18 Fetal Storage Disorders

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18

Fetal Storage Disorders

Mucolipidosis type II, or I-cell disease, is a rare and fatal disorder whose genetic transmission is autosomal recessive. Gellis and Feingold (1977) delineated the prin- cipal features of affected children. Hanai et al. (1971) emphasized the abundance of periodic acid-Schiff (PAS)- positive lysosomal inclusions in the cells of affected children. In 1974, Granström et al. and Rapola et al. separately reported that affected newborns may have coarse features similar to those of patients with Hurler’s syndrome, and demonstrated inclusions in leukocytes. Aula et al.

(1975) made the first prenatal diagnosis of this disease from an increase of amnionic fluid hydrolases. Later, they used fibroblasts of the aborted fetus to confirm the diagnosis. The investigators emphasized that paraffin sections do not allow the visualization of the inclusions; they are obvious, however, in epoxy-embedded material. The inclusions of this disorder are preferentially located in kidney and mesenchymal cells. Terashima et al. (1975) presented an extensive differential diagnosis of these inclusions in their description of three cases. Placental involvement with inclusion-bearing cells was first demonstrated in a case report of Powell et al. (1976). The syncytium and Hofbauer cells were primarily affected;

the vacuoles of formerly mucolipid-containing lysosomes were readily apparent in parafﬁn sections of the placenta (Figs. 18.1 and 18.2), but the features were much enhanced by processing the tissues in epoxy resin. The authors of this paper emphasized that only fetal cells contained the vacuoles. Affected tissue included the X cells of cell columns and the placental ﬂoor. There were no inclusions in decidual cells, and they used this to further identify X cells as being of fetal origin. The placenta was grossly pale and somewhat enlarged; the fetus was not hydropic.

The same report contained three additional and similar storage diseases that affected the placenta but the precise nature of their storage disorders could not be identiﬁed.

Abe et al. (1976) and Nagashima et al. (1977) described other morphologic studies. Several investigators further elaborated on placental aspects of mucolipidosis type II.

577 Many of the so-called errors in metabolism, the storage

diseases, produce inclusions or vacuoles in the tissues of affected individuals. The placenta is often similarly involved, and chorionic villus sampling (CVS) biopsy is now more often employed to make the diagnosis prena- tally, as for instance in diagnosing lipofuscinosis (Rapola et al., 1990). Electron microscopy and special enzyme studies are usually helpful for the precise diagnosis of the defect involved. Thus, appropriate fixation is needed when such disease is suspected and it must also be anticipated at the time of CVS, as many of the inclusions are highly water and lipid-solvent soluble. Because many of these diseases are the cause of fetal hydrops, the cases of nonimmune hydrops fetalis warrant special attention. An excellent ultrastructural study of 11 cases has been published by Jones et al. (1990) that details procedures and findings, and Fox (1997) has shown other material. These publications depict the findings in admirable detail and provide additional literature. Table 18.1 summarizes the current status of placental studies in various storage disorders.

Gaucher’s disease, as mentioned in Chapter 16, may cause fetal hydrops. It is a heterogeneous disease whose genetics and clinical manifestations were well described by Sidransky and Ginns (1993). In the case described by Ginsburg and Groll (1973), polyhydramnios complicated the second pregnancy of a patient in the second trimester. At 34 weeks, she delivered a macerated, hydropic fetus. The large and edematous placenta had the macroscopic features of erythroblastosis fetalis. The mother’s third pregnancy also resulted in neonatal demise due to Gaucher’s disease. The fetal ﬁndings were characteristic of type II Gaucher’s disease in the hydropic 21-week fetus described by Rice et al. (1984). The placenta was not described. Gillan et al. (1984) and Bouvier and Maire (1997) provided additional insight with numerous diverse cases. Soma et al. (2000) illustrated a characteristic case with recurrent hydrops fetalis in a Japanese pedigree.

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578 18. Fetal Storage Disorders

Thus, Rapola and Aula (1977) beautifully demonstrated the ultrastructural changes of the syncytium and suggested that the diagnosis could easily be made from this material alone (Fig. 18.3). With CVS biopsy, this would now be possible without having to resort to enzymatic study. Gehler et al. (1976) reported biochemical studies of I-cell disease. The differential diagnosis of mucolipidosis types I and III was discussed in a study by Herd et al.

