CLINICAL REPORT
A Patient With Simpson–Golabi–Behmel Syndrome, Biliary Cirrhosis and Successful Liver Transplantation Guillaume Jedraszak,1 Muriel Girard,2 Antonio Mellos,2 Djamal-Dine Djeddi,3 Christophe Chardot,4 Audrey Vanrenterghem,3 Marie-Pierre Moizard,5 Jean Gondry,6 Henri Sevestre,7 Michele Mathieu-Dramard,1 Florence Lacaille,2 and Benedicte Demeer1* 1
Medical Genetics Unit, Centre Hospitalier Universitaire d’Amiens, Amiens, France
2
Paediatric Hepatogastroenterology-Nutrition Unit, Necker-Enfants-Malades Hospital, Paris, France
3
Paediatric Hepatogastroenterology Unit, Centre Hospitalier Universitaire d’Amiens, Amiens, France Paediatric Surgical Unit, Necker-Enfants-Malades Hospital, Paris, France 5 Service de ge´ne´tique, INSERM U930–CHRU, Tours, France 4
6
Prenatal Diagnosis Unit, Camille Desmoulins Maternity Hospital, CHU d’Amiens/Jules Verne University, Amiens, France Pathology Department, Centre Hospitalier Universitaire d’Amiens, Amiens, France
7
Manuscript Received: 20 April 2013; Manuscript Accepted: 29 September 2013
Simpson–Golabi–Behmel syndrome type 1 (SGBS1) -OMIM 312870- is a rare X-linked inherited overgrowth syndrome caused by a loss of function mutation in the GPC3 gene. Affected patients present a variable phenotype with pre- and post-natal macrosomia, distinctive facial dysmophism, organomegaly, and multiple congenital anomalies. Intellectual disability is not constant. About 10% of patients have an increased risk of developing embryonic tumors in early childhood. Only one case of biliary disease has been described so far. GPC3 is localized on Xq26. It encodes for glypican 3, a heparan sulfate proteoglycan, which among its different known roles, negatively regulates liver regeneration and hepatocyte proliferation. This report concerns a male with a SGBS1, carrier of a GPC3 pathogenic mutation, and neonatal liver disease, who developed an early biliary cirrhosis. Together with the associated risk of cancer and developmental delay, liver transplantation was discussed and then successfully performed at the age of 19 months. A hypothesis on the role of GPC3 in the patient’s liver disease is also proposed. Ó 2013 Wiley Periodicals, Inc.
Key words: Simpson–Golabi–Behmel syndrome; biliary cirrhosis; liver transplantation; GPC3
INTRODUCTION Simpson–Golabi–Behmel syndrome (SGBS) -OMIM 312870-, first reported by Simpson et al. [1975], is a rare X-linked inherited overgrowth syndrome caused by a loss-of-function mutation in the GPC3 (SGBS type 1) [Pilia et al., 1996] or GPC4 gene (SGBS type 2) [Waterson et al., 2010]. Patients present a variable phenotype with pre- and post-natal macrosomia, distinctive facial dysmorphism,
Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Jedraszak G, Girard M, Mellos A, Djeddi D-D, Chardot C, Vanrenterghem A, Moizard M-P, Gondry J, Sevestre H, Mathieu-Dramard M, Lacaille F, Demeer B. 2014. A patient with Simpson–Golabi– Behmel syndrome, biliary cirrhosis, and successful liver transplantation. Am J Med Genet Part A 164A:774–777.
organomegaly, and numerous congenital anomalies, that is, diaphragmatic hernia, heart or renal defect, genito-urinary tract or gastrointestinal malformations, skeletal or hand abnormalities [Golabi et al., 2011; Cottereau et al., 2013]. Intellectual disability is not constant [Neri et al., 1998]. About 10% of patients develop embryonic tumors in early childhood [Li et al., 2001]. A single case of biliary disease (choledochal cyst) has been reported [Kim et al., 1999]. GPC3 is localized on Xq26 and encodes for Glypican-3, a glycosylphosphatidylinositol-linked cell surface heparan sulfate
Correspondence to: Be´ne´dicte Demeer, Unite´ de Ge´ne´tique me´dicale, pole Pe´diatrie, Hopital nord, CHU Amiens, place victor Pauchet, Amiens 80054, France. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 19 December 2013 DOI 10.1002/ajmg.a.36335
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JEDRASZAK ET AL.
