Hydrops Fetalis, Nonimmune
A number sign (#) is used with this entry because nonimmune hydrops fetalis (NIHF) is a feature of many genetic disorders.
DescriptionHydrops fetalis is a descriptive term for generalized edema of the fetus, with fluid accumulation in extravascular components and body cavities. It is not a diagnosis in itself, but a symptom and end-stage result of a wide variety of disorders. In the case of immune hydrops fetalis, a frequent cause is maternofetal incompatibility as in that related to a number of genetic anemias and metabolic disorders expressed in the fetus; in other instances, it remains idiopathic and likely multifactorial (summary by Bellini et al., 2009).
Nonimmune hydrops fetalis accounts for 76 to 87% of all described cases of hydrops fetalis (Bellini et al., 2009).
Genetic Heterogeneity of Hydrops Fetalis
In southeast Asia, alpha-thalassemia is the most common cause of hydrops fetalis, accounting for 60 to 90% of cases. Almost all of these cases result from homozygous deletion of the HBA1 (141800) and HBA2 (141850) genes. A few cases have been reported that had 1 apparently normal alpha-globin gene, termed the hemoglobin H (613978) hydrops fetalis syndrome (summary by Chui and Waye, 1998).
Other genetic disorders predisposing to NIHF include other congenital anemias, such as erythropoietic porphyria (e.g., 606938.0013), and many metabolic disorders, such as one form of Gaucher disease (e.g., 606463.0009), infantile sialic acid storage disease (269920), mucopolysaccharidosis type VII (253220), glycogen storage disease IV (232500), and congenital disorder of glycosylation type Ia (212065).
Clinical FeaturesIdiopathic hydrops fetalis may represent about half of all cases of hydrops fetalis of nonimmunologic origin (i.e., not due to RH blood group incompatibility (111700) or other fetal-maternal incompatibility). Schwartz et al. (1981) listed causes of nonimmunologic hydrops fetalis and reported 4 cases of the idiopathic form, including affected sisters, both stillborn. In a review of 47 series of unselected hydrops fetalis, totaling 804 cases, Machin (1989) found 179 in which the cause was not determined. A cardiovascular cause was found in 206. Tachyarrhythmia or bradyarrhythmia was responsible in 80 cases.
Njolstad et al. (1998) reported 3 sibs with nonimmune hydrops fetalis, diagnosed prenatally. Two also had congenital pulmonary lymphangiectasia (265300). The first affected baby died at 9 hours despite peritoneal and pleural drainage, transfusion, and intensive ventilatory support. The lungs were atelectatic with hyaline membranes without lymphangiectasia. The second child was found to be hydropic at 23 weeks of gestation. Chordocentesis, amniocentesis, and thoracal drainage were performed. In addition, the fetus was given 2 blood transfusions (there was, however, no anemia), albumin, and furosemide as a diuretic. Labor was induced at 34 weeks. There was no need for assisted ventilation. The baby had generalized subcutaneous edema and bilateral edema of the cornea. Pleural effusions and lymphedema of the legs persisted after disappearance of the generalized edema. Chest x-ray showed changes consistent with pulmonary lymphangiectasia. From early infancy, the patient suffered from frequent intercurrent upper airway infections with simultaneously increasing subcutaneous edema of the arms and face. She also had bilateral congenital glaucoma that was controlled by surgery and medical treatment. Her neurologic development was normal. The third pregnancy was again complicated by hydrops fetalis. Despite treatment similar to that used in the second pregnancy, intrauterine death occurred at 30 weeks. Pathologic changes diagnostic of pulmonary lymphangiectasia were found.
Alpha-Thalassemia-Related Hydrops Fetalis
Hydrops fetalis related to alpha-thalassemia results from severe anemia (and thus hypoxia) and heart failure. Fetuses that have deletion of all 4 alpha-globin genes (homozygous alpha(0)-thalassemia) have 80 to 90% Hb Bart's (gamma-4 tetramers). These fetuses almost always succumb in utero during the second or third trimester of gestation, or die within hours after birth. This is known as Hb Bart's hydrops fetalis syndrome, which is by far the most common cause of hydrops in Southeast Asia (summary by Lorey et al., 2001).
