PRENATAL DIAGNOSIS
Prenat 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 *, M´arcia Martins2 , Ana Fortuna3 , Umbelina Ramos4 , Carlos Ramos5 and Maria C´eu Rodrigues5 1
Centro Hospitalar do Porto-Unidade Maternidade J´ulio Dinis, Porto, Portugal Centro Hospitalar do Porto-Unidade Maternidade J´ulio Dinis, Pediatrics, Porto, Portugal 3 Instituto de Gen´etica M´edica Jacinto Magalh˜aes, Genetics, Porto, Portugal 4 Centro Hospitalar do Porto, Porto, Portugal 5 Centro Hospitalar do Porto-Unidade Maternidade J´ulio Dinis, Porto, Portugal 2
KEY WORDS: hydrops fetalis; lysosomal storage disease; galactosialidosis; fetal ultrasound; fetal imaging; fetal and placental pathology; genetic counseling
INTRODUCTION Hydrops fetalis, defined as abnormal accumulation of fluid in two or more fetal compartments, is a nonspecific finding that is easily detected on prenatal ultrasonography and may be associated with a wide range of associated abnormalities. Elucidation of aetiology is of primary importance because treatment and prognosis of this disorder are determined by the underlying fetal condition. In most series, aetiology is found in approximately 51 to 85% of cases before delivery and up to 95% after delivery depending in part on parental acceptance of autopsy and karyotype (Creasy and Resni, 2004). Cardiovascular, chromosomal, and infectious conditions are the most frequently identified causes of nonimmune hydrops. Hydrops fetalis has also been associated with more than 75 inborn errors of metabolism, chromosomal aberrations, genetic syndromes, and with some lysosomal storage disorders (LSDs). Galactosialidosis (GS) is a neurodegenerative lysosomal storage disease that is inherited as an autosomal recessive trait. It is caused by combined deficiency of the lysosomal enzymes beta-galactosidase and alphaneuraminidase. The combined deficiency has been found to result from a defect in protective protein/cathepsin A (PPCA), an intralysosomal protein which protects these enzymes from premature proteolytic processing (Patel et al., 1999). According to age of onset and severity of symptoms, three clinical phenotypes are recognized: congenital or early infantile, late infantile, and juvenile/adult form. The most severe form of GS, the early-infantile form, is marked by early onset of edema, ascites, visceromegaly, and skeletal dysplasia; it may appear as nonimmune fetal hydrops. Few patients with *Correspondence to: Susana Carvalho, Centro Hospitalar do Porto-Unidade Maternidade J´ulio Dinis, Porto, Portugal. E-mail:
[email protected]
Copyright 2009 John Wiley & Sons, Ltd.
the early-infantile form of GS have been described to date (Patel et al., 1999; Hide & Seek Foundation, 2009). We report a case of GS presenting with fetal hydrops at 20 weeks of gestation.
CASE REPORT The patient was a 28-year-old Caucasian woman, nullipara, without relevant medical or surgical history. Blood type was A Rh positive. Family history was remarkable for consanguinity (patient and her husband were first-degree cousins). She was referred to the prenatal diagnosis unit because of fetalis hydrops diagnosed at 20 weeks of gestation. Systematic approach to the prenatal diagnostic workup of nonimmune hydrops fetalis (NIFH) included an ultrasonographic survey, which revealed subcutaneous edema, ascites, pericardic effusion, and visceromegaly; a fetal echocardiography, which was normal; complete blood count was normal; a Kleihauer-Betke test showed no evidence of fetomaternal hemorrhage. TORCH test was negative for primary infection. Amniocentesis was performed for genetic studies: fetal karyotype was normal 46,XY. Enzymologic study of cultured fibroblasts revealed that both alpha-neuraminidase and betagalactosidase activities were severely reduced, confirming the biochemical diagnosis of a lysosomal storage disease (GS). The pregnancy was interrupted at 22 weeks. Post mortem study revealed vacuolation of lymphocytes and eosinophilic granulocytes confirming the ultrasonographic and biochemical findings. The consanguineous but otherwise healthy parents received genetic counseling for future pregnancies and were informed about the recurrence risk of 25% and the possibility of prenatal diagnosis in future pregnancies. Received: 22 January 2009 Revised: 17 April 2009 Accepted: 18 April 2009 Published online: 22 May 2009
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DISCUSSION We report a case of hydrops fetalis due to GS. A precise diagnosis of the cause of NIFH is of interest for prenatal diagnostic as well as for neonatological management. A variety of genetic metabolic diseases, particularly lysosomal storage diseases, can cause hydrops in the fetus. Gaucher’s disease, generalized gangliosidosis, Salla’s disease, sialidosis, mucopolysaccharidosis types IV and VII, Tay-Sachs disease, and others can all present in this manner. These conditions can recur in subsequent pregnancies because they are typically inherited in an autosomal recessive fashion. Establishing the correct diagnosis is therefore extremely important. This can be accomplished by analysis of oligosaccharides in fetal and neonatal urine or blood, enzyme analyses and carrier testing in the parents, or histologic examination of appropriate fetal tissue (Creasy and Resni, 2004). Landau et al. in 1995 added GS to the list of conditions that can cause NIFH. GS is a rare LSD. It is caused by neuraminidase and beta-galactosidase deficiencies resulting from a primary deficiency in a