Perinatal/Neonatal Case Presentation &&&&&&&&&&&&&& Mucopolysaccharidosis Type VII Presenting With Isolated Neonatal Ascites

Matthew Adam Saxonhouse, MD presented to our neonatal intensive care unit with isolated ascites Marylou Behnke, MD as the dominant clinical feature. Initial diagnostic evaluation Jonathan L. Williams, MD revealed no obvious cause for the ascites, but follow-up Douglas Richards, MD examinations and laboratory evaluation confirmed the diagnosis Michael D. Weiss, MD of MPS VII.

CASE REPORT + Mucopolysaccharidosis Type VII (MPS VII) is a lysosomal storage disease A 22-year-old, gravida 2, para 0101, A serologies (negative), caused by a deficiency of the , b-glucuronidase. MPS VII has a wide African–American female with limited prenatal care presented to our variation in phenotypic expression, including presentation in the neonatal Emergency Department at approximately 37 weeks’ gestation with period with nonimmune . We report a neonate with MPS VII vaginal bleeding and abdominal . A fetal ultrasound revealed a who initially presented with marked isolated ascites not associated with male infant with marked ascites. The had a blunt edge, and the hydrops fetalis. This appears to be a novel finding in patients with MPS VII. length was 58 mm (normal 45–58 mm). The abdominal Journal of Perinatology (2003) 23, 73 – 75 doi:10.1038/sj.jp.7210844 circumference was 6.5 SD above the mean for the gestational age. Other findings on the ultrasound included scrotal ascites and moderate dependent edema on the dorsal surfaces of the feet. There were no other signs of edema, effusions, or failure. Due to INTRODUCTION the anticipation of a difficult delivery, in utero paracentesis was 3 Mucopolysaccharidosis Type VII (MPS VII) is a lysosomal storage performed to decompress the abdomen. Approximately 50 cm of disease caused by a deficiency of the enzyme, b-glucuronidase.1 It is ascitic fluid was removed and an analysis revealed values reflective of generally a fatal, progressive, and degenerative disorder that has a both an exudate and transudate. The Gram stain and culture of the wide variation in phenotypic expression. Clinical features commonly fluid were both negative. seen include , coarse facial features, and Despite the prenatal decompression, the fetus’ abdomen remained dysostosis multiplex.2,3 There have been reports of neonates with large and a cesarean section was performed. The delivery was MPS VII presenting with nonimmune hydrops fetalis (NIHF).3–5 unremarkable and the APGAR scores were 9 and 9 at 1 and These patients had generalized skin edema and other clinical 5 minutes, respectively. manifestations commonly seen with NIHF as well as features On physical examination, the patient was afebrile, had stable vital associated with MPS VII. signs, and weighed 4883 g. Abdominal and genitourinary Ascites in the neonate without other concomitant abnormalities examinations were significant for massive abdominal and associated with NIHF is referred to as isolated neonatal ascites.6 scrotal ascites with bilateral inguinal (Figure 1). No hepatosplenomegaly was appreciated. Lower extremity nonpitting Infantile sialidosis, Salla disease, GM1 gangliosidosis, and Gaucher disease are lysosomal storage diseases that have been reported to peripheral edema was noted with no other abnormalities seen present with isolated neonatal ascites.7 However, we are aware of (Figure 1). Both the cardiac and pulmonary examinations were no cases of MPS VII presenting with isolated ascites in the within normal limits with no signs of respiratory distress. Skin neonatal period. We recently observed a case of MPS VII that examination was unremarkable. Laboratory evaluation on day of life 1 included a normal complete blood count with a peripheral smear that revealed no Department of Pediatrics ( M.A.S., M.B., M.D.W. ), University of Florida, Gainesville, FL, USA; abnormal inclusions or vacuoles. Chemistry profiles were within Department of Radiology ( J.L.W. ), University of Florida, Gainesville, FL, USA; and Department normal ranges and hepatic profiles revealed no significant of Obstetrics and Gynecology ( D.R. ), University of Florida, Gainesville, FL, USA. abnormalities. Urinalysis was normal and TORCH studies revealed no Address correspondence and reprint requests to Matthew Adam Saxonhouse, MD, Department evidence of congenital infection. The mother’s and infant’s blood of Pediatrics, Division of Neonatology, 1600 Southwest Archer Road, PO Box 100296, + Gainesville, FL 32610 - 0296, USA. type was A with negative direct Coombs test.