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proteoglycan [Pilia et al., 1996] which, among other functions, negatively regulate liver regeneration and hepatocyte proliferation. This report concerns a male infant with Simpson–Golabi–Behmel syndrome type 1, carrier of a GPC3 mutation. He had neonatal liver disease, and developed a biliary cirrhosis early on. Liver transplantation was discussed, considering the risks of cancer and intellectual disability, and performed successfully when the child was 19 months of age. A hypothesis on the role of GPC3 in this patient’s liver disease is proposed.
CLINICAL REPORT The boy was the first child of healthy unrelated parents, with healthy half-sibs on each parental side, and no known family history. Prenatal history was marked by the discovery of macrosomia, polyhydramnios, and bilateral nephromegaly at 27 gestational weeks (GW). He was delivered at 36 GW by cesarean section. Birth parameters were: weight 4,105 g (>97th centile), height 52 cm (>97th centile), and occipitofrontal circumference (OFC) 37 cm (>97th centile). On examination, he had hypotonia, facial dysmorphism with coarse features, hypertelorism, short nose with anteverted nares and macrosomia. Three abdominal supernumerary nipples, an abdominal diastasis recti and a left cryptorchidism were noted. Extremities were normal. He had feeding difficulties but no neonatal hypoglycemia was observed. Abdominal ultrasound confirmed a bilateral nephromegaly and no other visceromegaly. A Simpson–Golabi–Behmel syndrome was clinically suspected and confirmed by the study of the GPC3 gene, with a c.662delA (p. Lys221SerfsX13) mutation found in exon 3. The boy became progressively jaundiced, had dark urine, but never had acholic stools. On the abdominal ultrasound (US) moderately hyper-echogenic portal tracts, without dilatation of bile ducts, were observed, and no gallbladder was seen. At the age of 6 weeks, liver tests showed total and conjugated bilirubin 93/ 82 mM/L (N < 21 mM/L/N < 18 mM/L), GGT 217 IU/L (N < 51 IU/L), AST 126 IU/L (
A Patient With Simpson–Golabi–Behmel Syndrome, Biliary Cirrhosis and Successful Liver Transplantation Guillaume Jedraszak,1 Muriel Girard,2 Antonio Mellos,2 Djamal-Dine Djeddi,3 Christophe Chardot,4 Audrey Vanrenterghem,3 Marie-Pierre Moizard,5 Jean Gondry,6 Henri Sevestre,7 Michele Mathieu-Dramard,1 Florence Lacaille,2 and Benedicte Demeer1* 1
Medical Genetics Unit, Centre Hospitalier Universitaire d’Amiens, Amiens, France
2
Paediatric Hepatogastroenterology-Nutrition Unit, Necker-Enfants-Malades Hospital, Paris, France
3
Paediatric Hepatogastroenterology Unit, Centre Hospitalier Universitaire d’Amiens, Amiens, France Paediatric Surgical Unit, Necker-Enfants-Malades Hospital, Paris, France 5 Service de ge´ne´tique, INSERM U930–CHRU, Tours, France 4
6
Prenatal Diagnosis Unit, Camille Desmoulins Maternity Hospital, CHU d’Amiens/Jules Verne University, Amiens, France Pathology Department, Centre Hospitalier Universitaire d’Amiens, Amiens, France
7
Manuscript Received: 20 April 2013; Manuscript Accepted: 29 September 2013
Simpson–Golabi–Behmel syndrome type 1 (SGBS1) -OMIM 312870- is a rare X-linked inherited overgrowth syndrome caused by a loss of function mutation in the GPC3 gene. Affected patients present a variable phenotype with pre- and post-natal macrosomia, distinctive facial dysmophism, organomegaly, and multiple congenital anomalies. Intellectual disability is not constant. About 10% of patients have an increased risk of developing embryonic tumors in early childhood. Only one case of biliary disease has been described so far. GPC3 is localized on Xq26. It encodes for glypican 3, a heparan sulfate proteoglycan, which among its different known roles, negatively regulates liver regeneration and hepatocyte proliferation. This report concerns a male with a SGBS1, carrier of a GPC3 pathogenic mutation, and neonatal liver disease, who developed an early biliary cirrhosis. Together with the associated risk of cancer and developmental delay, liver transplantation was discussed and then successfully performed at the age of 19 months. A hypothesis on the role of GPC3 in the patient’s liver disease is also proposed. Ó 2013 Wiley Periodicals, Inc.
