Pretzel Syndrome is a rare medical condition characterized by physical manifestations affecting skeletal structure, brain development, and organ function. This complex disorder is notable for its specific observable traits, which often lead to its distinctive name.
Understanding Pretzel Syndrome
Pretzel Syndrome is a rare genetic disorder, sometimes referred to as polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE). It is characterized by skeletal deformities, malformations of the brain, and variable issues with the heart and other organs. The name “Pretzel Syndrome” stems from the unusual flexibility and postures affected children can exhibit due to low muscle tone and abnormal connective tissue.
Beyond the musculoskeletal system, approximately 40% of affected children experience strabismus, commonly known as “lazy eye,” due to weak eye muscles. About one-third of individuals with Pretzel Syndrome have anatomical heart defects, with atrial septal defect, a hole between the two upper chambers of the heart, being the most common.
Genetic and Other Factors
Pretzel Syndrome is an autosomal recessive genetic disorder, meaning an individual must inherit two copies of the defective gene, one from each parent, to develop the condition. The underlying cause is a homozygous deletion of exons 9 to 13 within the LYK5/STRADA gene. This gene encodes the pseudokinase STRADA, which plays a role in regulating the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway.
The loss of STRADA’s function leads to an overactivation of mTORC1 and its downstream effector, p70S6K. This dysregulation of the mTORC1 pathway interferes with normal cell growth and function, particularly impacting organ development during the earliest stages of pregnancy. The condition is particularly observed within the Old Order Mennonite population.
Recognizing the Signs and Diagnosis
Recognizing Pretzel Syndrome involves observing a combination of physical signs and developmental delays. Infants with the condition may present with severe hypotonia and characteristic craniofacial features. Infantile-onset, intractable seizures are a common symptom, often resistant to standard treatments.
Diagnosis involves a clinical evaluation, including physical examinations to assess skeletal deformities, joint flexibility, and muscle tone. Imaging scans, such as magnetic resonance imaging (MRI) of the brain, can reveal megalencephaly (enlarged brain) and cerebral white matter hypoplasia. Genetic testing is definitive, confirming the homozygous deletions in the LYK5/STRADA gene. Early identification aids in coordinating multidisciplinary neonatal management and improving patient care.
Treatment and Support Strategies
Management of Pretzel Syndrome involves a multidisciplinary approach to address the various symptoms and complications. Medical interventions focus on controlling seizures, which can be challenging. In some cases, drugs that modify the disease process, such as sirolimus, an mTORC1 inhibitor, have shown promise in minimizing seizures and improving receptive language. This approach stems from research on related disorders where mTOR activation is implicated.
Physical therapy and occupational therapy help manage hypotonia and improve motor skills, mobility, and daily functioning. Assistive devices may be used to support ambulation and positioning as needed. Addressing cardiac abnormalities, such as atrial septal defects, may involve monitoring or surgical intervention depending on their severity. For the 20-30% of children who develop kidney issues leading to diabetes insipidus, management involves addressing frequent urination and electrolyte imbalances.
Long-Term Outlook
The long-term outlook for individuals with Pretzel Syndrome is influenced by the severity of their symptoms and the effectiveness of ongoing management strategies. The condition often leads to severe intellectual disability and neurocognitive delay, impacting communication and independent living skills. Many individuals may remain wheelchair-bound and require complete dependency for daily care throughout their lives.
The progression of the condition can include ongoing challenges such as intractable seizures and complications related to organ malformations. While challenges exist, ongoing research, particularly into targeted therapies like mTORC1 inhibitors, offers hope for improved symptom management and potentially enhanced quality of life. Continued multidisciplinary care and supportive interventions maximize the well-being of affected individuals.