Fraser syndrome

Overview

Fraser Syndrome is a rare, inherited genetic disorder characterized by a combination of congenital malformations, particularly affecting the eyes, digits, genitalia, and internal organs. One of the hallmark features of the condition is cryptophthalmos—a condition in which the eyes are completely or partially covered by skin. First described by George Fraser in 1962, the syndrome exhibits a wide spectrum of severity and is often associated with high perinatal mortality due to internal organ anomalies, especially those affecting the kidneys and respiratory tract.

Causes

Fraser Syndrome is caused by mutations in one of several genes involved in embryonic development. These include:

• FRAS1 gene (most common)

• FREM2 gene

• GRIP1 gene

The disorder follows an autosomal recessive inheritance pattern, meaning an affected child must inherit two defective copies of the gene—one from each parent. Carriers (with only one copy of the mutated gene) do not show symptoms but can pass the gene to their children.

Symptoms

Fraser Syndrome presents with a wide range of symptoms, and not all individuals show every feature. The most commonly reported signs include:

Ocular Abnormalities

• Cryptophthalmos (skin covering the eyes, complete or partial)

• Microphthalmia (small eyes)

• Anophthalmia (absence of one or both eyes)

Craniofacial and Digital Abnormalities

• Low-set ears or malformed ears

• Broad nasal bridge

• Syndactyly (fusion of fingers or toes)

• Malformed or missing digits

Genitourinary and Internal Organ Anomalies

• Ambiguous or abnormal genitalia

• Renal agenesis or dysplasia (absent or malformed kidneys)

• Hydronephrosis or urinary tract abnormalities

• Laryngeal and tracheal malformations

Other Possible Features

• Umbilical hernia

• Delayed development in survivors

• High perinatal mortality due to severe malformations

Diagnosis

Diagnosis of Fraser Syndrome is based on clinical findings and genetic testing. Diagnostic steps include:

• Prenatal ultrasound: May detect major anomalies such as kidney agenesis or cryptophthalmos.

• Physical examination at birth: Identification of characteristic facial and digital features.

• Genetic testing: Confirms diagnosis by detecting mutations in the FRAS1, FREM2, or GRIP1 genes.

• Imaging studies: Ultrasound, CT, or MRI to evaluate internal organ involvement.

• Autopsy findings: In cases of stillbirth or neonatal death, postmortem evaluation can provide diagnostic confirmation.

Treatment

There is no cure for Fraser Syndrome. Treatment is supportive and focuses on managing individual malformations and complications. Management often requires a multidisciplinary team, including neonatologists, pediatric surgeons, ophthalmologists, nephrologists, and genetic counselors. Common interventions include:

Surgical Management

• Reconstructive surgery for cryptophthalmos or eyelid malformations

• Surgical correction of syndactyly or other limb anomalies

• Repair of genital or urinary tract malformations

• Management of airway anomalies if present

Supportive Therapies

• Renal support or dialysis in cases of kidney dysfunction

• Visual and developmental support for surviving children

• Special education and physical therapy for developmental delays

Genetic Counseling

• Essential for families with a history of Fraser Syndrome

• Carrier testing and prenatal diagnosis available for at-risk couples

Prognosis

The prognosis of Fraser Syndrome varies widely depending on the severity of organ involvement. In severe cases, particularly with bilateral kidney agenesis or significant airway malformations, the condition is often fatal in utero or shortly after birth. However, children with milder forms who receive early surgical and medical intervention can survive and have a better quality of life. Long-term outcomes depend on the extent of anomalies and the success of supportive treatments.