PRENATAL DIAGNOSISPrenat Diagn 2009; 29: 895–896.Published online 22 May 2009 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.2299

RESEARCH LETTER

Galactosialidosis presenting as nonimmune fetal hydrops:a case report

Susana Carvalho1*, Marcia Martins2, Ana Fortuna3, Umbelina Ramos4, Carlos Ramos5 andMaria Ceu Rodrigues5

1Centro Hospitalar do Porto-Unidade Maternidade Julio Dinis, Porto, Portugal2Centro Hospitalar do Porto-Unidade Maternidade Julio Dinis, Pediatrics, Porto, Portugal3Instituto de Genetica Medica Jacinto Magalhaes, Genetics, Porto, Portugal4Centro Hospitalar do Porto, Porto, Portugal5Centro Hospitalar do Porto-Unidade Maternidade Julio Dinis, Porto, Portugal

KEY WORDS: hydrops fetalis; lysosomal storage disease; galactosialidosis; fetal ultrasound; fetal imaging; fetaland placental pathology; genetic counseling

INTRODUCTION

Hydrops fetalis, defined as abnormal accumulation offluid in two or more fetal compartments, is a nonspe-cific finding that is easily detected on prenatal ultra-sonography and may be associated with a wide rangeof associated abnormalities. Elucidation of aetiologyis of primary importance because treatment and prog-nosis of this disorder are determined by the underly-ing fetal condition. In most series, aetiology is foundin approximately 51 to 85% of cases before deliveryand up to 95% after delivery depending in part onparental acceptance of autopsy and karyotype (Creasyand Resni, 2004). Cardiovascular, chromosomal, andinfectious conditions are the most frequently identi-fied causes of nonimmune hydrops. Hydrops fetalishas also been associated with more than 75 inbornerrors of metabolism, chromosomal aberrations, geneticsyndromes, and with some lysosomal storage disor-ders (LSDs).

Galactosialidosis (GS) is a neurodegenerative lysoso-mal storage disease that is inherited as an autosomalrecessive trait. It is caused by combined deficiency ofthe lysosomal enzymes beta-galactosidase and alpha-neuraminidase. The combined deficiency has been foundto result from a defect in protective protein/cathepsinA (PPCA), an intralysosomal protein which protectsthese enzymes from premature proteolytic processing(Patel et al., 1999). According to age of onset and sever-ity of symptoms, three clinical phenotypes are recog-nized: congenital or early infantile, late infantile, andjuvenile/adult form. The most severe form of GS, theearly-infantile form, is marked by early onset of edema,ascites, visceromegaly, and skeletal dysplasia; it mayappear as nonimmune fetal hydrops. Few patients with

*Correspondence to: Susana Carvalho, Centro Hospitalar doPorto-Unidade Maternidade Julio Dinis, Porto, Portugal.E-mail: susanapcarvalho@gmail.com

the early-infantile form of GS have been described todate (Patel et al., 1999; Hide & Seek Foundation, 2009).

We report a case of GS presenting with fetal hydropsat 20 weeks of gestation.

CASE REPORT

The patient was a 28-year-old Caucasian woman, nulli-para, without relevant medical or surgical history. Bloodtype was A Rh positive. Family history was remark-able for consanguinity (patient and her husband werefirst-degree cousins). She was referred to the prenataldiagnosis unit because of fetalis hydrops diagnosed at20 weeks of gestation.

Systematic approach to the prenatal diagnostic workupof nonimmune hydrops fetalis (NIFH) included anultrasonographic survey, which revealed subcutaneousedema, ascites, pericardic effusion, and visceromegaly;a fetal echocardiography, which was normal; completeblood count was normal; a Kleihauer-Betke test showedno evidence of fetomaternal hemorrhage. TORCH testwas negative for primary infection. Amniocentesis wasperformed for genetic studies: fetal karyotype was nor-mal 46,XY. Enzymologic study of cultured fibrob-lasts revealed that both alpha-neuraminidase and beta-galactosidase activities were severely reduced, confirm-ing the biochemical diagnosis of a lysosomal storagedisease (GS).

The pregnancy was interrupted at 22 weeks. Postmortem study revealed vacuolation of lymphocytesand eosinophilic granulocytes confirming the ultrasono-graphic and biochemical findings. The consanguineousbut otherwise healthy parents received genetic counsel-ing for future pregnancies and were informed about therecurrence risk of 25% and the possibility of prenataldiagnosis in future pregnancies.

