Raine syndrome

Overview

Raine syndrome, also known as osteosclerotic bone dysplasia, is a rare autosomal recessive genetic disorder characterized by abnormal bone development, particularly generalized osteosclerosis (excessive bone density), facial anomalies, and in most cases, early neonatal death. The condition was first described by Dr. J. Raine in 1989, and only a limited number of cases have been documented worldwide.

This syndrome typically presents in the neonatal period or prenatally, and is often fatal in the early stages of life due to severe respiratory distress and craniofacial abnormalities. However, in rare non-lethal forms, children may survive beyond infancy and may exhibit developmental delays and other complications. Raine syndrome is primarily associated with mutations in the FAM20C gene, which plays a role in phosphate metabolism and bone mineralization.

Causes

Raine syndrome is caused by mutations in the FAM20C gene, located on chromosome 7. This gene encodes a kinase protein involved in regulating biomineralization through phosphorylation of proteins in the bone and teeth. Mutations in FAM20C lead to abnormal deposition of bone minerals, resulting in dense, sclerotic bones that lack the normal flexibility and structure required for healthy growth and function.

The inheritance pattern is autosomal recessive, meaning both parents must carry and pass on a defective copy of the gene. Carriers usually do not show any symptoms themselves. In consanguineous populations, the risk of transmission is significantly higher due to shared genetic background.

Symptoms

The clinical features of Raine syndrome are typically evident at birth or during prenatal imaging. Common signs and symptoms include:

• Generalized osteosclerosis: Abnormally dense bones seen throughout the skeleton

• Craniofacial anomalies: Including prominent forehead (frontal bossing), midface hypoplasia, depressed nasal bridge, micrognathia (small jaw), and exophthalmos (bulging eyes)

• Intracranial calcifications: Often noted on imaging studies of the brain

• Failure to thrive: In surviving cases, infants may struggle with feeding and growth

• Respiratory distress: Due to narrowing of the nasal passages or thoracic insufficiency from skeletal abnormalities

• Dental anomalies: Hypoplastic or absent teeth may be observed in non-lethal cases

• Developmental delays: In children who survive infancy, intellectual and motor impairments are common

Most cases are classified as “lethal Raine syndrome” due to death occurring within days or weeks of birth, often from respiratory complications. However, non-lethal variants have been increasingly reported and may present with milder features and longer survival.

Diagnosis

Diagnosis of Raine syndrome is typically based on a combination of clinical evaluation, imaging studies, and genetic testing:

• Prenatal ultrasound: May reveal skeletal abnormalities and increased bone density in the fetus

• Postnatal X-rays: Show diffuse osteosclerosis and characteristic craniofacial bone abnormalities

• CT or MRI scans: Can reveal intracranial calcifications and further evaluate facial structure and brain abnormalities

• Genetic testing: Sequencing of the FAM20C gene confirms the diagnosis by identifying biallelic pathogenic variants

Because the syndrome is extremely rare, differential diagnosis may include other skeletal dysplasias such as osteopetrosis, pycnodysostosis, and other congenital osteosclerotic disorders.

Treatment

There is no definitive cure for Raine syndrome. Treatment is largely supportive and based on symptom management and improving quality of life in non-lethal cases. Treatment strategies include:

• Neonatal intensive care: Immediate respiratory support and feeding assistance in infants with breathing difficulties or failure to thrive

• Surgical intervention: In cases of severe craniofacial deformities that obstruct airways or vision

• Orthopedic monitoring: Regular assessments for bone deformities or fractures in survivors

• Physical and occupational therapy: To support motor development in surviving individuals

• Multidisciplinary care: Including pediatricians, geneticists, neurologists, and dental specialists

Genetic counseling is strongly recommended for affected families, especially in populations where consanguinity is common.

Prognosis

The prognosis of Raine syndrome depends on the severity of the mutation and clinical presentation. Most cases are lethal within the first few weeks of life due to severe respiratory complications and multiple organ system involvement. However, individuals with non-lethal variants may survive into childhood and adulthood, albeit with multiple disabilities and developmental challenges.

Long-term outcomes for survivors are still not well-documented due to the rarity of the condition, but they often require ongoing medical, rehabilitative, and developmental support. Continued research into the role of FAM20C and potential therapeutic interventions may offer hope for improved outcomes in the future.