Introduction

Fraser syndrome (FS) is a rare autosomal recessive genetic disorder characterized by fused eyelids, fusion of the skin between the fingers and toes and abnormalities of the genitalia and urinary tract. Signs and symptoms occur early in development and include malformation of the respiratory tract, failure of kidney development; umbilical hernia; abnormalities of the nose and ear; cleft lip and palate; skeletal abnormalities; and intellectual disability. This disease was initially identified as cryptophthalmos syndrome by George Fraser.¹

Due to wide clinical anomalies, diagnosis of Fraser Syndrome is challenging. People with this illness exhibit various cranial and facial deformities, such as:

• A flat nasal bridge
• A tiny or weakly defined chin
• Hypertelorism, or an extended distance between the eyes
• Microcephaly, in which the head is smaller than average
• Brachycephaly, in which the skull is shortened
• Brain abnormalities such agenesis of the corpus callosum and hydrocephalus

Fraser Syndrome also impacts various other systems, contributing to multi-organ abnormalities. FS can easily be diagnosed at birth by visible deformities or at prenatal ultrasonographic features. Early diagnosis is crucial for optimizing care and improving the quality of life for affected individuals. This includes genetic testing to confirm the diagnosis and a coordinated treatment plan involving specialists from various fields. Understanding the range of facial and cranial abnormalities associated with Fraser Syndrome is vital for accurate diagnosis and comprehensive care.

Overview of Fraser syndrome

Genetic basis 

Fraser Syndrome is as autosomal recessive disorder caused by mutations in the FRAS1 (4q21.21), FREM2 (13q13.3), and GRIP1 (12q14.3) genes. These code for extracellular matrix proteins necessary for the adhesion between the basement membrane of the epidermis and connective tissues of the dermal layer during embryological development, leading to failure in apoptosis. It is estimated that between 15% to 30%² of families with Fraser syndrome experience consanguinity.

This syndrome is related to a failure of the apoptosis program and formation of large blisters during embryonic development due to defects in epidermal adhesion. During embryo development the Fraser Complex (FC) mediates the connections between connective tissue and epithelium. This complex comprised of the Fras1/Frem family of extracellular matrix proteins. The loss of expression of FC components leads to Fraser Syndrome. 

Clinical presentation

Fraser syndrome presents a wide range of clinical features, including characteristic craniofacial irregularities such as a high forehead and broad nose. However, FS is clinically presented in numerous different ways, such as: 

Facial and cranial abnormalities: abnormalities of the eyes include colobomas and hearing loss that may be conductive or sensorineural. 

Genitourinary abnormalities: present in both the kidneys and reproductive organs.

Limb malformations: present as fused or nonexistent digits and skin abnormalities are visible as tags around the eyes and ears. There is also a chance of intellectual disability and developmental delays.

Facial and cranial abnormalities

Facial features include eyes that are completely covered by the skin and usually malformed (cryptophthalmos), eyes may be small (microphthalmia) and in some cases eyes maybe missing (bilateral anophthalmia) causing blindness. Facial anomalies included a low hairline, broad nose with depressed nasal bridge, low-set ears and hypertelorism (increased distance between the two eyes). Abnormal eye development include without eyebrows or eyelashes or a patch of hair extending from the side hairline to the eyebrow. The most common facial abnormality in Fraser syndrome are:

• Cryptophthalmos: Complete or partial covering of the eyes by the skin
• Microphthalmia: Small eyes
• Anophthalmia: Absence of eyes
• Cleft lip and palate: A gap or opening in the upper lip
• Low-set ears: Ears positioned lower than normal on the sides of the head
• Depressed nasal bridge: A flattened or sunken bridge of the nose
• Hypertelorism: Increased distance between the eyes
• Choanal stenosis: Narrowing or blockage of the nasal passages
• Facial asymmetry: Unequal features on the two sides of the face
• Encephalocele: Neural tube defect characterized by sac-like protrusions of the brain
• Oxycephaly: Pointed skull
• Turricephaly: Very high or towerlike skull with a vertical forehead.
• Microcephaly: Small head size
• Brachycephaly: Shortened skull

Diagnostic evaluation

A combination of imaging investigations, genetic testing, and clinical assessment can help diagnose Fraser syndrome.

Clinical assessment

1. Physical examination of the patient's face, ears, nose, mouth, and eyes can readily identify specific anomalies linked to Fraser syndrome
2. It is possible to determine any hereditary or congenital disorders by analysing the family medical history
3. Developmental delays in motor, verbal, or cognitive development seen in kids with fraser syndrome

Imaging studies

1. A thorough ophthalmologic assessment in order to detect eye abnormalities, such as cryptophthalmos, microphthalmia, or coloboma
2. Further, a prenatal ultrasound scan can identify abnormalities associated with Fraser syndrome, such as polyhydramnios (excess amniotic fluid)
3. More precise information regarding the anatomy of the brain, eyes, and other organs can be obtained by CT or MRI imaging studies

Genetic testing

1. Genetic tests such as Chromosomal analysis will help to detect mutation in genes associated with Fraser syndrome.
2. Genotypic analysis to confirm the mutation in specific genes involved in Fraser syndrome, such as the FRAS1 gene

Management and treatment

The management of Fraser syndrome involves a multidisciplinary approach, including surgical intervention and genetic counselling.

Surgical intervention

1. Surgery: In some cases where the facial malformations are severe, reconstructive surgery may be required to improve or correct structural defects. This can include procedures to correct cryptophthalmos, microphthalmia, or coloboma
2. Other surgical procedures: Depending on the specific abnormalities present, surgical intervention may be necessary to address issues such as nasal deformities or urinary tract abnormalities

Genetic counseling

1. Genetic counselling for families with history to understand the risk of syndrome to offspring with Fraser syndrome by prenatal testing, reproductive options, and genetic carrier testing
2. Genetic counselling can also extend emotional support and guidance to families affected by Fraser syndrome

Additional therapies

1. Individuals with developmental delays in Speech, impaired mobility and associated conditions can be treated with regular Physical and Speech therapy
2. Occupational therapy can assist in learning daily living skills and adapt to their environment for individuals with Fraser syndrome

Prognosis and quality of life

Life expectancy of patients with Fraser syndrome may be different and depends on how severe the patient’s condition is and whether the patient has other diseases. Majority of these cases cannot be cured but if diagnosed early and well managed, the quality of life of patients can be greatly enhanced.

Summary

In summary, a wide range of birth abnormalities, such as eye abnormalities, ear anomalies, and nasal deformities, are associated with Fraser syndrome. Fraser syndrome sufferers can have better lives if they receive early diagnosis and treatment, but there is no known cure. Supportive therapy and genetic counselling are essential for controlling the illness.