Clinical observations cell histiocytosis (LCH) and cytomegaly virus (CMV) infection in an infant – what is the chicken? What is the egg? Med Pediatr Oncol 2002;38:223 (abstract). [11] Higgins CR, Tatnall FM, Leigh IM. Vesicular Langerhans cell histiocytosis – an uncommon variant. Clin Exp Dermatol. 1994;19:350–2. [12] Girisch M, Fartasch M, Schroth M, Rauch R, Leipold G, Franz K, et al. Congenital Langerhans-cell histiocytosis
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presenting as a varicella infection. Klin Pediatr 1999;211: 403–5. [13] Johno M, Oishi M, Kohmaru M, Yoshimura K, Ono T. Langerhans cell histiocytosis presenting as a varicelliform eruption over the entire skin. J Dermatol 1994;21:197–204. [14] Scheker LE, Kasteler JS, Callen JP. Neonatal lupus erythematosus mimicking Langerhans cell histiocytosis. Pediatr Dematol 2003;20:164–6.
Fetal hydrops in GM1 gangliosidosis: A case report MARIA TERESA SINELLI, MARIO MOTTA, DONATELLA CATTARELLI, MARIA LUISA CARDONE & GAETANO CHIRICO Division of Neonatology and Neonatal Intensive Care, Spedali Civili, Brescia, Italy
Abstract GM1 gangliosidosis is a rare disorder characterized by deficiency of the b-galactosidase enzyme, with the resulting accumulation of glycolipids, oligosaccharides and especially GM1 ganglioside. It can be classified into three clinical types according to the time of onset: infantile, juvenile and adult form. We report a case of GM1 gangliosidosis presenting with fetal hydrops at 24 wk of gestation. The parents were consanguineous; the baby, born at 35 wk of gestation, was dysmorphic and presented severe generalized oedema. The most common cause of fetal hydrops was excluded. A lysosomal storage disease was suspected, and GM1 gangliosidosis was diagnosed. The child developed severe growth and mental retardation and died when she was 21 mo old. Conclusion: We suggest that the possible association between inborn errors of metabolism and antenatal ascites should be considered, in order to offer genetic counselling due to the high recurrence risk and the availability of early antenatal diagnosis.
Key Words: Fetal hydrops, GM1 gangliosidosis, lysosomal storage disease
Introduction Lysosome storage disease comprises a group of genetic disorders in which certain metabolites accumulate within the cells due to the deficiency of specific lysosomal enzymes. One of these diseases is generalized gangliosidosis or GM1 gangliosidosis, first recognized by O’Brien et al. in 1965 [1]. This disorder is characterized by deficiency of the b-galactosidase enzyme, with the resulting accumulation of glycolipids, oligosaccharides and especially GM1 ganglioside. The levels of GM1 ganglioside are considerably increased in all tissues, particularly in the brain, liver and spleen, causing progressive mental and motor deterioration associated with the impairment of liver function [2]. GM1 gangliosidosis can be classified into three clinical types. In the infantile form, symptoms appear during the first few months of life with growth failure, progressive neurological impairment and death by bronchopneumonia before 2 y of age. Hepatosplenomegaly, bone alterations of the multiple dysostosis type, grotesque facies, cherry-red spots on the retina
and macrocephaly are frequent. In the juvenile form, the onset is delayed and evolution is slower. The progressive neurological deterioration and repeated respiratory infections lead to death before 10 y of age. Bone alterations are less severe; usually there is no hepatosplenomegaly, grotesque facies, macrocephaly or retinal changes. In the adult form, patients start to show progressive cerebellar impairment during adolescence, and evolution is very slow [2]. GM1 gangliosidosis can be detected by urine oligosaccharide chromatography and measurement of b-galactosidase in leukocytes [3]. Although there is no specific treatment, diagnosis permits detection of heterozygotes in the family, appropriate genetic counselling and prenatal diagnosis [2]. We report a case of GM1 gangliosidosis presenting with prenatal hydrops fetalis. Case report The infant was born to a 23-y-old woman after 35 wk and 5 d of gestation. The parents were consanguineous
Correspondence: Gaetano Chirico, Divisione di Neonatologia e TIN, Spedali Civili, 25123 Brescia, Italy. Tel: +39 030 3995219. Fax: +39 030 3700817. E-mail:
[email protected] (Received 12 January 2005; revised 12 January 2005; accepted 28 February 2005) ISSN 0803-5253 print/ISSN 1651-2227 online # 2005 Taylor & Francis DOI: 10.1080/08035250510035625
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Clinical observations
Table I. Case reports.
Case # 1 2 3 4 5 6 7 ( present report)
Prenatal findings (time of detection) None Hydramnios None Bilateral hydrocele and hydramnios (34 wk), 2 dead siblings Transient ascites Transient ascites at (30 wk) Pleural effusion and mild ascites (23 wk)
Neonatal ascites
Hepatosplenomegaly at birth
Family history
Exitus
Yes Yes Yes Yes
Yes No Yes Yes
2 dead siblings 3 dead siblings Previous stillborn ?
