Case Report
161
Fanconi–Bickel Syndrome: Two Pakistani Patients Presenting with Hypophosphatemic Rickets Bushra Afroze1
Margaret Chen2
1 Department of Pediatrics and Child Health, Aga Khan University
Hospital, Karachi, Pakistan 2 Prevention Genetics, Marshfield, Wisconsin, United States
Address for correspondence Bushra Afroze, MBBS, FCPS, Department of Pediatrics and Child Health, Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan (e-mail: [email protected]).
Abstract Keywords
► Fanconi–Bickel syndrome ► hypophosphatemic rickets ► Pakistani patient
Fanconi–Bickel syndrome is a rare inherited disorder characterized by hepatorenal glycogen accumulation, renal tubular dysfunction, growth failure, and impaired utilization of glucose and galactose. We report the first two children with Fanconi– Bickel syndrome from Pakistan who presented with classical features of Fanconi–Bickel Syndrome. Both patients were found to be homozygous for a single nucleotide deletion in the SLC2A2 gene defined as c.339delC. This mutation was previously described in an Arab patient who was initially presented as permanent neonatal diabetes mellitus before developing classical features of Fanconi–Bickel syndrome.
Introduction Fanconi–Bickel Syndrome (FBS) (OMIM 227810) is a rare, autosomal recessive disorder caused by mutations in the glucose and galactose transporter gene SLC2A2, which is also called the facilitative glucose transporter 2 (GLUT2) gene.1,2 GLUT2 codes for the 524-amino acid glucose transporter protein 2 that is expressed in hepatocytes, pancreatic β-cells, enterocytes, and renal tubular cells.3 Mutations in the SLC2A2 gene result in defective glucose metabolism leading to hepatomegaly secondary to glycogen accumulation, fasting hypoglycemia, impaired glucose tolerance, short stature, and proximal renal tubular dysfunction including glucosuria, phosphaturia, bicarbonate wasting, and aminoaciduria. Global frequency of FBS is not known. The disease is predicted to be extremely rare since relatively few cases have been reported, and FBS can be detected by a positive newborn screening result for galactosemia. A little more than 100 cases of FBS have been reported from North America, Europe, Turkey, Israel, Japan, and Arabian countries.4 However, there is no case reported from Pakistan. We report two children from the same consanguineous family with FBS (Individuals V-3 and V7, ►Fig. 1). They presented with clinical features of rickets, severe bone pains leading to non-ambulation, short stature, and
received December 5, 2014 accepted after revision November 3, 2015 published online June 3, 2016
hepatomegaly. Both patients had biochemical features of fasting hypoglycemia, hypophosphatemia, phosphaturia, glucosuria, and impaired glucose tolerance. Histopathological features of liver biopsy supporting glycogen storage was seen in one patient. Both were found to be apparently homozygous for a single nucleotide deletion in the SLC2A2 gene defined as c.339delC. This microdeletion is predicted to result in a frameshift and premature protein termination (p.Phe114Leufs16).
