Introduction

Floating harbor syndrome (FHS) or Pelletier-Leisti syndrome is a disorder with short stature showing mineralisation of the bones, delayed bone age, delayed speech development, and difference in facial features.¹ It is seen in children between the ages of 6 and 12 years. Skeletal abnormalities like short thumbs, prominent joints and clavicular abnormalities. Other abnormalities like conductive hearing loss, seizures, gastroesophageal reflux and renal abnormalities are also seen. Growth deficiency is mainly seen in the first year of patients with floating harbor syndrome. 

A child with FHS agent 3 years will have bones the same as a 2-year-old child. Speech delay may be severe in children with floating harbor syndrome and lead to lack of verbal communication. Sometimes it affects the child's intellectual disability and motor skills, like crawling, sitting, walking, etc. Children with floating harbor syndrome have varied facial features unlike normal children, like a triangular face, low hairline, long lashes, thin lips, etc, additionally, other abnormalities include short fingers,  a high-pitched voice, clubbing of toes and fingers and pinky fingers. Floating harbor syndrome was named after 2 hospitals where this disorder was first reported in the 1970s:  Boston Floating Hospital and Harbor General Hospital in California.

Causes

Floating harbor syndrome is caused due to the mutation in the SRCAP gene. Genes help with protein formation and production, and if there is a mutation in the gene, it may result in the formation or absence of the particular protein in the body, leading to various diseases and disorders in the body.² Studies show that this genetic mutation is caused during the fertilisation process of the egg and the sperm, which is called sporadic or de novo mutation. This mainly occurs with the child only and not the family. Hence, this disorder is not passed from one generation to the other and occurs during conception. Rarely dominant inheritance is seen as the trait is transmitted from either the affected mother or the father to the child. Normally genetic diseases are determined by a combination of genes for a particular trait, whereas in dominant genetic diseases only one single copy of an abnormal gene is necessary for the appearance of the disorder. Studies also show that the risk of passing on abnormal genes is 50% in males and females.³

Signs and symptoms

The main signs and symptoms occurring with FHS in children are stated as follows:

• Growth and development:

In a few cases, we can see low birth weight, also called low birth weight, short stature and delayed bone aging.

• Abnormal facial features:

Children with FHS usually have triangular shaped faces, low set ears, deep set eyes with very long eyelashes, thin lips, large nostrils and low hanging columella.

• Speech and language:

Dysarthria and high pitched nasally voice in boys, expressive language deficits, verbal abnormalities.

• Cognitive and behavioral defects:

Patients with FSH have mild to moderate intellectual disability, learning and communication abnormalities and behavioral abnormalities like hyperactivity, a short attention span, an obsession to something, aggression and anxiousness.

• Skeletal abnormalities:

Patients with FHS have brachydactyly, which also refers to short fingers and toes, broad fingerprints and short broad thumbs, bent pinky fingers and clavicle abnormalities

• Additional symptoms:

In rare cases, you can also see 11 parrots if ribs, seizures, dysplastic hips, gastroesophageal reflux, conductive hearing loss, Dental abnormalities, early puberty, aging, kidney cysts, celiac disease, heart defects, hypertension and hypothyroidism in adults.

Diagnostic procedures of Floating-Harbor Syndrome

Various Diagnostic procedures include:

• Single gene testing:

In this test, they look for the specific SRCAP gene, which is associated with FHS, they check for changes in the gene, like deletion of the gene sequence and base pairs in the DNA, which can lead to this phenomenon. Analysis of small changes is done first, later, if no mutations are found, they move to larger deletions and duplications in the DNA.

• Multigene panel:

This test is different from single gene testing as it looks for multiple genetic defects including SRCAP. Their genes detected may differ from time to time, and lab to lab and may not be directly related to FHS.

