Introduction

Floating harbor syndrome (FHS) or pelletier-leisti syndrome is a disorder which involves short stature, showing of mineralisation of the bones, delayed bone age, delayed development of speech, and difference in facial features.¹ It is seen in children between the ages of 6 to 12 years. Skeletal abnormalities include 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 having floating harbor syndrome. A 3 year old child with FHS will have bones the same as a 2 year old child. Speech delay may be severe in children with floating harbor syndrome and eventually lead to the lack of verbal communication. Sometimes it affects the child's intellectual ability 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, high-pitched voice, clubbing of toes, fingers, and pinky fingers. Floating harbor syndrome was named after 2 hospitals where this disorder was first reported during the 1970s, the names of those hospitals are Boston Floating Hospital and Harbor General Hospital located in California.

Causes

Floating harbor syndrome is caused by a 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 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 fertilization 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 both 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, short stature, and delayed bone ageing.

• 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, and verbal abnormalities.

• Cognitive and behavioural defects:

Patients with FSH have mild to moderate intellectual disability, learning and communication abnormalities, and behavioural abnormalities like hyperactivity, short attention span, obsession with 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 pairs of ribs, seizures, dysplastic hips, gastroesophageal reflux, conductive hearing loss, dental abnormalities, early puberty, ageing, kidney cysts, celiac disease, heart defects, hypertension, and hypothyroidism in adults.

Growth patterns in Floating-Harbor Syndrome:

• Delayed growth and short stature: This is the first sign which occurs during the initial year where the affected child usually is below the 5th percentile in height for their age. In a few cases, doctors noticed that babies have prenatal growth retardation where the fetus is underweight at birth
• Delayed bone growth: In the first years children with floating harbor syndrome have delayed bone growth because the rate of calcification of bones is lower when compared to a normal fetus 
• Growth hormone deficiency: Somatotropin which is a growth hormone is seen in low levels in patients with floating harbor syndrome and treatment with this growth hormone is inconsistent as some children respond well while others don't
• Puberty effects: In some cases, rapid onset of bone growth may occur after puberty as Gonadotropin releasing hormone (GnRH) agonists have been used to slow down the rate of puberty and improve height⁶

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, and they check for changes in the gene like deletion or change in 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. The 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 having to guess 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 tests which can help with early diagnosis of FSH. Other tests like Prenatal and preimplantation genetic diagnostic options are also available and furthermore, studies are taking place to find out more diagnostic tools which are not very expensive and easy to use in the future.

Summary

Floating-Harbor Syndrome (FHS), also known as Pelletier-Leisti Syndrome, is a rare genetic disorder characterized 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 a range of skeletal abnormalities such as short thumbs, prominent joints, and clavicular issues. Additional complications may include conductive hearing loss, seizures, gastroesophageal reflux, and renal abnormalities. Growth deficiencies are often apparent within the first year of life, with affected children exhibiting delayed bone development. Speech delays can be severe, potentially leading to challenges in verbal communication, intellectual disabilities, and motor skill delays, such as difficulties with crawling, sitting, and walking are also common. Facial features distinctive of FHS include a triangular face, low hairline, long eyelashes, and thin lips. The syndrome was named after the Boston Floating Hospital and Harbor General Hospital in California, where it was first described in the 1970s.

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 fertilization, 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 ageing. 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 behavioural issues including mild to moderate intellectual disability, learning difficulties, and behavioural abnormalities like hyperactivity and aggression are also observed. Skeletal abnormalities such as brachydactyly, broad fingertips, and clavicle issues are typical. Additional symptoms can include seizures, dysplastic hips, gastroesophageal reflux, conductive hearing loss, and dental anomalies.

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. 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.