(1978). Hug et al. (1984) have shown that maternal serum hexosaminidase levels are increased in pregnancies

affected by I-cell disease, which allows diagnosis without uterine invasion. We strongly disagree with the inter- pretation of Cozzutto (1983), however, who reported on a macerated stillborn whose placenta also had extensive vacuolar changes. The placenta was structurally typical of I-cell disease. Cozzutto found vacuolated “stromal decidual cells,” but he did not depict these. He interpreted the changes as “convincingly demonstrating” that the foam cells are a transformation secondary to edema or fetal death. In our experience, such vacuolation never results Table 18.1. Summary of placental ﬁndings in various storage diseases

Disease Findings Reference

Glycogen storage type II Vacuoles full of glycogen in EM in stroma, endothelium, cytotrophoblast, Bendon and Hug, 1985

Pompe’s disease lysosomes Jones et al., 1990

Roberts et al., 1991 Mucopolysaccharidosis Vacuolization of ﬁbroblasts and syncytium Jones et al., 1990

Hurler’s disease

Sanﬁlippo’s disease Vacuolated syncytium, absent heparin-N-sulfatase in CVS Jones et al., 1990 Kleijer et al., 1986

Morquio’s disease, type IV Edema of villi Applegarth et al., 1987

b-glucuronidase deﬁciency Hofbauer cell vacuolization, hydrops Nelson et al., 1993 Sialic acid storage Salla’s Vacuolated syncytium and Hofbauer cells with amorphous and ﬁbrillar Gillan et al., 1984

disease material, vacuolated extravillous trophoblast and amnionic epithelium Jauniaux et al., 1987 Jones et al., 1990 Roberts et al., 1991

Gaucher’s disease Hydrops Ginsburg and Groll, 1973

Gillan et al., 1984 Rice et al., 1984

Sidransky and Ginns, 1993 Sphingomyelin storage Vacuolization and laminated inclusions (myelin bodies) in syncytium, Sarrut and Belamich, 1983

Niemann-Pick’s disease stroma, Hofbauer cells, umbilical cord ﬁbrocytes, hydrops Vanier et al., 1989

types A and C; Type B Meizner et al., 1990

may have inclusions Schoenfeld et al., 1985

Gangliosidoses GM 2, Vacuolated trophoblast and Hofbauer cells, amnion Lowden et al., 1973

gangliosidosis type I, Absent hexosaminidase in CVS Grebner et al., 1983

Tay-Sachs’ disease Roberts, 1991

Benirschke and Kaufmann, 1995 Type II Multiple parallel arrays in lysosomes of stroma, vacuolated syncytium, Fox, 1997

Sandhoff’s disease myelin bodies

Fabry’s disease Lamellar lysosomal inclusions in decidual cells, chorionic cells normal, in Popli et al., 1990 Glycosphingolipidosis heterozygous carrier

Mucolipidoses Vacuolated trophoblast and stroma, normal amnion Riches and Smuckler, 1983 Type I

Sialidosis Laver et al., 1983

Stevenson et al., 1983 Gillan et al., 1984 Baldwin et al., 1985 Mahmood and Haleem,

1989

Bouvier and Maire, 1997 Type II Vacuolated syncytium, vacuolated Hofbauer and X cells Powell et al., 1976

I-cell disease Occasional myelin ﬁgures in EM Rapola and Aula, 1977

Sarrut and Belamich, 1983 Type IV Vacuolated stroma with lamellar inclusions of endothelium Sekeles et al., 1978

Galactosialidosis Vacuolated trophoblast and stroma, hydrops Scully, 1997

Neuronal ceroid Vacuoles in syncytium, amnion, endothelium with “ﬁngerprint” Rapola et al., 1988

lipofuscinosis inclusions Conradi et al., 1989

CVS, chorionic villus sampling; EM, electron microscopy.

