human Growth Hormone: A Case Report and Literature Review’ Frontiers in Pediatrics, vol. 9, Nov. 2021, p.747353, Accessible at https://doi.org/10.3389/fped.2021.747353.