• Comprehensive genomic testing:

This test looks at a large portion of genes to find the genetic defect, rather than the specific gene which can be involved in FHS. This test focuses on exome sequencing (looks for protein coding genes) and genome sequencing (focuses on the entire genome)

• Epigenetic Signature Analysis:

This test looks for methylation of DNA, which is a chemical change that might be responsible for affecting the gene without altering the DNA sequence itself. This testing is done by collecting blood samples from the patient to identify distinctive patterns of FHS.⁴

These are some tests, which can help with early diagnosis of FSH. Also,  prenatal and preimplantation genetic diagnostic options are available, and studies are taking place to find more diagnostic tools that are less expensive and easier to use in future.

Management and treatment strategies:

There are no exact standardised treatments or guidelines due to the rarity of the disease and not enough background research. Specialised and unique treatment strategies may be required as each individual responds to the disease differently. No treatment trials are performed on large patients with FHS to determine long-term safety and effectiveness of specific medications. One study has shown that growth hormone therapy helps with floating harbor syndrome. The study was performed on a child aged 6 years and 9 months who had delayed language development and short stature from childhood. Sanger sequencing was performed and a heterozygous mutation was detected, which was SRCAP associated with FHS. The treatment option was the administration of rhGH, which is a growth hormone. This study was performed with 22 more children. During treatment, patients did not complain of any discomfort or side effects, and after 6 months of treatment with rhGH, most of the patients demonstrated an increase in height.⁵ Further research is being carried out with growth hormone therapy. Patients who show other symptoms like seizures can be treated with anti-seizure medication, children can be given speech and physical therapy as a treatment of delayed developmental interventions. There are no major lifestyle issues with patients with FHS as they often remain in good health and lead a good life.

Summary

Floating-Harbor Syndrome (FHS) is a rare genetic disorder characterised by a distinct set of symptoms including short stature, delayed bone age, speech development delays, and unique facial features. The syndrome typically becomes noticeable in children aged 6 to 12 years and is associated with skeletal abnormalities. Growth deficiencies are often apparent within the first year of life, with affected children exhibiting delayed bone development. Speech delays, intellectual disabilities,  and motor skill delays, are also common. 

The primary cause of FHS is a mutation in the SRCAP gene, which plays a crucial role in protein formation. This mutation often occurs spontaneously during fertilisation, known as a sporadic or de novo mutation, and is not typically inherited from parents. However, in rare cases, FHS can follow an autosomal dominant inheritance pattern, where a single copy of the mutated gene from an affected parent can lead to the disorder in the child. The risk of passing on the gene is approximately 50% for both males and females.

The signs and symptoms of FHS are varied and can include growth and developmental issues such as low birth weight, short stature, and delayed bone aging. Facial abnormalities are common, with features like a triangular face, low-set ears, and large nostrils. Speech and language challenges are prevalent, with many children experiencing dysarthria, a high-pitched nasally voice, and expressive language deficits. Cognitive and behavioral issues, including mild to moderate intellectual disability, learning difficulties, and behavioral abnormalities like hyperactivity and aggression, are also observed. Skeletal abnormalities such as brachydactyly, broad fingertips, and clavicle issues are typical. 

Diagnosis of FHS involves various genetic testing methods. Single-gene testing targets the SRCAP gene specifically, while multigene panels assess multiple genes to identify potential genetic defects. Comprehensive genomic testing, including exome and genome sequencing, examines large portions of the genome to pinpoint genetic abnormalities. Epigenetic signature analysis, which looks at DNA methylation patterns, can also aid in diagnosis when genetic testing results are inconclusive.

Management and treatment of FHS are primarily symptomatic and supportive due to the rarity of the disorder and limited research. Growth hormone therapy has shown promise in improving height in affected children. Other treatments may include anti-seizure medications, speech therapy, and physical therapy to address developmental delays. Despite the challenges associated with FHS, many individuals can lead healthy lives with appropriate medical and therapeutic interventions. Continued research is essential to develop more effective and accessible diagnostic and treatment options for this rare disorder.