4 mo ? 51 d 15 mo
No Yes Yes
Yes No No
Primi gravida Primi gravida 1 sibling well
? 14 mo 21 mo
1, 2: Abu Dalu’s cases, 1982; 3: Guillan’s case, 1984; 4: Vajro’s case, 1990; 5: Bonduelle’s case, 1991; 6: Tasso’s case, 1996; 7: our case.
and of Pakistani origin. An elder sibling is alive and well. During pregnancy the mother, because of disseminated tubercular disease, was treated with isoniazide and rifampicin. At 23 wk of gestation she was admitted to the hospital to undergo T5 laminectomy and the drainage of tubercular paravertebral and prevertebral abscesses. Investigations for hepatitis B surface antigen, HIV, HCV and Parvovirus B19 antibodies, and VDRL were all negative. Laboratory evaluations revealed immunity to CMV, Toxoplasma, herpesvirus 1 and rubella. History of sexually transmitted disease and cytological evaluation of vaginal secretions were negative. The mother’s blood group was 0, Rh positive. Kleihauer test for fetal haemoglobin in the mother’s red cells was less than 0.01%. Isoimmunization and chromosomal abnormalities were excluded by amniocentesis and cordocentesis. An umbilical blood specimen showed fetal blood group 0, Rh positive, negative Coombs test, platelets 314 000/ml, WBC 5300/ml, Hb 10.8 g/dl, Ht 32%, MCV 103 fl. A fetal ultrasonogram, at 23 wk of gestation, showed slight ascites, pleural effusion, thickening of the scalp and skin, and hydropic placenta. Because of worsening of fetal hydrops, induction of delivery was decided at 35 wk. Amniorexis led to the passage of copious amounts of amniotic fluid with meconium traces. After birth, the baby presented severe generalized hypotonia. Apgar scores were 4 at 1 min, 0 at 5 min and, after cardiopulmonary resuscitation, 10 at 10 min. The infant was transferred to the intensive care unit. On admission, physical examination revealed a weight of 3300 g, hypoactivity and hyporeflexia, severe generalized oedema and dysmorphic features (hypertelorism, dolichocephalism, lumbar kyphosis and narrowing of the chest upper diameter). No hepatosplenomegaly or ambiguity of genitalia were found. Laboratory investigation showed: Hb 18.8 g/dl, Ht 58%, MCV 98 fl, platelets 157 000/ml, WBC 7000/ml. Serum albumin concentration was 2.6 g/dl. Glucose, urea, creatinine, triglycerides, cholesterol, bilirubin and liver enzymes were all within normal limits. Cultural findings and Coombs test were negative. Vacuolated lymphocytes were observed in peripheral
blood smears. No cherry-red spot could be visualized on funduscopy. Further investigations (chest X-ray, and cerebral, abdomenal and cardiac ultrasonography) did not detect any organ malformations. Blood culture for Mycobacterium tuberculosis was negative. Because of the exclusion of the most common causes of non-immune hydrops fetalis, a lysosomal storage disease was suspected and proper studies were done. Spot test for mucopolysacchariduria was weakly positive. Urine oligosaccharide chromatography revealed a pattern compatible with GM1 gangliosidosis. The activity of the enzyme b-galactosidase in leukocytes was 4.4 nmol/h/mg (normal value 84–292). Subsequently, the infant showed a latero-cervical swelling due to generalized oedema, and persisting mild ascites. Thereafter, she developed marked hypertension with hyponatraemia and hypernatriuria, high levels of aldosteron, renin and 17 OH-progesteron, both before and after stimulation with ACTH, probably due to renal involvement, a rare finding in GM1 gangliosidosis. Because of these problems, the newborn remained in the intensive care unit for 3 mo. After discharge from the hospital, she was followed for severe mental and growth retardation. She needed ACE inhibitors to control hypertension even if renal function was normal. Abdomen ultrasonography showed persistent ascites and hepatomegaly without spleen enlargement. At 20 mo of age she was admitted to the Department of Paediatric Neuropsychiatry for clonic lateralized crisis unresponsive to fenobarbital. One month later she died from severe respiratory distress. Discussion Non-immunological fetal hydrops (NIHF) is an extremely rare event that occurs in about 1 out of 3000 pregnancies [4]. The most common causes of NIHF are cardiac anomalies (40%), followed by chromosomal abnormalities (10–15%), haematological diseases (10%), chest and abdomen defects, infection, inherited skeletal dysplasias, fetal tumours, and placental
