Shprintzen-Goldberg syndrome is an extremely rare genetic disorder that affects the body’s connective tissue. Because connective tissue provides structure and support, the syndrome’s effects are widespread, impacting the development of the skeletal, cardiovascular, and nervous systems. Individuals often have a unique combination of craniofacial differences, bone abnormalities, and potential heart issues. The signs and symptoms can vary significantly but follow a recognizable pattern that helps distinguish it from similar conditions.
Genetic Origins of the Syndrome
Shprintzen-Goldberg syndrome is caused by mutations in the SKI gene. This gene provides instructions for a protein that helps regulate cell activity, including growth and maturation. The SKI protein acts as a brake on a chemical signaling pathway known as transforming growth factor beta (TGF-β). This pathway is instrumental in guiding the development of many tissues, particularly bone, skin, and the brain.
The mutations in the SKI gene are almost always de novo, meaning they are new mutations that occur in the individual and are not inherited. These genetic changes alter the SKI protein, preventing it from effectively applying its braking function. As a result, the TGF-β signaling pathway becomes overactive.
This uncontrolled signaling disrupts normal developmental processes. The excess signaling is the underlying reason for the widespread developmental disruptions seen in the syndrome, leading to the characteristic features affecting the skull, skeleton, and other body systems.
Physical and Developmental Characteristics
The physical traits of Shprintzen-Goldberg syndrome are diverse and affect multiple areas of the body, creating a distinct clinical picture. The combination of these features provides the first clues that lead to a comprehensive evaluation.
Craniofacial Features
Many of the most recognizable characteristics involve the head and face. A common feature is craniosynostosis, the premature fusing of the skull’s bony plates, which can result in a long, narrow head shape. Other facial differences often include widely spaced and sometimes protruding eyes, a high forehead, and a small lower jaw. The roof of the mouth may be high and narrow, and the ears may be low-set.
Skeletal Abnormalities
The skeletal system is broadly affected, often resulting in a tall, slender build with unusually long limbs, fingers, and toes. Joint hypermobility, or an unusually large range of movement in the joints, is common. Spinal issues such as scoliosis, an abnormal side-to-side curvature, can also develop. Some individuals may have a chest that appears sunken or protrudes, and flat feet are frequently observed.
Cardiovascular Issues
A primary cardiovascular concern is the potential for aortic root dilation, where the base of the aorta becomes enlarged. This enlargement can increase the risk of serious complications. Other heart-related findings may include mitral valve prolapse, where the valve between the heart’s left chambers does not close properly.
Neurological and Developmental Aspects
Neurological and developmental differences can also be part of the syndrome. Some individuals may experience developmental delays, and intellectual disability can occur, though its severity varies widely. Structurally, some may have brain anomalies such as hydrocephalus, an accumulation of fluid in the brain, or a Chiari malformation, where brain tissue extends into the spinal canal. Low muscle tone, or hypotonia, is another common finding.
Diagnosis and Evaluation
Diagnosis begins with a clinical evaluation to identify the disorder’s characteristic features. A definitive diagnosis is confirmed through molecular genetic testing that identifies a pathogenic variant, or mutation, in the SKI gene. The presence of this mutation, combined with the clinical findings, solidifies the diagnosis.
An important part of the evaluation is distinguishing Shprintzen-Goldberg syndrome from other connective tissue disorders with similar features. Conditions like Marfan syndrome and Loeys-Dietz syndrome also involve skeletal and cardiovascular abnormalities. However, the presence of craniosynostosis and the higher likelihood of intellectual disability in Shprintzen-Goldberg syndrome are key differentiators. Additionally, dislocation of the lens in the eye, a finding in Marfan syndrome, is not a feature of this condition.
Syndrome Management and Monitoring
Managing Shprintzen-Goldberg syndrome requires a coordinated, lifelong effort from a multidisciplinary team of specialists. This team often includes a geneticist, cardiologist, orthopedic surgeon, neurosurgeon, and developmental pediatricians. Physical, occupational, and speech therapists are also involved.
Cardiovascular monitoring is a central component of care. Regular echocardiograms are used to track the size of the aortic root to manage aneurysm risk. Medications may be prescribed to reduce stress on the aorta and slow the rate of dilation.
Skeletal and neurological issues are addressed based on individual needs. Surgery may be performed for craniosynostosis to correct the premature fusion of the skull bones, allowing for normal brain growth. If hydrocephalus is present, a neurosurgeon may place a shunt to drain excess fluid. Scoliosis may be managed with bracing or surgical correction.
Physical and occupational therapy help with joint hypermobility, low muscle tone, and motor skills. Early intervention programs that include these therapies, along with speech therapy, are important for addressing developmental delays and supporting cognitive development.
Prognosis and Life Expectancy
The long-term outlook for individuals with Shprintzen-Goldberg syndrome is highly variable and depends on the severity of specific medical issues. The degree to which the cardiovascular and neurological systems are affected plays a large part in determining the prognosis. With comprehensive and proactive medical care, many individuals live into adulthood.
The most significant factor influencing life expectancy is the management of cardiovascular complications like aortic root dilation. Consistent monitoring and timely intervention to prevent aortic dissection, a tear in the artery’s wall, have greatly improved the long-term outlook.
While there can be significant medical challenges, ongoing care from a dedicated team helps manage symptoms and prevent serious complications. This allows for the best possible quality of life. The prognosis is individualized, reflecting the unique presentation of the syndrome in each person.