Loeys-Dietz syndrome in pregnancy

Introduction

Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disease that has been initially described in 2005 [1]. The first reported genetic causes of LDS were defined by mutations in the genes encoding transforming growth factor β receptor I (TGFBR1) and transforming growth factor β receptor II (TGFBR2) [2]. These mutations can potentially lead to aneurysmal and vascular complications [2].

A paucity of literature exists regarding pregnancy management recommendations in women with LDS. In addition, concerns regarding a potential higher risk of vascular complications and uterine rupture present an obstetrical challenge regarding optimal management. Most available resources recommend early elective cesarean section to avoid potential intrapartum and postpartum vascular complications [3, 4]. In this case study, we present a pregnancy complicated by maternal LDS that successfully resulted in an uncomplicated vaginal delivery at 36 weeks of gestation.

Case

A 22-year-old female at 9 weeks of gestation was referred to the maternal-fetal medicine department at our institution for a history of factor V Leiden. Her obstetrical history was notable for one pregnancy that ultimately resulted in a 13-week spontaneous pregnancy loss. Her medical history was complicated by depression and recurrent urinary tract infections. She had no personal history of venous thromboembolism. The karyotype on the conception products was normal, and there were no gross malformations on pathology examination. However, there was evidence of placental abruption that prompted a thrombophilia evaluation by her primary obstetrician. Her antiphospholipid antibody syndrome evaluation was negative, but she was diagnosed as heterozygous for the factor V Leiden mutation. Despite recommendations from hematology that no anticoagulation was indicated in the current pregnancy, the patient began taking low-dose aspirin at a daily basis to reduce her risk of miscarriage.

During her initial consultation with maternal-fetal medicine, the patient stated that her brother died at age 17 years due to suspected viral myocarditis. She also reported having a cousin (paternal uncle’s son) with severe autism and a sister with developmental delay and learning disabilities. The patient was referred to reproductive genetics for further evaluation of her familial risk of autism spectrum disorders. Genetic counseling and pedigree analysis revealed that her affected sister was found to have left cerebellum hypoplasia during infancy. Her autistic cousin was diagnosed with LDS. The patient’s uncle was then subsequently diagnosed with LDS. No other family members are known to have the condition, including the patient’s father. However, her paternal grandmother had a history of abdominal aneurysm and protein S deficiency.

The patient was referred to medical genetics for further evaluation and testing recommendations. A thorough history and physical exam confirmed no patient evidence of cardiovascular disease, developmental delay, or Marfanoid habitus. She did display some degree of joint hyperextensibility, although her skin was normal. The patient’s testing for fragile X mutation was normal. She did test positive for the same TGFBR2 mutation found in other family members, confirming her diagnosis of LDS. The patient underwent a maternal echocardiogram that showed normal cardiac structure and function, as well as full body magnetic resonance angiograms (MRAs) that were negative for aneurysms.

The patient’s anatomic ultrasound at 19 weeks of gestation showed a unilateral choroid plexus cyst but no anatomic defects. Her second trimester serum screening was normal. She declined an amniocentesis for fetal karyotype and Loeys-Dietz mutation testing. The choroid plexus cyst was not visualized in subsequent ultrasound examinations. The estimated fetal weight was consistently >90% for gestational age, and the amniotic fluid volume was normal.

At 25+5 weeks of gestation, the patient was admitted for right flank pain, nephrolithiasis, and urinary tract infection with suspicion for pyelonephritis. A renal ultrasound showed moderate right-sided hydronephrosis and a 5 mm non-obstructing renal calculus in the upper pole of the left kidney. No calculi or focal lesions were seen in the right kidney. She received intravenous fluids and ceftriaxone, and passed a small calculus on hospital day 2. At that time, she was discharged home on nitrofurantoin prophylaxis given her history of recurrent UTIs.