Clinical observations disorders [5]. Inborn errors of metabolism cause only 1% of NIHF. The risk of recurrence in subsequent pregnancies is high [6]. Only a few cases of GM1 gangliosidosis presenting with NIHF have been reported so far; their features are summarized in Table I. It is interesting to note that our patient is the only one to have a very early onset of symptoms (23 wk of gestation) and to have a thorax involvement. GM1 gangliosidosis does not usually have a prenatal presentation; when it happens, the most common finding is fetal or neonatal ascites, although the reason is still unclear. Storage material in Kupffer cells, sinusoidal obstruction and subsequent portal hypertension, or hypoproteinaemia due to hepatocellular dysfunction, have been hypothesized as possible explanations. However, in our case, liver ultrasound and hepatic function were normal. Abu Dalu considered the possibility that lymphatic vessels may enhance permeability resulting in fluid extravasation into the peritoneal cavity. In addition, our baby also had pleural effusion that could not be justified by these hypotheses. An interesting aspect of our patient is the presence of hyponatraemia and hypernatriuria, suggesting a tubular dysfunction, not previously described in GM1 gangliosidosis. The real incidence of metabolic diseases as a cause of fetalis hydrops is unknown. In the past they were often not suspected and many cases were not detected. We suggest that the possible association between inborn errors of metabolism and antenatal ascites should be considered, in order to offer genetic
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counselling due to the high recurrence risk and the availability of early antenatal diagnosis. References [1] O’Brien JS, Stern MB, Landing BH, O’Brien JK, Donnell GN. Generalized gangliosidosis. Am J Dis Child 1965;109:338. [2] O’Brien JS. The gangliosidosis. In: Stambury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, editors. The metabolic basis of inherited disease. 5th ed. New York: McGraw Hill; 1983. p 945–69. [3] Singer HS, Schafer IA. White cell beta-galactosidase activity. N Engl J Med 1970;282:571. [4] Hutchison AA, Drew JH, Yu VYH, Williams ML, Fortune DW, Beischer NA. Nonimmunologic hydrops fetalis: a review of 61 cases. Obstet Gynecol 1982;59:347–52. [5] Heffner LJ, Roberts DJ, Nanowitz M. A premature newborn infant with congenital ascites. New Engl J Med 1997;337:260–7. [6] Norton ME. Nonimmune hydrops fetalis. Semin Perinatol 1994;18:321–32. [7] Abu-Dalu KI, Tamary H, Livni N, Rivkind AI, Yatziv S. GM1 gangliosidosis presenting as neonatal ascites. J Pediatr 1982; 100:940–3. [8] Guillan JE, Lowden JA, Gaskin K, Cutz E. Congenital ascites as a presenting sign of lysosomal storage disease. J Pediatr 1984;104:225–31. [9] Vajro P, Strisciuglio P, Fontanella A, De Vincenzo A. Neonatal ascites disclosing GM1 gangliosidosis. Arch Fr Pediatr 1990; 47:544. [10] Bonduelle M, Lissens W, Goossens A, De Catte L, Foulon W, Denis R, Jauniaux E, Liebaers I. Lysosomal storage diseases presenting as transient or persistent hydrops fetalis. Genet Couns 1991;2:227. [11] Tasso MJ, Martinez-Gutierrez A, Carrascosa C, Vazquez S, Tebar R. GM1-gangliosidosis presenting as nonimmune hydrops fetalis: a case report. J Perinat Med 1996;24:445–9.
Cirrhosis in an infant heterozygous for classical citrullinaemia ˘ LU1, ¨ HEYL EZGU ¨ 1, LEYLA TU ¨ MER1, BUKET DALGIC FATIH SU ¸ 2, ALEV HASANOG 3 3 KEIKO KOBAYASHI & TAKEYORI SAHEKI 1
Department of Paediatric Metabolism and Nutrition, Gazi University Faculty of Medicine, Ankara, Turkey, 2Department of Paediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey, and 3Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan Abstract Classical citrullinaemia is caused by the inherited deficiency of argininosuccinate synthetase. Although varying degrees of liver involvement have been observed in urea cycle defects, including classical citrullinaemia, the co-existence of liver failure in a patient heterozygous for the disease has not been reported before. A female infant was investigated to find out the aetiology of early infantile liver failure. She was later found to be a heterozygote for the G390R mutation found in severe citrullinaemia patients. Conclusion: Classical citrullinaemia is a phenotypically heterogeneous disease, and observations for signs of its presence should be made even in heterozygotes.
Key Words: Infantile, urea cycle disorder, cirrhosis
Correspondence: F. S. Ezgu¨, Gazi University Hospital, Department of Paediatrics, 10th Floor, Besevler, 06500, Ankara, Turkey. Tel: +90 312 2026027. Fax: +90 312 215 01 43. E-mail:
[email protected] (Received 11 December 2004; revised 11 December 2004; accepted 25 February 2005) ISSN 0803-5253 print/ISSN 1651-2227 online # 2005 Taylor & Francis DOI: 10.1080/0803525051003078
