A 2470-g, male infant was born at 30 weeks' gestation to a 37-year-old woman gravida 6, para 4 (3 term infants, 1 premature infant, 1 abortion, and 3 living children) by spontaneous vaginal delivery. There was a history of hydrops fetalis in the previous preterm pregnancy, resulting in death of the infant at 1 month of age. On physical examination, the infant was hydropic with extensive generalized edema and massive ascites. Echocardiography revealed dilated ventricles, a large patent ductus arteriosus with a left-to-right shunt, and a mild decrease in left ventricular function. Despite aggressive supportive care, the patient's condition deteriorated and he died at 5 days of age.

The autopsy revealed a hydropic male infant (Figure 1) with generalized edema, massive ascites, and an enlarged liver that weighed 115.3 g (normal weight, 55.4 g). There was dilation of the heart. No other gross structural malformations were detected. The placenta was enlarged and weighed 600 g. Fibroblast skin cultures were obtained and tissue samples were frozen.

A microscopic section of the liver (Figure 2) showed extensive vacuolization of hepatocytes and Kupffer cells. Electron microscopic studies revealed numerous membrane-bound, washed out, mostly empty vacuoles in the cytoplasm of the hepatocytes, with occasional vacuoles containing fine fibrillar and granular material. Microscopic section of the kidney (Figure 3) showed vacuolization of the tubular epithelial cells. Electron microscopic studies revealed renal glomerular epithelial cells, mesangial cells, and endothelial cells, with numerous membrane-bound, washed out, and mostly empty vacuoles. In addition, vacuolization of cells was seen in many organs, including cardiac myocytes, choroid plexus epithelium, and islets cells of pancreas. Microscopic section of the placental villi (Figure 4) showed vacuoles in amnion cytotrophoblast cells and Hofbauer cells. Identical changes were seen in the placenta of the previous hydropic sibling but not in the products of conception in the aborted pregnancy.

What is your diagnosis?

Several lysosomal storage diseases, such as Gaucher disease, mucopolysaccharidoses, GM gangliosidosis, Salla disease, and sialidosis may present at birth with nonimmunologic hydrops fetalis.1 The hydrops fetalis, ascites, hepatomegaly, and a history of previous pregnancy with hydrops suggested the possibility of a metabolic disorder; therefore, tissue samples were frozen and fibroblast cultures were obtained. The diagnosis was confirmed at a molecular level and supported by characteristic histopathologic changes and electron microscopy. These findings consisted of the presence of vacuolated cells in many organs by light microscopy, including cytotrophoblast and villi of placenta, tubules of kidney, cardiac myocytes, Kupffer cells and hepatocytes of the liver, and choroid plexus epithelium. Electron microscopy showed membrane-bound vacuoles that contained reticulogranular and flocculent material, dense bodies, lamellar inclusions, and lipofuscin. Analysis of the fibroblast cultures obtained at autopsy revealed a sialidase level of 2.1 nmol/mg of protein per hour (reference range, 14.00–38.40 nmol/mg), which confirmed the diagnosis of mucolipidoses I (ML I).

Sialidase (neuraminidase) is a lysosomal enzyme that removes tertiary sialic acid residues from sialogly conjugates. Sialidosis III or ML I is a rare inherited autosomal recessive disorder that results from deficiency of sialidase. There are 4 types of ML I based on the age of onset: congenital (in utero), infantile (0–12 months), juvenile (2–20 years), and adult.2 The congenital type may present with hydrops fetalis. Other characteristic findings are coarse facies with large and long head with frontal bossing; a broad, flat, and flared nose; and a depressed bridge similar to the appearance of patients with Hurler syndrome. In addition, there may be moderate mental retardation, dysostosis multiplex, hepatosplenomegaly, and vacuolated lymphocytes on blood smears. The infant discussed in this case had placental changes with hydrops, suggestive of the congenital type.

Besides using the gross autopsy and histopathologic findings to arrive at a diagnosis, tissue samples taken at autopsy may be collected for more specific diagnostic testing with the aid of other modalities, including electron microscopy, cytogenetics, molecular genetics, flow cytometry, and specific mutational analysis when appropriate.3 By cytogenetics, the deficiency of neuraminidase enzyme is coded by a locus on chromosome 22. The enzyme normally cleaves terminal 2 → 3 and 2 → 6 sialyl linkages of several oligosaccharides and glycoproteins. The combined deficiency of neuraminidase and β-galactosidase results from the primary loss of a protein required to protect the galactosidase and neuraminidase complex from proteolytic degradation.2 At a molecular level, the definitive diagnostic can be obtained by measurement of neuraminidase and β-galactosidase activity in skin fibroblasts, cultured amniotic fluid cells, or white blood cells. Fibroblast culture was the method used to make the diagnosis in this case.

If ML I is clinically suspected based on the prior history of a sibling with ML I or on the features of a patient, a screening test of thin-layer chromatography can be performed on urine to assess for any abnormal patterns and amounts of glycoprotein-derived compounds, such as oligosaccharides and sialylglycopeptides, which are seen in all forms of ML I. Additionally, the imaging studies can be used to reveal dysostosis multiplex characterized by anterior beaking of the vertebral bodies, widening of ribs, hypoplastic ilia, and expanded metacarpal and phalangeal shafts.

The pathologist can play a pivotal role in making the diagnosis by following the guidelines in obtaining material at autopsy in a case of suspected metabolic disease.3 Making such a diagnosis may have important implications for investigating other family members and for planning for future pregnancies, estimating recurrence risks, and facilitating prenatal diagnosis.

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Reprints not available from the authors.

Author notes

Corresponding author: Cyril D'Cruz, MD, Department of Pathology and Laboratory Medicine, Newark Beth Israel Medical Center, 201 Lyons Ave, Newark, NJ 07112