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Figure 18.1. Villus (left) and X-cell column of placenta, affected by mucolipidosis II (I-cell disease). Note the abundance of vacuoles in the syncytium and Hofbauer cells; similar inclusions are present in the cytoplasm of X cells. H&E ¥240.

Figure 18.2. Syncytium in case of I-cell disease. Note the extensive, ﬁne vacuolation, the storage site of washed-out glycolipids in the syncytial cytoplasm. EM ¥6700. (Cour- tesy of Dr. J. Rapola, Helsinki, Finland.)

from fetal death or edema. The abundance of foam cells, the disposition of trophoblastic vacuoles, and irregular calciﬁcations observed by him (and us as well) all are indicative of an unidentiﬁed fetal storage disorder.

Because the cellular glycolipids are highly water-soluble, the empty appearance of the vacuoles is the usual ﬁnding in many fetal storage disorders. We saw another case with

extensive and typical syncytial vacuolization (courtesy of S. Romansky, Los Angeles). The neonate was well and had no signs of disease when 4 months old. The enlarged placenta had also numerous vascular lesions, mostly in the villous stem arteries, varying from fibrinoid necrosis to complete obliteration, with occasional histologic findings of the nonspecific “hemorrhagic endovasculitis”. In

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580 18. Fetal Storage Disorders

addition, there were numerous foci of villous calcifica- tions. Because of the simultaneous presence of numerous myelin figures in electron micrographs, the diagnosis of I-cell disease was thought unlikely; moreover, neonatal screening tests were negative. Follow-up with skin biop- sies at herniorrhaphy at age 8 months showed vacuolar changes in fibroblasts and coarse facial features became evident. Very high levels of lysosomal enzymes were then found and I-cell disease was diagnosed. The infant became severely retarded.

Hurler’s syndrome (mucopolysaccharidosis I) showed

“striking vacuolation of stromal cells,” including Hofbauer cells (Jones et al., 1990).

Other storage diseases affect fetal and placental tissue.

By amniocentesis at 14 weeks, Lowden et al. (1973) identified, the absence of b-galactosidase. That absence is diag- nostic of type 1 G_M1gangliosidosis. The pregnancy was terminated; typical inclusions (zebra bodies) were ultra- structurally identified in the fetal ganglion cells. Although other fetal cells were unremarkable in paraffin sections, vacuoles were seen in epon-embedded material. The placenta showed numerous “empty vacuoles” in the syncytial cytoplasm, extravillous trophoblast, and Hofbauer cells (Roberts et al., 1991). They were visible even in paraffin sections. Presumably, these contain the water-soluble storage product, and galactose-rich mucopolysaccharide.

Other case descriptions of the disease do not include descriptions of the placenta (Giugliani et al., 1985).

Absence of a-galactosidase A results in Fabry’s disease, a disorder of glycosphingolipid metabolism. The tissues accumulate ceramide trihexose. A pregnancy in a patient with this disease was described by Popli et al. (1990) after she had received a renal allograft. The placenta of the

term fetus was normal but the decidual cells contained argyrophilic granules that electron micrographically had the appearance similar to zebra bodies. The fetal portions of the placenta were normal. O’Brien (1982) reviewed many lysosomal disorders and their enzymatic deﬁcien- cies and provided details of the enzymatic defect.

In the studies by Jones et al. (1990), Tay Sachs’ disease (G_M2-gangliosidosis type I) was found to produce vacuolation of syncytiotrophoblast, with occasional myelin bodies in villous stromal cells. In Sandhoff’s disease (type II), “the most striking feature . . . was the occurrence of parallel membranous arrays in occasional lysosomes within stromal cells.” Myelin bodies were found in trophoblast and endothelium.

Mucolipidosis IV (Morquio syndrome type B) is due to the deﬁciency of b-galactosidase and also referred to as G_M1-gangliosidosis. This disease has been diagnosed from cultured amnionic ﬂuid cells by Kohn et al. (1977).

The amnion cells contained multiple single-membrane bounded inclusions. Mesodermal elements, however, were negative. Although it may appear superﬁcially that this disease is similar to I-cell disease, in this condition the amnion, not syncytium and Hofbauer cell, has the vacuolation. The placenta of a case we saw was much enlarged (950 g) and much paler and softer than normal.