Copyright 2009 John Wiley & Sons, Ltd. Received: 22 January 2009Revised: 17 April 2009

Accepted: 18 April 2009Published online: 22 May 2009

896 S. CARVALHO ET AL.

DISCUSSION

We report a case of hydrops fetalis due to GS. A precisediagnosis of the cause of NIFH is of interest for prenataldiagnostic as well as for neonatological management.A variety of genetic metabolic diseases, particularlylysosomal storage diseases, can cause hydrops in thefetus. Gaucher’s disease, generalized gangliosidosis,Salla’s disease, sialidosis, mucopolysaccharidosis typesIV and VII, Tay-Sachs disease, and others can all presentin this manner. These conditions can recur in subsequentpregnancies because they are typically inherited in anautosomal recessive fashion. Establishing the correctdiagnosis is therefore extremely important. This can beaccomplished by analysis of oligosaccharides in fetaland neonatal urine or blood, enzyme analyses and carriertesting in the parents, or histologic examination ofappropriate fetal tissue (Creasy and Resni, 2004).

Landau et al. in 1995 added GS to the list of condi-tions that can cause NIFH. GS is a rare LSD. It is causedby neuraminidase and beta-galactosidase deficienciesresulting from a primary deficiency in a third lysoso-mal protein: the bifunctional protein PPCA. PPCA bindswith beta-galactosidase and neuraminidase, forming amultienzymatic complex, and ensures their activity andstability within the lysosome. This enzyme works withbeta-galactosidase and neuraminidase to break downlong sugar chains in the lysosome. Individuals with GSshow the typical physical characteristics shared by manyof the lysosomal storage diseases, including coarse facialfeatures, abnormal bone formation, and cherry-red spotsseen on ophthalmology evaluation. Transmission is auto-somal recessive. The gene has been located on 20q13.1(Maire and Nivelon-Chevallier, 1981; Mueller et al.,1986), it has been cloned and several mutations havebeen identified (Shimmoto et al., 1990, 1993). Groeneret al. reported, in 2003, the first two Dutch cases ofearly-infantile GS, both presenting with neonatal ascites.The mutation analysis of both mRNA and genomic DNAfrom the patients identified two novel mutations in thePPCA locus. Case 1 was a compound heterozygote, witha single missense mutation in one allele, which resultedin Gly57Ser amino acid substitution, and a single Cinsertion at nucleotide position 899 in the second allele,which gave rise to a frame shift and premature termina-tion codon. Case 2 was homozygous for the same C899insertion found in case 1 (Groener et al., 2003). A singleA-G base transition at position 146 of exon 1 (Q49R)in PPCA gene was found in a case described by Mat-sumoto et al. in 2008. This mutation has been reportedpreviously in a Japanese patient with different pheno-types. However, homozygous Q49R mutation detectedin the case had a severe prognosis (Matsumoto et al.,2008).

There are three different types of GS. They are char-acterized by the age of onset and type of physical andmental manifestations. Type I is called the early-infantiletype, and onset is typically between birth and 3 monthsof age. Individuals with this type of GS present edema,ascites, hepatosplenomegaly (it may appear as fetalhydrops), neurologic disorders, kidney failure, facialdysmorphism, and skeletal and opthalmologic disorders

(cherry-red spots and early blindness). Cognitive andmotor delay is also present. Echocardiogram may showcardiomegaly, kidney function can be impaired, andthere may be increased protein detected in the urine. Car-diac and/or renal failure is typically the cause of deathin individuals with early-infantile GS, usually within thefirst year of life. Biological diagnosis of GS is made byfinding a characteristic chromatographic profile of uri-nary oligosaccharides. Results are confirmed by measur-ing the enzymatic activity of the alpha-D-neuraminidaseand beta-galactosidase or carboxypeptidase A in fibrob-lasts, amniocytes, or the trophoblast. The only treatmentis symptomatic (Maire and Nivelon-Chevallier, 1981;Mueller et al., 1986).

Although LSDs are rare, they are among the few casesof NIFH in which an accurate recurrence risk can bequoted. So after excluding the more frequent causes ofNIFH, an LSD investigation should be considered toclarify the aetiology of such cases and making geneticcounseling possible. Unfortunately, most of these testsare performed after fetal and neonatal death, becausethe prognosis is poor (Haverkamp et al., 1996; Janssens,2004).

The value of the diagnosis of LSDs lies in the opportu-nity for risk evaluation, genetic counseling, and targetedprenatal diagnostics in case of subsequent pregnancies,at an earlier time point in gestation—should the familyso desire (Creasy and Resni, 2004).

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Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 895–896.DOI: 10.1002/pd