Chan et al. (1997) determined the molecular basis of 2 cases described as 'hemoglobin H hydrops fetalis' because they were not caused by homozygous alpha-thalassemia-1 (deletion of all 4 alpha-hemoglobin genes). Both cases were due to coinheritance of a nondeletion defect in the alpha-2 (HBA2) gene on one chromosome, at codon 30 (delta-GAG, glu; 141850.0072) and codon 59 (G-A, gly-asp; 141850.0073) respectively, and a zeta-alpha thal-1 or alpha-thal-1 genotype on the other. These 2 nondeletion defects resulted in severe anemia of the fetuses. Hb Bart's levels of 31% and 39%, respectively, within the range of classic hemoglobin H disease, were present at birth. Alpha-chain production in the form of HbF and HbA totaling 66% and 48%, respectively, unlike cases of classic Hb Bart's hydrops fetalis due to homozygous alpha-thalassemia-1. The second child received an intrauterine transfusion at 29 weeks' gestation and was delivered at 34 weeks. He survived a turbulent neonatal period and was discharged at 3 months. He required monthly blood transfusions and at the age of 2 years had passed normal developmental milestones.
Lorey et al. (2001) reported a case of HbH hydrops fetalis syndrome caused by a point mutation in HBA2 (S35P; 141850.0074) on one chromosome and the Filipino deletion (--(FIL)), which removes all zeta- and alpha-globin genes in cis, on the other. The proband developed pericardial effusion and fetal distress and was delivered by cesarean section at 34.5 weeks' gestation, when he was observed to have severe anemia and congenital anomalies. Karyotype was 46,XY. Lorey et al. (2001) summarized 9 published cases of hemoglobin H hydrops fetalis, including their patient.
PathogenesisBellini et al. (2009) established 14 different diagnostic categories for nonimmune hydrops fetalis based on a systematic review of 51 published articles encompassing 5,437 individuals. The results of Machin (1989) were included in the review. Etiologic categories included cardiovascular (21.7%), hematologic (10.4%), chromosomal (13.4%), syndromic (4.4%), lymphatic dysplasia (5.7%), inborn errors of metabolism (1.1%), infections (6.7%), thoracic (6.0%), urinary tract malformations (2.3%), extra thoracic tumors (0.7%), twin-to-twin transfusion-placental (5.6%), gastrointestinal (0.5%), miscellaneous (3.7%), and idiopathic (17.8%). Most of the pathophysiologic mechanisms could be linked by high interstitial fluid resulting from low plasma oncotic pressure, high central venous pressure, or reduced lymph flow.
DiagnosisBased on the findings of Bellini et al. (2009), Bellini et al. (2009) provided a diagnostic flow chart for the evaluation of nonimmune hydrops fetalis.
Moreno et al. (2013) evaluated the cause of nonimmune hydrops fetalis in 53 cases. The main diagnostic groups were chromosomal anomalies (28.3%), syndromic (18.9%), isolated cardiovascular anomaly (7.5%) and congenital infection (7.5%). Metabolic causes were found in 5.7%, all of which were lysosomal storage disorders (LSD). In 7 cases (13.2%), no diagnosis was found in part because of incomplete evaluation. The hydrops was identified prenatally in 90.5% of cases. In 5.7%, a spontaneous and complete resolution of the hydrops occurred during pregnancy; however, overall mortality was 75.5%. The frequency of inborn errors of metabolism was higher than that usually reported, suggesting that it would be beneficial to study these if more common causes are excluded.
Population GeneticsThe estimated number of worldwide annual births of patients with Hb Bart's hydrops is 5,183 (Modell and Darlison, 2008 and Weatherall, 2010).