Its amnionic epithelium, trophoblast, Hofbauer cells, and circulating lymphocytes showed striking vacuolation, similar to those of I-cell disease. Calcified thrombi were found in large surface vessels. The 4050-g neonate had massive ascites but no organomegaly. Another case of mucolipidosis IV, supplied by Dr. P. J. Cera, also had surface vessel calcified thrombi, ascites, and massive trophoblastic vacuolization. We have seen endothelial Figure 18.3. Appearance of villi in I-cell disease (mucolipidosis II).The syncytium is characteristi- cally uniformly finely vacuolated. (Courtesy of Dr. Scott Hyde, 1999.)

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damage, perhaps secondary to lipid accumulation, in other cases of storage disease. In a case of G_M1gangliosi- dosis (mucolipidosis IV) fetal endothelial vacuolization was demonstrable in villous stem vessels (K. Winn, per- sonal communication, 1974).

Morquio’s disease (mucopolysaccharidosis type IV A) has also been diagnosed from enzyme analysis of chorionic villus biopsy (Applegarth et al., 1987). Within the family reported by these authors, nonimmune hydrops fetalis had occurred in previous pregnancies. The authors drew attention to previous reports of hydrops with Gaucher’s, Wolman’s, and Salla’s diseases, with sialidosis and mucopolysaccharidosis type VII. In their family, they had a hydropic fetus with a bulky placenta. Vacuolar villous edema and prominent Hofbauer cells were found, but there was no histologic evidence of storage products in the trophoblast.

Maroteaux et al. (1978) and See et al. (1978) have described the general features of sialidosis (“nephrosiali- dosis”; mucolipidosis type I). They depicted the inclusions in the neuraminidase-deﬁcient cells, but did not describe the placenta. In other case reports (Aylsworth et al., 1980;

Stevenson et al., 1983), the inclusions of tissues and cultured cells are all well depicted, but these authors did not describe the associated placentas either. Laver et al.

(1983) found typical storage vacuoles in Hofbauer cells and the villous syncytium. Amniocyte morphology in this disease has been reported to be normal by electron microscopic study (Stevenson et al., 1983). In a similar disorder, hydrops fetalis resulted in two pregnancies from a combined deﬁciency of neuraminidase and b-galactosidase (Kleijer et al., 1979). The placenta of these fetuses was not described. Gillan et al. (1984), who discussed congenital ascites in various storage disorders (sialidosis, Salla’s disease, gangliosidosis, Gaucher’s disease), depicted a placental villus with vacuolated syncytial cytoplasm of a fetus with Salla’s disease.

Niemann-Pick disease (type C) does not result in visible storage products of the placenta. When tissue is obtained from CVS and cultured under special condi- tions, however, the tissue-cultured cells of affected fetuses have been shown to accumulate laminated inclusions of nonesterified cholesterol (myelin bodies), which can then be stained with filipin for unesterified cholesterol, and the diagnosis may thus be secured (Vanier et al., 1989;

Jones et al., 1990). Nonimmune hydrops with hydramnios, commencing at 19 weeks’ gestation, has been described by Meizner et al. (1990) in Niemann-Pick disease. Fetal death occurred at 36 weeks and the inclusions were identified electron microscopically in the enlarged spleen. The placenta was not described. Niemann-Pick disease type A, due to sphingomyelin diphosphodiester- ase deficiency, can be diagnosed from absent enzyme in amnionic fluid. Unusual echogenic densities in the placentas of several cases that also had thick chorionic plates

were sonographically demonstrated by Schoenfeld et al.

(1985). Vacuolated syncytium, Hofbauer cells, and ﬁbro- cytes of the umbilical cords contained accumulations of sphingomyelin, as did the chorion laeve.

Desai et al. (1985) found lysosomal lipid deposits in cholesterol ester storage disease in which the fetal adrenal glands had foci of necrosis and many other tissues possessed a vacuolated cytoplasm. In a detailed Cabot Case description in the New England Journal of Medi- cine, Scully (1997) described a child with hydrops of unknown etiology whose placenta had extensive vacuolation of the syncytium and stromal cells. Because of deﬁ - cient levels of b-galactosidase and a-neuramidase from cultured cells obtained at amniocentesis the diagnosis of galactosialidosis was established. This discussion included a consideration of the pathogenesis of the fetal hydrops that is still not clariﬁed for most storage diseases.