Key words: Simpson–Golabi–Behmel syndrome; biliary cirrhosis; liver transplantation; GPC3
INTRODUCTION Simpson–Golabi–Behmel syndrome (SGBS) -OMIM 312870-, first reported by Simpson et al. [1975], is a rare X-linked inherited overgrowth syndrome caused by a loss-of-function mutation in the GPC3 (SGBS type 1) [Pilia et al., 1996] or GPC4 gene (SGBS type 2) [Waterson et al., 2010]. Patients present a variable phenotype with pre- and post-natal macrosomia, distinctive facial dysmorphism,
Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Jedraszak G, Girard M, Mellos A, Djeddi D-D, Chardot C, Vanrenterghem A, Moizard M-P, Gondry J, Sevestre H, Mathieu-Dramard M, Lacaille F, Demeer B. 2014. A patient with Simpson–Golabi– Behmel syndrome, biliary cirrhosis, and successful liver transplantation. Am J Med Genet Part A 164A:774–777.
organomegaly, and numerous congenital anomalies, that is, diaphragmatic hernia, heart or renal defect, genito-urinary tract or gastrointestinal malformations, skeletal or hand abnormalities [Golabi et al., 2011; Cottereau et al., 2013]. Intellectual disability is not constant [Neri et al., 1998]. About 10% of patients develop embryonic tumors in early childhood [Li et al., 2001]. A single case of biliary disease (choledochal cyst) has been reported [Kim et al., 1999]. GPC3 is localized on Xq26 and encodes for Glypican-3, a glycosylphosphatidylinositol-linked cell surface heparan sulfate
Correspondence to: Be´ne´dicte Demeer, Unite´ de Ge´ne´tique me´dicale, pole Pe´diatrie, Hopital nord, CHU Amiens, place victor Pauchet, Amiens 80054, France. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 19 December 2013 DOI 10.1002/ajmg.a.36335
774
JEDRASZAK ET AL.
775
proteoglycan [Pilia et al., 1996] which, among other functions, negatively regulate liver regeneration and hepatocyte proliferation. This report concerns a male infant with Simpson–Golabi–Behmel syndrome type 1, carrier of a GPC3 mutation. He had neonatal liver disease, and developed a biliary cirrhosis early on. Liver transplantation was discussed, considering the risks of cancer and intellectual disability, and performed successfully when the child was 19 months of age. A hypothesis on the role of GPC3 in this patient’s liver disease is proposed.
CLINICAL REPORT The boy was the first child of healthy unrelated parents, with healthy half-sibs on each parental side, and no known family history. Prenatal history was marked by the discovery of macrosomia, polyhydramnios, and bilateral nephromegaly at 27 gestational weeks (GW). He was delivered at 36 GW by cesarean section. Birth parameters were: weight 4,105 g (>97th centile), height 52 cm (>97th centile), and occipitofrontal circumference (OFC) 37 cm (>97th centile). On examination, he had hypotonia, facial dysmorphism with coarse features, hypertelorism, short nose with anteverted nares and macrosomia. Three abdominal supernumerary nipples, an abdominal diastasis recti and a left cryptorchidism were noted. Extremities were normal. He had feeding difficulties but no neonatal hypoglycemia was observed. Abdominal ultrasound confirmed a bilateral nephromegaly and no other visceromegaly. A Simpson–Golabi–Behmel syndrome was clinically suspected and confirmed by the study of the GPC3 gene, with a c.662delA (p. Lys221SerfsX13) mutation found in exon 3. The boy became progressively jaundiced, had dark urine, but never had acholic stools. On the abdominal ultrasound (US) moderately hyper-echogenic portal tracts, without dilatation of bile ducts, were observed, and no gallbladder was seen. At the age of 6 weeks, liver tests showed total and conjugated bilirubin 93/ 82 mM/L (N < 21 mM/L/N < 18 mM/L), GGT 217 IU/L (N < 51 IU/L), AST 126 IU/L (
