Introduction

Do you know someone who is affected by genetic syndromes? Are you interested in learning more about what they are and the different types? In this article, we will discuss a genetic disorder known as Floating-Harbor Syndrome (FHS) and how it compares to other genetic disorders.

So, what are genetic syndromes? They are disorders that are caused by a change (a mutation) in the normal DNA sequence.¹ These mutations can be monogenic (mutation in one single gene); mutations in multiple genes (polygenic disorders) – which can be also caused by the interaction of genes with environmental factors (multifactorial inheritance); causing damage to chromosomes by changes in their structure or number (chromosomal mutations).¹

Genetic mutations can affect our lives in different ways. Some of these genetic syndromes can be inherited from the parents and will be present at birth, while some can be acquired through mutations during a person’s life due to either spontaneous mutations or an environmental factor (for example, smoking).¹

In this article, we will focus on a genetic syndrome known as Floating-Harbor Syndrome (FHS). 

FHS is a very rare genetic condition that is characterised by a particular facial appearance, skeletal deformities, delayed bone growth, and delays in language/speech skills.² This syndrome was named after the first two hospitals that identified these cases in the 1970s, which were Boston Floating Hospital and Harbor General Hospital.²

On the other hand, we will also tackle other genetic syndromes like Rubinstein-Taybi syndrome (RTS), three M syndrome, and Russell-Silver syndrome (RSS).

Floating-Harbor syndrome

Overview

Fetal alcohol syndrome is a rare genetic disorder, often observed in affected children due to the presence of a distinct appearance.³ It is caused by the mutation in a certain gene known as the SRCAP gene.³ Since genes are important for the formation of proteins, this mutation can result in a faulty protein, low amounts of it, or its complete absence – which can affect the whole body and impact the growth process.³

The SRCAP gene is found on chromosome 16; chromosomes are carriers of genetic information. These chromosomes are in pairs and are numbered from 1-22, while the sex chromosomes are designated by X and Y (the 23^rd).² In terms of FHS, the mutation of the gene is rather sporadic and new (de novo mutation), meaning that cases of FHS occur during the formation of the egg or sperm of one of the parents of the affected child, while other siblings and family members will not be affected.² Additionally, if a child carries the mutated SRCAP gene, the symptoms will be present, and there are no silent or asymptomatic carriers.²

However, there are cases when FHS was inherited from a parent in an autosomal dominant inheritance manner, where either the mother or father are affected and transmit this mutation to their offspring.2 In autosomal dominant genetic syndromes, only one copy of the mutated gene is enough to cause the illness, hence, the risk is 50% for each pregnancy.²

Symptoms

Multiple symptoms arise from FHS, such as:³

• Abnormal head and facial features like a triangular face, a long nose with a narrow bridge, low-set ears, deep-set eyes, a broad base, and a short philtrum
• Mild to moderate intellectual disability
• Temper tantrums and restlessness
• Short stature and low birth weight
• Delayed bone age
• Short neck, short thumbs and broad fingertips
• Possible hearing loss
• Seizures
• Gastro-oesophageal reflux, which can be severe
• Dental/teeth issues like caries and teeth loss
• Heart issues and malformations

Diagnosis and treatment

Diagnosis of FHS is based on finding the key characteristic symptoms (physical examination), family history, and the use of specialised tests. It might be difficult to diagnose based on physical examination alone as it may overlap with other disorders. In this case, genetic and genomic testing can be performed to confirm this syndrome. Prenatal diagnosis is also possible for parents with a known mutated gene.^2,3

In terms of treatment, it is focused on the symptoms present where a team of specialised healthcare providers will be required to give the proper plan for the child; for example, orthopaedists will assess and treat skeletal issues and ophthalmologists will assess and treat vision-related concerns.^2,3

Currently, there is no cure or standardised treatment for FHS due to the rarity of the disease, but there are options that can be taken to enhance the child’s quality of life. For example, physical and speech therapies, growth hormone therapies if required, and anti-epileptic medication in cases of the occurrence of seizures. Overall, patients with FHS tend to lead a good quality of life with overall good health.^2,3

Similar genetic syndromes

Rubinstein-Taybi syndrome (RSTS)

Rubinstein-Taybi syndrome is a rare genetic syndrome that affects multiple organs in the human body.⁴ It is sometimes mistaken by FHS due to the overlapping symptoms. However, it happens when there is a mutation in the gene that codes for the CREB-binding protein.⁴ Most mutations are de novo, and the risk of having another child with RSTS is below 1%.⁴ Similar to FHS, it can also be inherited in an autosomal dominant manner, so each pregnancy carries a 50% risk of having a child with RSTS.⁴