Bendon and Hug (1985) reported placental abnor- malities in five cases of Pompe’s disease (glycogen storage disease type II; a-1,4-glucosidase deficiency). In routine examination of the placenta, the only unusual finding was the cytoplasmic vacuolation of amnionic connective tissue cells and the villous capillary endothelial cells (Roberts et al., 1991). Electron microscopy, however, showed typical membrane-bounded, glycogen-filled inclusions in capillary endothelial cells and in the villous stroma. They were present even in middle trimester abortuses. Hug et al.

(1991) described the diagnosis from CVS at 10 weeks.

The previous pregnancy had resulted in an affected child. Electron-microscopic examination 5 days after biopsy identified the typical glycogen-packed membrane- enclosed inclusions in many fetal cells, including fibrocytes that appear as vacuoles in histologic study. These authors insisted that the demonstration of vacuoles alone is insufficient for the diagnosis. Jones and her collaborators (1990) made similar findings of lysosomal glycogen accumulation. These were seen in cytotrophoblast, endothelium, fibrocytes, and pericytes. We have seen the placenta of a neonate with glycogen storage disease, type IV (amy- lopectinase deficiency). It had vacuoles in amnionic epithelium, but no specific lesions were identified. There were none of those cells that had been identified in Pompe’s disease. The pregnancy was complicated by hydramnios.

The newborn had Lafora bodies in heart, liver, and muscle, had pleural transudate, was dysmorphic, and suffered fatal pulmonary hypoplasia. The placenta was enlarged.

A second pregnancy was similarly involved.

Similarly, in sialic acid storage disease, Jones et al.

(1990) identiﬁed the Hofbauer cells, endothelium, and syncytium to be packed with clear, membrane-bound vacuoles (Jauniaux et al., 1987). Roberts et al. (1991) also found vacuolization in extravillous trophoblast and amnionic epithelium. And from chorionic villus biopsy material, more sophisticated culture methods we can anticipate more complex storage diseases to be identiﬁed in the

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582 18. Fetal Storage Disorders future, just as had been anticipated by Nadler and Gerbie

many years earlier (1970). Thus, Menkes’ disease was diagnosed by the absence of copper from CVS samples (Tønnesen et al., 1985).

It is apparent from these descriptions that many congenital enzyme deﬁciencies can be diagnosed from amnionic ﬂuid cultures, and chorionic villus samples, and that they may be accompanied by placental manifestations.

The location and type of inclusion cannot always be anticipated. Thus, the inclusions of lipofuscinosis were mainly in the fetal capillary endothelium, although they had earlier been suggested to be in syncytiotrophoblast (Rapola et al., 1990). The villus specimens, therefore, should be processed for optimal ultrastructural studies.

Chorionic villus biopsy has become of great value in selected cases, especially for prenatal counseling. In this area of research, some published animal models closely parallel the human disease. Most known animal models of storage disease and spontaneous occurrences of inborn errors of metabolism were reviewed by Jolly and Walkley (1997). Their use may be of value, particularly in attempts at therapy, but also for the study of their placentas (Baker et al., 1976).

References

Abe, K., Matsuda, I., Arashima, S., Mitsuyama, T., Oka, Y. and Ishikawa, M.: Ultrastructural studies in fetal I-cell disease.

Pediatr. Res. 10:669–676, 1976.

Applegarth, D.A., Toone, J.R., Wilson, R.D., Long, S.L. and Baldwin, V.J.: Morquio disease presenting as hydrops fetalis and enzyme analysis of chorionic villus tissue in a subsequent pregnancy. Pediatr. Pathol. 7:593–599, 1987.

Aula, P., Rapola, J., Autio. S., Raivio, K. and Karjalainen, O.:

Prenatal diagnosis and fetal pathology of I-cell disease (Mucolipidosis Type II). J. Pediatr. 87:221–226, 1975.

