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Nonimmune fetal hydrops and lysosomal storage disease: the finding of vacuolated lymphocytes in ascitic fluid in two cases

Nonimmune fetal hydrops (NIFH) describes the abnormal accumulation of fluid in at least two fetal compartments, including soft tissue edema, or fluid accumulation in body cavities such as ascites, pleural effusion, or pericardial effusion. Polyhydramnios and placentomegaly frequently accompany fetal hydrops. NIFH is a heterogeneous condition and establishing a diagnosis can be challenging. Bellini et al. reviewed and classified causes of NIFH in order of prevalence: cardiovascular disorders (21.7%), chromosome imbalances (13.4%), hematologic abnormalities (10.4%), infections (6.7%), intrathoracic masses (6.0%), lymph vessel dysplasias (5.7%), twin-to-twin transfusions and placental causes (5.6%), syndromic (4.4%), urinary tract malformations (2.3%), inborn errors of metabolism (1.1%), extra-thoracic tumors (0.7%), gastrointestinal disorders (0.5%), miscellaneous causes (3.7%), and idiopathic (17.8%). After excluding immune causes of fetal hydrops, the search for an underlying cause of NIFH may be extensive and include ultrasound, fetal echocardiogram, evaluation for infectious etiologies, and invasive testing for fetal karyotype. What constitutes appropriate work-up beyond this initial investigation is controversial, but could include screening for metabolic conditions, such as lysosomal storage disease (LSD) via enzyme analysis in cultured cells from amniocytes or fibroblasts, microarray analysis to detect microdeletions or duplications, or single gene testing (e.g. Noonan syndrome). Sequential protocols for investigation of NIFH have been proposed to optimize diagnosis and avoid cost prohibitive investigations. Despite these efforts, such protocols are not universally practiced. It remains essential to establish diagnostic algorithms for NIFH, which optimize resources and to define appropriate indications for metabolic disease testing. Key to these efforts is identifying factors that may facilitate a specific prenatal diagnosis in these complicated cases resulting in improved detection rates and allowing providers to better care for and counsel their patients. We present two cases of NIFH caused by underlying lysosomal storage disease: galactosialidosis (case 1) andmucopolysaccharidosis type VII (case 2). The in utero presentation and the unique finding of vacuolated lymphocytes in fetal peritoneal fluid lead to the diagnosis. Patient 1, a 27 year old G1P0 female, presented to our institution at 25 2/7weeks gestation due to known NIFH. Family history was noncontributory/without consanguinity. Fetal ascites was first suspected at 18weeks gestation during routine fetal survey. Follow-up ultrasound at 19 5/7weeks revealed fetal ascites and ventricular septal defect. Concurrent amniocentesis revealed normal male karyotype (46,XY), normal amniotic fluid alpha-fetoprotein at 1.3MoM, normal single nucleotide polymorphism microarray analysis, and negative PCR for parvovirus B19, cytomegalovirus, varicella zoster virus, herpes simplex virus, and Toxoplasma gondii. Ultrasound at 25weeks gestation revealed a hydropic fetus with appropriate biometry, massive ascites, scalp edema, mild ventriculomegaly, cardiomegaly with a ventricular septal defect, dilated loops of bowel with dilated rectum, placentomegaly, and normal Doppler velocimetry in umbilical and middle cerebral arteries. At 30 1/7weeks of gestation, peak systolic velocities of the middle cerebral artery were elevated at 1.55MoM. Given this and further progression of fetal hydrops of unknown etiology, the patient underwent ultrasound guided cordocentesis with fetal blood transfusion for mild anemia (hematocrit 30%). A fetal paracentesis was performed to remove 500 cc of ascites because of concern that the upward compression of the diaphragm by the ascites contributed to the worsening hydrops. Review of fetal ascitic fluid revealed predominantly histiocytes (93%) and rare vacuolated lymphocytes. Despite initial improvement in hydrops, reaccumulation occurred. Repeat fetal paracentesis removing 300 cc was undertaken to decompress the abdomen and facilitate vaginal delivery prior to induction at 36weeks of gestation (head circumference to abdominal circumference ratio was 0.73). A 2240 g male infant was delivered with Apgar scores of 2 and 5 at 1 and 5min. Physical exam revealed poor