Case Report Patient 1 A 5-year-old girl, the fourth child of first-cousin parents, was seen in the metabolic clinic for medial bowing of the legs and inability to walk, secondary to severe bone pain. Her parents reported a spontaneous pathological fracture of the right femur at age 3.5 years, after which she was unable to walk without support. On examination, her weight was 12.2 kg ( T
p.Arg365
Indian
Turkey
1,12 ; (reviewed in 10)
c.1330T > C
p.Trp444Arg
Indian
Japan
13,15
c.1375–10 _1429delins10
(Deletion/insertion encompassing intron 9 splice acceptor site and 5′ end of exon 10)
Indian
India
14
FBS can be found in ethnically diverse populations, and no mutations are predominant.9 For an extensive list of SLC2A2 mutations found in the Middle and Far East, the reader can refer to the recent review by Al-Haggar.10 To our knowledge, the family presented here represents the first reported cases of FBS in Pakistan. However, in recent years, at least four individuals with FBS from neighboring India have also been reported.11–14 It is worth noting that two of the four patients were found to be homozygous for mutations previously identified in individuals from other countries (►Table 2). The first patient was a 6-year-old girl seen in the genetics clinic in Vellore who was found to be homozygous for a c.1093C > T nonsense mutation that was previously identified in a boy from Turkey.1,12 The second patient was a 4-yearold boy from Maharashtra who was found to be homozygous for a c.1330T > C missense mutation that was originally identified in an affected Japanese individual.13,15 The c.339delC mutation found in our family has been previously reported in an Arab patient.16 While single nucleotide deletions commonly occur within DNA regions containing a polynucleotide tract, examination of the SLC2A2 sequence surrounding the c.339 nucleotide reveals no such repetitive element. More likely, the mutation reported in our family represents population migration of the Arab haplotype to Pakistan, as opposed to an identical, de novo founder mutation arising via a common mechanism. It is worth noting that Arab traders have been in contact with the Indian subcontinent since the 600s. Furthermore, in 711, the Umayyad dynasty extended control into Sindh, the land around the Indus river in the northwestern part of the subcontinent, in present-day Pakistan. Thus, the presence of an Arab genetic haplotype in Pakistan would not be unexpected and has been suggested by disease-causing mutations in other genes. For example, for TRAPPC9-associated nonsyndromic autosomal recessive mental retardation, the same homozygous nonsense mutation (c.1422C > T; p.R475X) has been reported in both Israeli Arab and Pakistani kindred.17,18 The c.339delC mutation was previously reported as being associated with permanent neonatal diabetes mellitus (PNDM).16 On direct inquiry about the symptoms of PNDM from parents of both of our patients, no concerns were reported in the perinatal period nor were any clinical clues
found suggestive of PNDM. Both pairs of parents denied any need to seek medical care in early infancy and reported initial satisfactory growth. However, failure to thrive was noted in late infancy. A small number of patients with SLC2A2 mutations are known to have neonatal diabetes as initial presentation of FBS, before the typical findings of FBS become evident. It is not known if the majority of FBS patients who are not diagnosed with neonatal diabetes have mild resolving diabetes that is undetected or, despite the fluctuation of glucose levels seen in FBS, do not meet the diagnostic criteria for diabetes.19 Overall, prognosis of FBS patients for survival to adulthood seems favorable. Even successful pregnancy has been reported in a patient with FBS.20 However, there is no specific treatment for this disorder of carbohydrate metabolism. Symptomatic replacement of phosphate, bicarbonate, and vitamin D along with avoidance of fasting and small frequent meals provide relief to patients. Symptomatic improvement was noted in our patients on oral phosphate replacement through Joulie’s solution and 1,25- dihydroxy vitamin D3 at the 5 month follow-up.
References 1 Santer R, Schneppenheim R, Dombrowski A, Götze H, Steinmann B,
2
3
4 5
6
7