Aylsworth, A.S., Thomas, G.H., Hood, J.L., Malouf, N. and Libert, J.: A severe infantile sialidosis: clinical, biochemical, and microscopic features. J. Pediatr. 96:662–668, 1980.

Baker, H.J., Mole, J.A., Lindsey, J.R. and Creel, R.M.: Animal models of human ganglioside storage diseases. Fed. Proceed.

35:1193–1201, 1976.

Baldwin, V.J., Applegarth, D.A., Pantzar, T.R., Smyth, J. and McGillivray, B.C.: Congenital sialidosis. Lab. Invest. 52:1P (abstract), 1985.

Bendon, R.W. and Hug, G.: Morphologic characteristics of the placenta in glycogen storage disease type II (b-1,4-glucosi- dase deﬁciency). Amer. J. Obstet. Gynecol. 152:1021–1026, 1985.

Benirschke, K. and Kaufmann, P.: Pathology of the Human Pla- centa. Third edition. Springer-Verlag, New York, 1995.

Bouvier, R. and Maire, I.: Fetal presentation of 23 cases of lysosomal storage disease. A collaborative study of the French Society of Fetal Pathology. Pediatr. Pathol. Lab. Med. 17:675, 1997.

Conradi, N.G., Uverbrandt, P. Hökegård, K.-H., Wahlströmm T.

and Mellqvist, L.: First-trimester diagnosis of juvenile neuro-

nal ceroid lipofuscinosis by demonstration of ﬁngerprint inclusions in chorionic villi. Prenat. Diagn. 9:283–287, 1989.

Cozzutto, C.: Case report. Foamy degeneration of placenta. Vir- chows Arch. Pathol. Anat. 401:363–368, 1983.

Desai, P.K., Astrin, K.H., Gordon, R.E., Thung, S., Strauss, L. and Desnick, R.J.: Cholesterol ester storage disease: prenatal diagnosis and fetal pathology. Lab. Invest. 52:4P, 1985.

Fox, H.: Pathology of the Placenta. 2nd edition. W.B. Saunders, London, 1997.

Gehler, J., Cantz, M., Stoeckenius, M. and Spranger, J.: Prenatal diagnosis of mucolipidosis II (I-cell disease). Europ. J. Pediatr.

122:201–206, 1976.

Gellis, S.S. and Feingold, M.: Picture of the month. I-cell disease (mucolipidosis II). Amer. J. Dis. Childr. 131:1137–

1138, 1977.

Gillan, J.E., Lowden, J.A., Gaskin, K. and Cutz, E.: Congenital ascites as a presenting sign of lysosomal storage disease. J.

Pediatr. 104:225–231, 1984.

Ginsburg, S.J. and Groll, M.: Hydrops fetalis due to infantile Gaucher’s disease. J. Pediatr. 82:1046–1048, 1973.

Giugliani, R., Dutra, J.C., Pereira, M.L.S., Rotta, N., Drachler, M.d.L., Ohlweiler, L., Neto, J.M.d.P., Pinheiro, C.E. and Breda, D.J.: GM1gangliosidosis: Clinical and laboratory ﬁndings in eight families. Hum. Genet. 70:347–354, 1985.

Granström, M.-L., Aula, P. ja Rapola, J.: Kliinis-patologinen kokousselostus XY. Kudosviljelyn avulla selvitetty aineenvai- hduntasairaus. Duodecim 90:421–430, 1974.

Grebner, E.E., Wapner, R.J., Barr, M.A. and Jackson, L.G.: Pre- natal Tay-Sachs diagnosis by chorionic villi sampling. Lancet ii:286–287, 1983.

Hanai, J., Leroy, J. and O’Brien, J.S.: Ultrastructure of cultured ﬁbroblasts in I-cell disease. Amer. J. Dis. Childr. 122:34–38, 1971.

Herd, J.K., Dvorak, A.D., Wiltse, H.E., Eisen, J.D., Kress, B.C.

and Miller, A.L.: Mucolipidosis type II. Multiple elevated serum and urine enzyme activities. Amer. J. Dis. Childr.

132:1181–1186, 1978.