There are multiple symptoms that rise from RSTS, like:⁴

• Abnormal broad tips of thumbs and toes
• Delayed growth and short stature in children
• Inability to gain weight in infancy
• Developmental delays: delayed physical and mental skills like crawling, standing or speech
• Facial features: distinct beak-shaped nose with a broad bridge, slanted eyelids, small head, small mouth with a short thin upper lip, and underdeveloped upper jawbone
• Widely spaced eyes that can be crossed (having strabismus), droopy eyelids, and skin folds on the side of the nose that can cover the inner eye corners
• Scoliosis or kyphosis
• Undescended testes (cryptorchidism)
• Underdeveloped or missing kidneys, repeated UTIs, and kidney stones
• Heart defects
• Lung lobulation
• Behavioural issues like short attention spans, low tolerance to noise, and aggressive behaviour

Similar to FHS, RSTS is diagnosed via physical examination and genetic testing.⁴

In terms of treatment, the case varies between individuals as different children can present different symptoms.⁴ Aside from symptomatic treatment, surgery and physical therapy can be supportive techniques to improve the child’s quality of life.⁴

Three M syndrome

The three M syndrome is another rare genetic disorder that is characterised by having low birth weight, dwarfism, and abnormal facial or head features, along with skeletal abnormalities.⁵ Unlike FHS and RSTS, this syndrome is passed on in an autosomal recessive pattern, which requires two abnormal gene copies to be inherited from each of the parents for the disease to occur.⁵ Hence, a couple carrying the faulty genes would have a 25% risk on each pregnancy to have an affected child. The disorder occurs when there is a mutation in the genes CUL7, OBSL1, and CCDC8.⁵

The symptoms of the three M syndrome include:⁵

• Growth deficiency
• Triangular face shape, thick eyebrows, midface retrusion, thick lips, fleshy nose tip and pointed chin
• Short and broad neck
• Hyperlordosis
• Prominent heels
• Loose joints

Diagnosis of three M syndrome is done via physical examination, an endocrinology consult to test for growth hormone deficiency or testosterone check-ups, and genetic testing.⁵

Treatment for this syndrome will involve surgery for bone lengthening – for short stature, when possible – and hormone therapy using growth hormone – in a controlled manner, under the supervision of a specialist.⁵

Silver-Russell syndrome (SRS)

Silver-Russell syndrome is another rare syndrome that affects the growth of infants and causes physical malformations. This genetic disorder is heterogeneous, meaning that multiple genetic mutations and abnormalities arise to cause this syndrome. Around 60% of cases involve abnormalities in chromosome 7 or 11, while 40% of the cases are of unknown origin.⁶

There are several symptoms involved in SRS, including:⁶

• Low birth weight
• Poor appetite and difficulty in weight gain
• Delayed bone age in early childhood, followed by accelerated bone age at the ages of 8-9 years
• Asymmetry – one side of the body being smaller than the other, e.g. different arm or leg lengths
• Large head and small jaw giving a triangular face shape
• Prominent forehead
• Blue sclera in infancy
• Downturned corners of the mouth
• Small or absent teeth
• Oesophagitis
• Gastro-oesophageal reflux (GORD)
• Hypoglycaemia
• Delayed physical and mental skills like walking and speaking

Due to the overlapping symptoms with other disorders, it is difficult to diagnose SRS from others, however, genetic testing can be performed and can catch up to 60% of cases.⁶

In terms of treatment, assessment via a specialised healthcare provider is required to have a proper personalised plan for each patient.⁶ Failure to thrive and grow is common in children who have SRS due to both digestion problems and feeding difficulties.⁶ Hence, it is important for the child to have the right amount of calories in the first 2 years of life and that can even imply the use of tube feeding to avoid malnutrition.⁶ However, it is also important to not overfeed the infants as this can cause medical issues later on in life, like insulin resistance.⁶ Growth hormone therapy can also be an option to help improve the quality of life of the patients.⁶

Summary

Genetic syndromes can have a wide range of effects on our bodies, from silent mutations that cause no effect to more prominent ones like FHS. FHS can cause distinct facial features in children, affecting their physical as well as mental abilities. There are multiple other genetic disorders that can overlap or have similar symptoms to FHS, which makes the diagnosis based on physical examination difficult. It is important to diagnose each case appropriately, to provide the child with the right treatment and care, and to improve their quality of life.