Journal of Perinatology 2003; 23:73 – 75 # 2003 Nature Publishing Group All rights reserved. 0743-8346/03 $25 www.nature.com / jp 73 Saxonhouse et al. Mucopolysaccharidosis Type VII Presenting With Isolated Neonatal Ascites

mild hypertelorism. There was relative macrocephaly with a head circumference of 51 cm (75–90%), a length of 81 cm ( <3%), and a weight of 12 kg (25%). There were no gross ophthalmologic or hearing deficits noted. The extremities demonstrated thin fingers with no evidence of brachydactyly or thickened bony areas. The abdomen was remarkable for an umbilical with no evidence of hepatosplenomegaly. Cardiac and pulmonary exams were normal. Genitourinary was significant for healed scars from prior surgery with no scrotal edema. Developmental and neurologic exam revealed an ambulatory child with significant delay of fine motor skills and speech. The patient was able to follow simple verbal and visual commands. He had a marked deficit in language Figure 1. Neonate in supine position at day of life 1. Significant development and his level was comparable to that of an abdominal and scrotal ascites is present along with dependent edema of the 8-month-old child. left foot. Plain views of the spine demonstrated abnormalities in the thoracolumbar region. The L1 vertebral body was small and Plain film views of the chest were normal with no bony posteriorly displaced with deformities noted in L2 and L3. Scoliosis abnormalities. Computed tomography of the abdomen and pelvis was present and concave to the right at the level of T8–T12. The iliac revealed abdominal and scrotal ascites with no other abnormalities wings were abnormally shaped and the femoral heads demonstrated noted. A voiding cystourethrogram demonstrated no evidence of delayed ossification. Plain views of the skull showed an enlarged sella bladder perforation, posterior urethral valves, or any other anatomic turnica. abnormalities. Laboratory evaluation of lysosomal enzyme screening panel The patient was given no treatment and was observed for several demonstrated a b-glucuronidase level of 5.8 nmol/mg per hour days. Normal urine output was demonstrated and full enteral diet (normal: 363±85.1) from cultured leukocytes, confirming a 8 was tolerated. Repeat laboratory studies were obtained on day of life diagnosis of MPS VII. 4 and were similar to admission laboratory values. A diagnostic paracentesis was performed on day of life 6 after the neonate had been on a full enteral diet for several days. The ascitic fluid again DISCUSSION demonstrated properties of both an exudate and transudate and was Neonatal ascites may be part of the spectrum of NIHF or can present not consistent with chylous fluid. A Gram stain and culture of the as an isolated finding. NIHF is a fetal condition that can be fluid revealed no organisms. diagnosed by ultrasound, demonstrating generalized skin edema of The infant demonstrated a minimal decrease in both the >5 mm with two or more of the following: ascites, pleural effusions, abdominal and scrotal ascites and was discharged on day of life pericardial effusions, or a thickened placenta of >6 cm.9 However, 7 weighing 4642 g with a tentative diagnosis of idiopathic neonatal isolated neonatal ascites may present with peripheral edema and ascites. hydroceles but lack the other properties of NIHF. Further outpatient evaluation revealed normal growth and The most common causes of isolated neonatal ascites involve development for the first few months of life with complete resolution anomalies of the urinary tract.10,11 Many pathological processes of the ascites. Laboratory evaluation continued to demonstrate no cause isolated neonatal ascites; however, a significant percentage of significant abnormalities. However, the infant began demonstrating cases never had a cause identified despite extensive laboratory tests signs of developmental delay by 6 months of life. A magnetic and radiological studies.10 A review performed by Machin et al.10 resonance imaging (MRI) of the was performed, examined 146 cases of isolated neonatal ascites of which 6% had demonstrating normal brain formation with normal basal ganglia no identifiable pathology and was therefore considered to be density for age. However, cystic periventricular leukomalacic changes idiopathic. were present and distributed symmetrically involving all the deep There are case reports of lysosomal storage diseases white matter of the frontal and parietal areas. Urine was tested for presenting with isolated neonatal ascites.7,12,13 Most of the infants sialic acid and was measured to be within normal limits. Serum presented in these reports had a positive family history for the chromosome analysis revealed a normal 46, XY male. Unfortunately, disease or a maternal history of unexplained abortions or still the patient was lost to follow-up and did not return for evaluation births. In contrast to our case, the infants possessed at birth other until he was 27 months of age despite numerous attempts to contact previously reported characteristic features of their syndromes, and the family. had a rapid degenerative clinical course. MPS VII has not been Physical examination at 27 months demonstrated coarse facial mentioned among these diseases and has only been reported in features, macrostomia, a broad filtrum with smooth upper lip, and cases involving NIHF. To our knowledge, this is the first case

74 Journal of Perinatology 2003; 23:73 – 75 Mucopolysaccharidosis Type VII Presenting With Isolated Neonatal Ascites Saxonhouse et al.