Hug, G., Bove, K.E., Soukup, S., Ryan, M., Bendon, R., Babcock, D., Warren, N.S. and Dignan, P.S.J.: Increased serum hexosaminidase in a woman pregnant with a fetus affected by muco- lipidosis II (I-cell disease). NEJM 311:988–989, 1984.

Hug, G., Chuck, G., Chen, Y.-T., Kay, H.H. and Bossen, E.H.:

Chorionic villus ultrastructure in type II glycogen storage disease (Pompe’s disease). NEJM 324:342–343, 1991.

Jauniaux, E., Vamos, E., Libert, J., Elkhazen, N., Wilkin, P. and Hustin, J.: Placental electron microscopy and histochemistry in a case of sialic acid storage disorder. Placenta 8:433–442, 1987.

Jolly, R.D. and Walkley, S.U.: Lysosomal storage diseases of animals: an essay in comparative pathology. Vet. Pathol.

34:527–548, 1997.

Jones, C.J.P., Lendon, M., Chawner, L.E. and Jauniaux, E.:

Ultrastructure of the human placenta in metabolic storage disease. Placenta 11:395–411, 1990.

Kleijer, W.J., Hoogeveen, A., Verheijen, F.W., Niermeijer, M.F., Galjaard, H., O’Brien, J.S. and Warner, T.G.: Prenatal diagnosis of sialidosis with combined neuraminidase and b-galacto- sidase deﬁciency. Clin. Genet. 16:60–61, 1979.

Kleijer, W.J., Janse, H.C., Vosters, R.P.L., Niermeijer, M.F. and v.d. Kamp, J.J.P.: First-trimester diagnosis of mucopolysac-

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charidosis IIIA (Sanﬁlippo A disease). NEJM 314:185–186, 1986.

Kohn, G., Livni, N., Ornoy, A., Sekeles, E., Beyth, Y., Legum, C., Bach, G. and Cohen, M.M.: Prenatal diagnosis of mucoli- pidosis IV by electron microscopy. J. Pediatr. 90:62–66, 1977.

Laver, J., Fried, K., Beer, S.I., Iancu, T.C., Heyman, E., Bach, G.

and Zeiger, M.: Infantile lethal neuraminidase deﬁciency (sialidosis). Clin. Genet. 23:97–101, 1983.

Lowden, J.A., Cutz, E., Conen, P.E., Rudd, N. and Doran, T.A.:

Prenatal diagnosis of GM1-gangliosidosis. NEJM 288:225–228, 1973.

Mahmood, K. and Haleem, A.: Placental morphology in sialido- sis: report of a case. Ann. Saudi Med. 9:302–304, 1989.

Maroteaux, P., Humbel, R., Strecker, G., Michalski, J.-C. and Mande, R.: Un nouveau type de sialidose avec atteinte renale:

La nephrosialidose. Arch. Franç. Pédiatr. 35:819–829, 1978.

Meizner, I., Levy, A., Carmi, R. and Robinsin, C.: Niemann-Pick disease associated with nonimmune hydrops fetalis. Amer. J.

Obstet. Gynecol. 163:128–129, 1990.

Nadler, H.L. and Gerbie, A.B.: Role of amniocentesis in the intrauterine detection of genetic disorders. NEJM 282:596–

599, 1970.

Nagashima, K., Sakakibara, K., Endo, H., Konishi, Y., Nakamura, N., Suzuki, Y. and Abe, T.: I-cell disease (mucolipidosis II). Pathological and biochemical studies of an autopsy case. Acta Pathol. Jap. 27:251–264, 1977.

Nelson, J., Kenny, B., O’Hara, D., Harper, A. and Broadhead, D.:

Foamy changes of placental cells in probable beta glucuronidase deﬁciency associated with hydrops fetalis. J. Clin. Pathol.

46:370–371, 1993.

O’Brien, J.F.: The lysosomal storage diseases. Mayo Clin.

Proceed. 57:192–197, 1982.

Popli, S., Leehey, D.J., Molnar, Z.V., Nawab, Z.M. and Ing, T.S.:

Demonstration of Fabry’s disease deposits in placenta. Amer.