Schaub J Jr. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 1997;17(3):324–326 Online Mendelian Inheritance in Man. OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 227810. 2006. World Wide Web URL: http://omim.org/ Sakamoto O, Ogawa E, Ohura T, et al. Mutation analysis of the GLUT2 gene in patients with Fanconi-Bickel syndrome. Pediatr Res 2000;48(5):586–589 Pascual JM. [Glucose transport hereditary diseases]. Med Clin (Barc) 2006;127(18):709–714 Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect 2014;3(1):R13–R30 Fanconi G, Bickel H. Chronic aminoaciduria (amino acid diabetes or nephrotic-glucosuric dwarfism) in glycogen storage and cystine disease. Helv Paediatr Acta 1949;4(5):359–396 Santer R, Schneppenheim R, Suter D, Schaub J, Steinmann B. Fanconi-Bickel syndrome—the original patient and his natural Journal of Pediatric Genetics
Vol. 5
No. 3/2016
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Table 2 Summary of recently-identified SLC2A2 mutations in Pakistan and India
Fanconi–Bickel Syndrome
8 9
10 11
12
13 14
Afroze, Chen
history, historical steps leading to the primary defect, and a review of the literature. Eur J Pediatr 1998;157(10):783–797 Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: 2008 update. Genome Med 2009;1(1):13 Santer R, Groth S, Kinner M, et al. The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome. Hum Genet 2002; 110(1):21–29 Al-Haggar M. Fanconi-Bickel syndrome as an example of marked allelic heterogeneity. World J Nephrol 2012;1(3):63–68 Gopalakrishnan A, Kumar M, Krishnamurthy S, Sakamoto O, Srinivasan S. Fanconi-Bickel syndrome in a 3-year-old Indian boy with a novel mutation in the GLUT2 gene. Clin Exp Nephrol 2011;15(5):745–748 Ekbote AV, Mandal K, Agarwal I, Sinha R, Danda S. Fanconi-Bickel Syndrome: mutation in an Indian patient. Indian J Pediatr 2012; 79(6):810–812 Kehar M, Bijarnia S, Ellard S, et al. Fanconi-Bickel syndrome - mutation in SLC2A2 gene. Indian J Pediatr 2014;81(11):1237–1239 Kehar M, Bijarnia S, Ellard S, et al. Fanconi-Bickel syndrome— mutation in SLC2A2 gene. Indian J Pediatr 2014;81(11):1237–1239
Journal of Pediatric Genetics
Vol. 5
No. 3/2016
15 Tsuda M, Kitasawa E, Ida H, Eto Y, Owada M. A newly recognized
16
17
18
19
20
missense mutation in the GLUT2 gene in a patient with FanconiBickel syndrome. Eur J Pediatr 2000;159(11):867 Habeb AM, Al-Magamsi MSF, Eid IM, et al. Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia. Pediatr Diabetes 2012;13(6):499–505 Mochida GH, Mahajnah M, Hill AD, et al. A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am J Hum Genet 2009;85(6): 897–902 Mir A, Kaufman L, Noor A, et al. Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-β-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet 2009;85(6):909–915 Sansbury FH, Flanagan SE, Houghton JAL, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia 2012;55(9): 2381–2385 Pena L, Charrow J. Fanconi-Bickel syndrome: report of life history and successful pregnancy in an affected patient. Am J Med Genet A 2011;155A(2):415–417
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
166
161
Fanconi–Bickel Syndrome: Two Pakistani Patients Presenting with Hypophosphatemic Rickets Bushra Afroze1
Margaret Chen2
1 Department of Pediatrics and Child Health, Aga Khan University
Hospital, Karachi, Pakistan 2 Prevention Genetics, Marshfield, Wisconsin, United States
Address for correspondence Bushra Afroze, MBBS, FCPS, Department of Pediatrics and Child Health, Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan (e-mail: [email protected]).
Abstract Keywords
► Fanconi–Bickel syndrome ► hypophosphatemic rickets ► Pakistani patient
Fanconi–Bickel syndrome is a rare inherited disorder characterized by hepatorenal glycogen accumulation, renal tubular dysfunction, growth failure, and impaired utilization of glucose and galactose. We report the first two children with Fanconi– Bickel syndrome from Pakistan who presented with classical features of Fanconi–Bickel Syndrome. Both patients were found to be homozygous for a single nucleotide deletion in the SLC2A2 gene defined as c.339delC. This mutation was previously described in an Arab patient who was initially presented as permanent neonatal diabetes mellitus before developing classical features of Fanconi–Bickel syndrome.