The patient had multiple admissions for preterm labor, the first at 32+2 weeks of gestation. She received tocolysis and betamethasone for fetal lung maturity and was discharged home on hospital admission day 8 with her cervix stable at 3 cm dilation. At 35+6 weeks of gestation returned with spontaneous rupture of membranes. Oxytocin was necessary for labor augmentation, and she had an uncomplicated spontaneous vaginal delivery of a live-born female infant weighing 3104 g. APGARs were 8 and 9. Her postpartum course was uncomplicated, and she was discharged in stable condition on postpartum day 3. The patient had an etonogestrel implant placed for postpartum birth control and reported no maternal or neonatal complications at her six week postpartum visit.

Discussion

Significant progress has been made in the recognition of several genes underlying the development of premature arterial disease. TGFBRI/TGFBRII testing has been indicated as one of the initial tests to perform in individuals with a positive familial history of arterial dissection or aortic disease [5]. Testing for mutations in fibrillin-1 (FBN-1) should also be considered in those with a family history of ocular or cardiovascular abnormalities to distinguish LDS from Marfan syndrome and other genetic connective tissue disorders [6]. Unlike patients with Marfan syndrome, those with LDS do not have an alteration with the FBN-1 gene [6].

LDS is typically characterized by four main clinical findings: vascular dilation and tortuosity, craniofacial dysmorphology, skeletal features, and cutaneous symptoms. In initial reports, LDS patients were subdivided into two categories depending on the severity of physical findings. Those with craniofacial involvement were classified as type 1 LDS, and those with cutaneous features were designated type 2 LDS [5]. Mutations in the transforming growth factor β receptors (TGFBRI or TGFBRII) were found to be the primary genetic causes of LDS in these individuals [5]. However it is now recognized that LDS is a continuum with a wide variety of clinical presentations. Subsequent gene mutations in decapentaplegic homolog 3 (SMAD3) and the transforming growth factor-β ligand gene (TGFB2) have shown similar cardiovascular and craniofacial features of LDS [5, 7, 8]. Given that vascular disease is a major concern with affected individuals, LDS is currently classified into four proposed types based on the specific gene mutation involved: TGFBR1 (LDS type 1), TGFBR2 (LDS type 2), SMAD3 (LDS type 3), and TGFB2 (LDS type 4) [5, 7, 8].

Previous published case reports suggest that pregnancies are subject to significant risk. In 21 pregnancies among 12 women with TGFBR mutations, six women (five with type 2 LDS and one with type 1 LDS) had a major complication during pregnancy, including uterine rupture in both patients with type 2 LDS [1]. In an additional cohort of nine women with LDS 1 and 22 women with LDS 2, only one woman experienced a significant vascular complication associated with pregnancy. No pregnancy or postpartum complications have been noted in the remainder of these women [9]. In a TGFBR2 cohort of 17 women, in whom 39 pregnancies occurred, no vascular complications were reported [10] .

Early delivery by means of elective cesarean section has been recommended by some in an effort to reduce the risk of obstetric complications [5]. In a case report of a primigravida with a familial history of LDS and evidence of a missense mutation found in TGFB2, an elective cesarean section was performed at 34+5 weeks of gestation to avoid potential severe trauma to the birth canal and potential vascular and uterine rupture [4]. However, there are no studies comparing outcomes between cesarean and vaginal delivery. Together, the lack of characteristics that define women with LDS, who are at increased risk of obstetric complications and absence of evidence-based management guidelines, makes pregnancy counseling and planning difficult.

The management of the reproductive-age woman with LDS should include full vascular imaging prior to pursuing pregnancy and preconception genetic counseling regarding the autosomal-dominant inheritance, suspected variable expressivity and/or penetrance, and genetic testing options [5]. Upon confirmation of pregnancy, maternal echocardiography in each trimester and in the postpartum period is recommended [5]. Ultrasound and fetal echocardiogram may be helpful in detecting prenatal features of LDS [11]. As more women are identified with this syndrome, the range of presentation and management recommendations will continue to develop. While our experience has been limited to one case, in a patient with a mild phenotype and in the absence of any vascular manifestations or characteristics of Ehlers-Danlos, vaginal delivery at term may be considered a reasonable approach in this group of women.