third lysosomal protein: the bifunctional protein PPCA. PPCA binds with beta-galactosidase and neuraminidase, forming a multienzymatic complex, and ensures their activity and stability within the lysosome. This enzyme works with beta-galactosidase and neuraminidase to break down long sugar chains in the lysosome. Individuals with GS show the typical physical characteristics shared by many of the lysosomal storage diseases, including coarse facial features, abnormal bone formation, and cherry-red spots seen on ophthalmology evaluation. Transmission is autosomal 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 have been identified (Shimmoto et al., 1990, 1993). Groener et al. reported, in 2003, the first two Dutch cases of early-infantile GS, both presenting with neonatal ascites. The mutation analysis of both mRNA and genomic DNA from the patients identified two novel mutations in the PPCA locus. Case 1 was a compound heterozygote, with a single missense mutation in one allele, which resulted in Gly57Ser amino acid substitution, and a single C insertion at nucleotide position 899 in the second allele, which gave rise to a frame shift and premature termination codon. Case 2 was homozygous for the same C899 insertion found in case 1 (Groener et al., 2003). A single A-G base transition at position 146 of exon 1 (Q49R) in PPCA gene was found in a case described by Matsumoto et al. in 2008. This mutation has been reported previously in a Japanese patient with different phenotypes. However, homozygous Q49R mutation detected in the case had a severe prognosis (Matsumoto et al., 2008). There are three different types of GS. They are characterized by the age of onset and type of physical and mental manifestations. Type I is called the early-infantile type, and onset is typically between birth and 3 months of age. Individuals with this type of GS present edema, ascites, hepatosplenomegaly (it may appear as fetal hydrops), neurologic disorders, kidney failure, facial dysmorphism, and skeletal and opthalmologic disorders Copyright 2009 John Wiley & Sons, Ltd.
(cherry-red spots and early blindness). Cognitive and motor delay is also present. Echocardiogram may show cardiomegaly, kidney function can be impaired, and there may be increased protein detected in the urine. Cardiac and/or renal failure is typically the cause of death in individuals with early-infantile GS, usually within the first year of life. Biological diagnosis of GS is made by finding a characteristic chromatographic profile of urinary oligosaccharides. Results are confirmed by measuring the enzymatic activity of the alpha-D-neuraminidase and beta-galactosidase or carboxypeptidase A in fibroblasts, amniocytes, or the trophoblast. The only treatment is symptomatic (Maire and Nivelon-Chevallier, 1981; Mueller et al., 1986). Although LSDs are rare, they are among the few cases of NIFH in which an accurate recurrence risk can be quoted. So after excluding the more frequent causes of NIFH, an LSD investigation should be considered to clarify the aetiology of such cases and making genetic counseling possible. Unfortunately, most of these tests are performed after fetal and neonatal death, because the prognosis is poor (Haverkamp et al., 1996; Janssens, 2004). The value of the diagnosis of LSDs lies in the opportunity for risk evaluation, genetic counseling, and targeted prenatal diagnostics in case of subsequent pregnancies, at an earlier time point in gestation—should the family so desire (Creasy and Resni, 2004). REFERENCES Creasy RK, Resni KR. 2004. Maternal-fetal medicine. Sauders 31: 563–575. Haverkamp F, Jacobs D, Cantz M, Hansmann M, Fahnenstich H, Zerres K. 1996. Nonimmune hydrops fetalis with galactosialidosis: consequences for family planning. Fetal Diagn Ther 11: 114–119. Groener J, Maaswinkel-Mooy P, Smit V, et al. 2003. New mutations in two Dutch patients with early infantile galactosialidosis. Mol Genet Metab 78: 222–228. Janssens PM. 2004. Hydrops fetalis as an indication for a systematic investigation into the presence of lysosomal storage diseases. Ned Tijdschr Geneeskd 148: 264–268. Landau D, Zeigler M, Shinwell ES, Meisner I, Bargal R. 1995. Hydrops fetalis in four siblings caused by galactosialidosis. Isr J Med Sci 31: 321–322. Maire I, Nivelon-Chevallier A. 1981. Combined deficiency of betagalactosidase and neuraminidase: three affected siblings in a French family. J Inherit Metab Dis 4: 221–223. Matsumoto N, Gondo K, Kukita J, Higaki K, Paragison RC, Nanba E. 2008. A case of galactosialidosis with a homozygous Q49R point mutation. Brain Dev 30: 595–598. Mueller OT, Henry WM, Shws TB. 1986. Sialidosis and galactosialidosis: chromosomal assignment of two genes associated with neuraminidase-deficiency disorders. Proc Natl Acad Sci U S A 83: 1817–1821. Patel MS, Callahan JW, Zhang S, et al. 1999. Early-infantile galactosialidosis: prenatal presentation and postnatal follow-up. Am J Med Genet 85: 38–47. Shimmoto M, Fukuhara Y, Itoh K, Oshima A, Sakuraba H, Suzuki Y. 1993. Protective protein gene mutations in galactosialidosis. J Clin Invest 91: 2393–2398. Shimmoto M, Takano T, Fukuhara Y, Oshima A, Sakuraba H, Suzuki Y. 1990. Japanese-type adult galactosialidosis: a unique and common splice junction mutation causing exon skipping in the protective protein/carboxypeptidase gene. Proc Jpn Acad 66B: 217–222. Hide & Seek Foundation. 2009. www. Hide and seek.org/diseases/ galactosialisosis.html. Prenat Diagn 2009; 29: 895–896. DOI: 10.1002/pd
