Shprintzen-Goldberg Syndrome

Shprintzen-Goldberg syndrome is a rare autosomal dominant disorder caused by variants in SKI, with craniosynostosis, marfanoid habitus, intellectual disability and aortic root dilatation. It overlaps with Marfan and Loeys-Dietz syndromes but differs by the neurodevelopmental findings.

Pathophysiology. Missense variants in the SKI proto oncogene, which regulates TGF-beta signalling, alter this signalling in connective tissue and brain. Most cases arise de novo.

Aortic dilatation is usually less severe than in Loeys-Dietz syndrome, but dissection has been reported.

Skeletal and neurological features dominate early management.

• Craniosynostosis (often sagittal or coronal)
• Dolichocephaly, proptosis, downslanting palpebral fissures, high palate
• Marfanoid habitus: long limbs, arachnodactyly, pectus deformity, scoliosis
• Joint hypermobility with camptodactyly
• Hypotonia and delayed motor development
• Intellectual disability of mild to severe degree
• Chiari malformation and hydrocephalus
• Mitral valve prolapse and aortic root dilatation

• Genetic testing of SKI (most variants occur in a hot spot in exon 1), as a single gene or within a connective tissue panel.
• Clinical evaluation: craniofacial examination, skeletal assessment for arm span to height ratio and thumb and wrist signs.
• Cardiac imaging: echocardiography for aortic root and mitral valve.
• Neuroimaging: brain MRI for Chiari malformation, hydrocephalus and structural anomalies.
• Eye examination: lens position and myopia.
• Neurodevelopmental assessment and spine radiographs.

Differential diagnosis.

• Marfan syndrome
• Loeys-Dietz syndrome
• Beals syndrome (congenital contractural arachnodactyly)
• Homocystinuria
• Antley-Bixler and other craniosynostosis syndromes
• Sotos syndrome

• Craniosynostosis: neurosurgical or craniofacial surgery, with monitoring for raised intracranial pressure.
• Hydrocephalus or symptomatic Chiari malformation: shunt or decompression.
• Aortic surveillance and drug treatment: losartan 25 mg orally daily, titrated to 50 to 100 mg daily (children 0.4 to 1.4 mg/kg daily, maximum 100 mg), or a beta blocker such as atenolol 25 to 100 mg daily (children 0.5 to 1 mg/kg daily), based on aortic growth.
• Aortic surgery: valve sparing root replacement is considered at 4.5 cm in adults, or earlier with fast growth or family history of dissection. In children use z-scores and growth rate.
• Spine and chest wall: bracing and fusion for progressive scoliosis, and treatment of pectus deformity when symptomatic.
• Development: early intervention, speech and occupational therapy, and educational support.
• Airway and sleep: sleep study for obstructive apnoea, and anaesthetic caution for cervical spine and airway.
• Eye care: correction of myopia, and management of lens subluxation.

Special groups.

• Women planning pregnancy: stop losartan before conception, continue a beta blocker, and plan delivery in a cardiac centre.

Monitoring. Echocardiography every 6 to 12 months. Neurodevelopmental review yearly. Brain and spine imaging as symptoms dictate.

Referral and escalation. Refer to clinical genetics, cardiology, craniofacial surgery and neurology. Emergency for headache with vomiting or drowsiness, and for chest or back pain that suggests dissection.