report of MPS VII presenting in the neonatal period with isolated (beta-glucuronidase deficiency) presenting as nonimmune hydrops fetalis. ascites. J Pediatr 1982;101:574–6. MPS VII is a lysosomal storage disease in which the enzymatic 4. Molyneux AJ, Blair E, Coleman N, Daish P. Mucopolysaccharidosis type VII defect has been demonstrated in cultured skin fibroblasts and associated with hydrops fetalis: histopathological and ultrastructural features leukocytes of affected patients.3,17,18 From prior reports, it is clear that with genetic implications. J Clin Pathol 1997;50:252–4. there is marked variation in the phenotypic expression of the disease.3 5. Kagie MJ, Kleijer WJ, Huijmans JG, Maaswinkel-Mooy P, Kanhai HH. Beta- glucuronidase deficiency as a cause of fetal hydrops. Am J Med Genet 1992; The patient presented had ascites and inguinal hernias but 42:693–5. demonstrated no other findings at birth to support a diagnosis of 6. Winn HN, Stiller R, Grannum PA, Crane JC, Coster B, Romero R. Isolated MPS VII. However, at 27 months of age, there were features present fetal ascites: prenatal diagnosis and management. Am J Perinatol 1990;7: that clearly demonstrated the syndrome. This underscores the 370–3. importance of follow-up examinations in neonates with idiopathic 7. Gillan JE, Lowden JA, Gaskin K, Cutz E. Congenital ascites as a presenting neonatal ascites. sign of lysosomal storage disease. J Pediatr 1984;104:225–31. Inclusion of MPS VII in the differential diagnosis for isolated 8. Wenger DA, Williams C. Screening for lysosomal disorders. In: Hommes FA, neonatal ascites is of great importance. Potential treatments, editor. Techniques in Diagnostic Human Biochemical Genetics: A Laboratory including marrow transplantation, adeno-associated virus Manual. New York: Wiley; 1990. p. 587–617. gene transfer, or enzyme infusion therapy, can be performed to 9. Moore TR, Tipton EE. Amniotic fluid and nonimmune hydrops fetalis. In: prevent long-term sequelae.14,15 MPS VII is an autosomal recessive Fanaroff AA, Martin RJ, editors. Neonatal–Perinatal Medicine. Diseases of the disease with a 25% recurrence risk for future pregnancies. Therefore, Fetus and Infant. St. Louis: Anne S. Patterson; 1997. p. 312–26 (Vol. 1). 10. Machin GA, et al. Diseases causing fetal and neonatal ascites. Pediatr Pathol genetic counseling can occur earlier with a rapid diagnosis. 1985;4:195–211. Prenatal diagnosis in the first trimester of pregnancy can also be 11. Woodall DL, Birken GA, Williamson K, Lobe TE. Isolated fetal–neonatal 16 offered. abdominal ascites: a sign of intrauterine intussusception. J Pediatr Surg Patients with MPS VII demonstrate by early adulthood a 1987;22:506–7. significant degree of storage within neuronal, 12. Abu-Dalu KI, Tamary H, Livni N, Rivkind AI, Yatziv S. GM1 gangliosidosis glial, and leptomeningeal cells.19 Neuroimaging commonly presenting as neonatal ascites. J Pediatr 1982;100:940–3. demonstrates delayed myelination, atrophy, , and 13. Daneman A, Stringer D, Reilly BJ. Neonatal ascites due to lysosomal storage white matter changes. Atrophic and white matter changes tend to disease. Radiology 1983;149:463–7. occur earlier in patients with MPS VII. In our case, on reevaluation of 14. Daly TM, Ohlemiller KK, Roberts MS, Vogler CA, Sands MS. Prevention of the MRI that was performed at 6 months of age, the findings were systemic clinical disease in MPS VII mice following AAV-mediated neonatal consistent with a diagnosis of MPS VII. gene transfer. Gene Ther 2001;8:1291–8. 15. Vogler C, Barker J, Sands MS, Levy B, Galvin N, Sly WS. Murine muco- polysaccharidosis VII: impact of therapies on the phenotype, clinical course, Acknowledgements and pathology in a model of a lysosomal storage disease. Pediatr Dev Pathol We would like to thank W.B. Cumming (Department of Radiology) for his 2001;4:421–33. assistance with reviewing the plain films and magnetic resonance images, C.A. 16. Bonduelle M, Lissens W, Goossens A, et al. Lysosomal storage diseases Williams (Division of Genetics) for his assistance with the diagnosis and outpatient presenting as transient or persistent hydrops fetalis. Genet Couns 1991;2: management of the patient, and the Biomedical Resource Services at the University 227–32. of Florida Health Science Center for preparing the photograph. 17. Sly WS, Quinton BA, McAlister WH, Rimoin DL. Beta glucuronidase de- ficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J Pediatr 1973;82:249–57. References 18. Beaudet AL, DiFerrante NM, Ferry GD, Nichols BL Jr, Mullins CE. Variation in 1. Casal ML, Wolfe JH. Mucopolysaccharidosis type VII in the developing mouse the phenotypic expression of beta-glucuronidase deficiency. J Pediatr 1975; fetus. Pediatr Res 2000;47:750–6. 86:388–94. 2. Sheridan O, Wortman J, Harvey C, Hayden J, Haskins M. Craniofacial 19. Sferra TJ, Qu G, McNeely D, et al. Recombinant adeno-associated virus- abnormalities in animal models of mucopolysaccharidoses I, VI, and VII. mediated correction of lysosomal storage within the central of J Craniofac Genet Dev Biol 1994;14:7–15. the adult mucopolysaccharidosis type VII mouse. Hum Gene Ther 2000;11: 3. Nelson A, Peterson L, Frampton B, Sly WS. Mucopolysaccharidosis VII 507–19.

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