J. Obstet. Gynecol. 162:464–465, 1990.

Powell, H.C., Benirschke, K., Favara, B.E. and Pﬂueger, O.H.:

Foamy changes of placental cells in fetal storage disorders.

Virchows Arch. A Pathol. Anat. Histol. 369:191–196, 1976.

Rapola, J. and Aula, P.: Morphology of the placenta in fetal I-cell disease. Clin. Genet. 11:107–113, 1977.

Rapola, J., Autio, S., Aula, P. and Nanto, V.: Lymphocytic inclu- sions in I-cell disease. J. Pediatr. 85:88–90, 1974.

Rapola, J., Santavuori, P. and Heiskala, H.: Placental pathology and prenatal diagnosis of infantile type of neuronal ceroid- lipofuscinosis. Amer. J. Med. Genet. Suppl. 5:99–103, 1988.

Rapola, J., Salonen, R., Ämmälä, P. and Santavuori, P.: Prenatal diagnosis of the infantile type of neuronal ceroid lipofuscino-

sis by electron microscopic investigation of human chorionic villi. Prenat. Diagn. 10:553–559, 1990.

Rice, G.E., Mostouﬁ-Zadeh, M. and Driscoll, S.G.: Hydrops fetalis in Gaucher’s disease. Teratology 29:53A–54A, 1984.

Riches, W.G. and Smuckler, E.A.: A severe infantile mucolipidosis. Clinical, biochemical, and pathologic features. Arch.

Pathol. Lab. Med. 107:147–152, 1983.

Roberts, D.J., Ampola, M.G. and Lage, J.M.: Diagnosis of unsus- pected fetal metabolic storage disease by routine placental examination. Pediatr. Pathol. 11:647–656, 1991.

Sarrut, S. and Belamich, P.: Étude du placenta dans trois obser- vations de dyslipide à révélation neonatale. Arch. D’Anat.

Cytol. Pathol. 31:187–189, 1983.

Schoenfeld, A., Abramovici, A., Klibanski, C. and Ovadia, J.:

Placental ultrasonographic biochemical and histochemical studies in human fetuses affected with Niemann-Pick disease Type A. Placenta 6:33–44, 1985.

Scully, R.E. (Ed.): Cabot case No. 23-1997. NEJM 337:260–267, 1997.

See, G.L., Stanescu, R. and Lyon, G.: Un nouveau type de sialidose avec atteinte renale: la nephrosialidose. Arch. Franç.

Pédiatr. 35:830–844, 1978.

Sekeles, E., Ornoy, A., Cohen, R. and Kohn, G.: Mucolipidosis IV: fetal and placental pathology. A report on two subsequent interruptions of pregnancy. Monogr. Human Genet. 10:47–50, 1978.

Sidransky, E. and Ginns, E.I.: Clinical heterogeneity among patients with Gaucher’s disease. JAMA 269:1154–1157, 1993.

Stevenson, R.E., Lubinsky, M., Taylor, H.A., Wenger, D.A., Schroer, R.J. and Olmstead, P.M.: Sialic acid storage disease with sialuria: clinical and biochemical features in the severe infantile type. Pediatrics 72:441–449, 1983.

Soma, H., Yamada, K., Osawa, H., Hata, T., Oguro, T. and Kudo, M.: Identiﬁcation of Gaucher cells in the chorionic villi associated with recurrent hydrops fetalis. Placenta 21:412–

416, 2000.

Terashima, Y., Tsuda, K., Isomura, S., Sugiura, Y. and Nogami, H.: I-cell disease. Report of three cases. Amer. J. Dis. Childr.

129:1083–1090, 1975.

Tønnesen, T., Horn, N., Søndergaard, F., Boué, J., Damsgaard, E. and Heydorn, K.: Measurement of copper in chorionic villi for ﬁrst-trimester diagnosis of Menkes’ disease. Lancet i:1038–1039, 1985.

Vanier, M.T., Rousson, R.M., Mandon, G., Choiset, A., Lake, B.D. and Pentchev, P.G.: Diagnosis of Niemann-Pick disease type C on chorionic villus biopsy. Lancet i:1014–1015, 1989.