Introduction
Pretzel syndrome, also known as polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), is a rare congenital disorder found in the Old Order Mennonite population with less than 50 cases reported in medical literature. It is caused by homozygous deletions of exons 9 to 13 on the LYK5/STRADA gene which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Clinical manifestations of affected individuals include facial dysmorphisms, infantile intractable seizures, severe hypotonia, neurocognitive delay, and cerebral white matter hypoplasia. While a handful of postnatal individuals with this condition have been described in the literature, the prenatal phenotype of Pretzel syndrome has yet to be fully elucidated. We present a case report of Pretzel syndrome diagnosed prenatally using ultrasonographic markers and genetic testing in a multiparous patient.

Case Presentation
A 29-year-old Mennonite woman (Gravida 4, Para 2) at 24 weeks 1 day was referred to Maternal-Fetal Medicine for a routine anatomical survey and genetic counseling. This pregnancy was complicated by a prior child born with Pretzel syndrome in 2015. Prenatal ultrasound revealed an appropriately grown fetus with normal amniotic fluid, bilateral clubbed feet, an absent right fetal kidney, and narrowing of the right ventricular outflow tract.

Diagnostic Workup
The patient underwent an amniocentesis with chromosomal microarray that was significant for small regions of homozygosity across multiple chromosomes. Additionally, targeted testing for known pathogenic variants in the parents for the STRADA gene was done and showed homozygous deletions (c.471-1974_1047+2194del) causing STRADA deficiency in the fetus. Incidentally, through targeted testing for known pathogenic variants in the parents, the fetus was also found to be a carrier of a variant in PYGL which causes glycogen storage disease type 6.

 

Treatment and Management
As the pregnancy progressed, polyhydramnios developed. Serial antenatal surveillance was performed, and the patient was counseled on the implications of the prenatal genetic diagnosis of Pretzel syndrome.  

 

Outcome and Follow-Up
The pregnancy was delivered at 38 weeks 3 days by normal spontaneous vaginal delivery. The female infant weighed 8 pounds and 3 ounces with APGARS of 9 and 9 at 1 and 5 minutes of life, respectively. Neonatal physical exam demonstrated an overall well-appearing infant with normal head circumference. However, she had bilateral clubbed feet, anteriorly displaced anus, small, low set ears, high arched palate, imperforate hymen, and hypotonia. The neonate was discharged home with the mother from the hospital on day 2 of life.

 

Discussion
Herein, we report a prenatally diagnosed case of Pretzel Syndrome, which is a rare autosomal recessive genetic disorder. Our case further defines the prenatal phenotype of Pretzel syndrome, which can present with late onset polyhydramnios, genitourinary anomalies, cardiac abnormalities, and clubbed feet. While complete facial dysmorphisms could not be fully elucidated prenatally, this case contributes to the constellation of ultrasonographic findings associated with Pretzel syndrome. As advancements in 3D ultrasonography are made, these ultrasonographic markers can lead to earlier detection and diagnosis of Pretzel syndrome, potentially impacting clinical practice through more accurate genetic counseling, targeted testing, and informed decision-making. Early identification can also help with coordinating multidisciplinary neonatal management, ultimately improving patient care and outcomes.

 

Conclusion
Pretzel syndrome is a multisystem recessive disorder that can present with various sonographic abnormalities including polyhydramnios and multiple congenital anomalies. Future research should be aimed at establishing prenatal genotype-phenotype correlations to better inform prognosis and counseling.