Journal of Perinatology (2007) 27, 252–254 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 www.nature.com/jp
PERINATAL/NEONATAL CASE PRESENTATION
Nonimmune hydrops fetalis in two cases of consanguineous parents and associated with hereditary spherocytosis and hemophagocytic hystiocytosis S Yetgin, S Aytac, F Gurakan and M Yurdakok HUTF Pediatric Hematology Department, Hacettepe University, Ankara, Turkey
Nonimmune hydrops fetalis may occur as a result of different etiological conditions and in about one-third of cases no cause could be identified. Here, we report two cases of nonimmune hydrops fetalis associated with hereditary spherocytosis and hemophagocytic hystiocytosis. We think that babies with hydrops fetalis born of consanguineous parents should be examined for hereditary diseases, and that these rare causes should be taken into account in problematic cases. Journal of Perinatology (2007) 27, 252–254. doi:10.1038/sj.jp.7211657
Keywords: nonimmune hydrops fetalis; hereditary spherocytosis; hemophagocytic hystiocytosis
Introduction Nonimmune hydrops fetalis may occur as a result of different, rare and obscure etiological conditions.1,2 There are very rare reports of hydrops fetalis owing to hereditary spherocytosis (HS) and hemophagocytic lymphohistiocytosis (HLH).3–6 HS is principally an autosomal dominantly (AD) inherited disease, with a small percent showing autosomal recessive (AR) inheritance. The genes responsible for HS include ankyrin, spectrin, band 3 protein and protein 4.2 genes.7 HLH is caused by a benign abnormal proliferation of histiocytes, which leads to multiorgan failure.8 Patients present with pancytopenia, splenomegaly, coagulopathy and encephalopathy. Hemophagocytosis in the bone marrow (BM) or spleen is a hallmark for the diagnosis. Familial hemophagocytic lymphohistiocytosis (FHL) is recessively inherited. A secondary form can affect all ages.9 Both types are fatal when untreated.10 We would like to report and stress that babies of consanguineous parents with hydrops fetalis must be examined for hereditary diseases. Correspondence: Dr S Yetgin, HU¨TF Pediatric Hematology Department, Hacettepe University, Sihhiye, Ankara 6100, Turkey. E-mail:
[email protected] Received 31 May 2006; revised 27 September 2006; accepted 28 November 2006
Case 1 A 3-day-old baby was the third child of a healthy mother and first-degree cousin parents. The first child also had hydrops fetalis and the second child was a healthy 7-year-old boy. At the 28th week of pregnancy, ultrasonography (US) had revealed polyhydramnios. Cordocentesis blood counts revealed anemia and thrombocytopenia (hemoglobin (Hb), 2.5 g/dl; platelet (Plt) count, 10.3 109/l). The patient needed four intrauterine transfusions until birth at week 37. Remarkable abnormal physical findings at 3 days were as follows: body weight, 2290 g; age-appropriate length and head circumference, heart rate, 130–140/min; and respiratory rate, 50/min. The baby had generalized edema and hepato-splenomegaly of 3 and 4 cm under costal margins, respectively. Laboratory evaluation included complete blood count (CBC) with Hb, 6.9 g/dl; white blood cell (WBC), 8.9 109/l; Plt, 146 109/l; red cell mean corpuscular volume (MCV), 78 fl; and reticulocyte count, 1%. Peripheral blood smear revealed 110% normoblasts at 100 white blood cell count with hemolytic findings of red cell morphology. Coombs’ test was negative. Total serum bilirubin was 18 mg/dl, with 12.8 mg unconjugated bilirubin. Lactic dehydrogenase level was 772 U/l, total protein 4.8 g/dl and albumin 3.1 g/dl. BM aspiration, viral studies, toxoplasma gondii, other microorganisms (e.g., syphilis), rubella virus, cytomegalovirus (CMV) and herpes simplex virus (HSV) (TORCH screen), erythrocyte enzyme levels and some other normal laboratory findings in detailed examination are shown in Table 1. Abdominal ultrasonography detected splenomegaly, and echocardiographic examination was normal. Serum ferritin was 3669 mg/dl. She required four exchange transfusions within 1 week of birth. During 11 months of follow-up period, she required monthly blood transfusions at her local hospital. When she was readmitted to our hospital at 11 months of age with Hb 6.5 g/dl, laboratory examination revealed increased red cell fragility and mean corpuscular hemoglobin concentration (MCHC) of 40 and clearly presented spherocytic cells on peripheral smear. Parents’ red cell morphology revealed slight findings confirming spherocytic hemolytic disease with slight increased MCHC and red cell fragility test.
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Table 1 Clinical and laboratory findings of nonimmune hydrops fetalis cases
Hb (g/dl) Htc (%) WBC ( 109/l) Plt ( 109/l) MCV (fl) RDW Reticulocyte (%) Normoblast (%) Peripheral smear findings
BM aspiration Blood group
Case 1
Case 2
6.9 20 8.9 146 78 (blood transfusion+) 17 1 110 42% PNL 40% lymphocyte 18% monocyte Normal 0 Rh + B Rh+ (mother) 0 Rh+ (father) Negative Negative
10 29.9 5.1-2.7 9 105 19 0.6 2 86% lymphocyte 8% PNL 6% monocyte Hemophagocytosis A Rh+ A Rh+ (mother) A Rh+ (father) Negative Negative
Normal
Normal
18/12.8
19/12
Normal Negative Negative Splenomegaly Normala,c
Normal Negative Negative Hepatosplenomegaly Normalb,c
Subgoup incompatibility Coombs’ test G6PD Pyruvate kinase P50 nucleotidase Total bilirubin (mg/dl)/conjugated bilirubin (mg/dl) Urine and blood amino acid Viral studies (EBV, HIV, Parvovirus BI9) TORCH screen Abdominal US Other a
Sweat chloride test, a1-antitrypsin, lysosomal disease screening tests. Leukocyte b-galactosidase and acid sphingomyelinase levels. c Blood and urine cultures. b
Patient was transfusion-dependent and folic acid was also added to the therapy. Case 2 A male baby was referred to our clinic at 3 h of age because of low Apgar scores and respiratory distress. He was the second child of his family, and was born at 36 weeks of gestation. He had been diagnosed as nonimmune hydrops fetalis. His parents were first-degree relatives and had a healthy 7-year-old boy. Birth weight was 2730 g; the head circumference and length were age-appropriate. His temperature and blood pressure were normal, heart rate 140/min and respiratory rate 40–50/min. He required intubation and mechanical ventilation for respiratory distress. Physical examination revealed disseminated body edema and a liver and spleen enlargement, 3 and 4 cm under costal margins, respectively.
Laboratory examination was remarkable for anemia, thrombocytopenia and hemolytic findings of red cell morphology. Although BM aspirates showed hemophagocytosis with increased histiocytes consistent with HLH, prominent finding was large cells with blue cytoplasm including fatty inclusion, which strongly suggested storage cell disease, leading to misdiagnosis. Biochemical tests: alanine aminotransferase, 632 IU/l; aspartate aminotransferase, 4037 IU/l; alkaline phosphatase, 262 IU/l; total bilirubin, 19 mg/dl; conjugated bilirubin, 12 mg/dl; albumin, 2 g/dl; triglyceride, 130 mg/dl; fibrinogen, 130 mg/dl; prothrombin and active partial thromboplastin time were increased, Coombs’ test was normal. Unremarkable tests of the patient are shown in Table 1. The cerebrospinal fluid protein was high, 182 mg/dl. Chest radiography showed pulmonary edema. The patient progressed to pancytopenia and required multiple red cell, platelet and fresh-frozen plasma transfusions. Granulocyte colony-stimulating factor was given for neutropenia. Massive edema and multiorgan failure developed gradually resulting in death. Since definite diagnosis of HLH was made with post-mortem BM and spleen aspirates, he was not administered chemotherapy. Discussion In this study, we report nonimmune hydrops fetalis in two cases owing to very rare and different diseases. Definition of nonimmune hydrops fetalis can be made on the basis of absent identifiable circulating antibodies for red cell antigens. In both cases, Coombs’ tests were negative. There are many causes of nonimmune hydrops fetalis (infections, cardiac, hypoproteinemia, red cell defects, cytogenetic abnormalities, etc).1,2 In the first case, family history of consanguinity, a sibling with hydrops fetalis, and laboratory findings owing to red cell morphology in addition to Coombs’ test negativity defined the HS diagnosis. Mild laboratory findings of HS of the parents supported the diagnosis. HS is a heterogeneous disease in clinical presentation.7 Asymptomatic disease of the parents may be due to heterozygote and/or autosomal dominantly silent forms of HS.11,12 We speculate that their first child with hydrops fetalis also had homozygote or double heterozygote HS. In this case, intrauterine blood transfusions prevented the fetal death. Severe form of HS resulting in hydrops fetalis has been seen in a-spectrin deficiency and in a few double-dominant cases.3,7 It is correlated with extensive spectrin deficiency. Severe HS with no family history was found in spectrin Prague and Lepra.13 Fatal hydrops fetalis has been reported in a patient homozygous for a mutation of L2025R in a region of spectrin.4 Unfortunately, we do not have the technical resources to study membrane protein defects of HS.11 Nonimmune hydrops fetalis may be associated with all other congenital hemolytic anemias.14–15 The diagnosis of HLH was made according to the guidelines of the Histiocyte Society Criteria8 with pancytopenia, splenomegaly, hypofibrinogenemia, prominent hemophagocytosis and increased Journal of Perinatology
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cerebrospinal liquid proteins. Ferritin level was not obtained. Hepatic enzyme abnormalities, jaundice and coagulopathy may provide supportive evidence of HLH. The primary form, familial hemophagocytic lymphohistiocytosis, seen during infancy and childhood may mimic a number of diseases mentioned above. We did not detect an underlying disease causing secondary HLH. Parental consanguinity was also suggestive for primary HLH. Genetic analysis of perforin, which is seen in 20 to 40% of patients, and Munc13-14 mutation for HLH was not available.16 Lysosomal storage-like cells in this patient may be explained by histiocytic hyperactivity and inflow of lipids to the decreased number of phagocytic cells. These cells may be seen in diseases with phagocytic cell deficiency or function disorders.17 In summary, HS, other congenital hemolytic anemias and HLH must be considered in diagnosis of hydrops fetalis, even if family history is nonpredictive.
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