Introduction Fanconi–Bickel Syndrome (FBS) (OMIM 227810) is a rare, autosomal recessive disorder caused by mutations in the glucose and galactose transporter gene SLC2A2, which is also called the facilitative glucose transporter 2 (GLUT2) gene.1,2 GLUT2 codes for the 524-amino acid glucose transporter protein 2 that is expressed in hepatocytes, pancreatic β-cells, enterocytes, and renal tubular cells.3 Mutations in the SLC2A2 gene result in defective glucose metabolism leading to hepatomegaly secondary to glycogen accumulation, fasting hypoglycemia, impaired glucose tolerance, short stature, and proximal renal tubular dysfunction including glucosuria, phosphaturia, bicarbonate wasting, and aminoaciduria. Global frequency of FBS is not known. The disease is predicted to be extremely rare since relatively few cases have been reported, and FBS can be detected by a positive newborn screening result for galactosemia. A little more than 100 cases of FBS have been reported from North America, Europe, Turkey, Israel, Japan, and Arabian countries.4 However, there is no case reported from Pakistan. We report two children from the same consanguineous family with FBS (Individuals V-3 and V7, ►Fig. 1). They presented with clinical features of rickets, severe bone pains leading to non-ambulation, short stature, and
received December 5, 2014 accepted after revision November 3, 2015 published online June 3, 2016
hepatomegaly. Both patients had biochemical features of fasting hypoglycemia, hypophosphatemia, phosphaturia, glucosuria, and impaired glucose tolerance. Histopathological features of liver biopsy supporting glycogen storage was seen in one patient. Both were found to be apparently homozygous for a single nucleotide deletion in the SLC2A2 gene defined as c.339delC. This microdeletion is predicted to result in a frameshift and premature protein termination (p.Phe114Leufs16).
Case Report Patient 1 A 5-year-old girl, the fourth child of first-cousin parents, was seen in the metabolic clinic for medial bowing of the legs and inability to walk, secondary to severe bone pain. Her parents reported a spontaneous pathological fracture of the right femur at age 3.5 years, after which she was unable to walk without support. On examination, her weight was 12.2 kg ( T
p.Arg365
Indian
Turkey
1,12 ; (reviewed in 10)
c.1330T > C
p.Trp444Arg
Indian
Japan
13,15
c.1375–10 _1429delins10
(Deletion/insertion encompassing intron 9 splice acceptor site and 5′ end of exon 10)
Indian
India
14
FBS can be found in ethnically diverse populations, and no mutations are predominant.9 For an extensive list of SLC2A2 mutations found in the Middle and Far East, the reader can refer to the recent review by Al-Haggar.10 To our knowledge, the family presented here represents the first reported cases of FBS in Pakistan. However, in recent years, at least four individuals with FBS from neighboring India have also been reported.11–14 It is worth noting that two of the four patients were found to be homozygous for mutations previously identified in individuals from other countries (►Table 2). The first patient was a 6-year-old girl seen in the genetics clinic in Vellore who was found to be homozygous for a c.1093C > T nonsense mutation that was previously identified in a boy from Turkey.1,12 The second patient was a 4-yearold boy from Maharashtra who was found to be homozygous for a c.1330T > C missense mutation that was originally identified in an affected Japanese individual.13,15 The c.339delC mutation found in our family has been previously reported in an Arab patient.16 While single nucleotide deletions commonly occur within DNA regions containing a polynucleotide tract, examination of the SLC2A2 sequence surrounding the c.339 nucleotide reveals no such repetitive element. More likely, the mutation reported in our family represents population migration of the Arab haplotype to Pakistan, as opposed to an identical, de novo founder mutation arising via a common mechanism. It is worth noting that Arab traders have been in contact with the Indian subcontinent since the 600s. Furthermore, in 711, the Umayyad dynasty extended control into Sindh, the land around the Indus river in the northwestern part of the subcontinent, in present-day Pakistan. Thus, the presence of an Arab genetic haplotype in Pakistan would not be unexpected and has been suggested by disease-causing mutations in other genes. For example, for TRAPPC9-associated nonsyndromic autosomal recessive mental retardation, the same homozygous nonsense mutation (c.1422C > T; p.R475X) has been reported in both Israeli Arab and Pakistani kindred.17,18 The c.339delC mutation was previously reported as being associated with permanent neonatal diabetes mellitus (PNDM).16 On direct inquiry about the symptoms of PNDM from parents of both of our patients, no concerns were reported in the perinatal period nor were any clinical clues
found suggestive of PNDM. Both pairs of parents denied any need to seek medical care in early infancy and reported initial satisfactory growth. However, failure to thrive was noted in late infancy. A small number of patients with SLC2A2 mutations are known to have neonatal diabetes as initial presentation of FBS, before the typical findings of FBS become evident. It is not known if the majority of FBS patients who are not diagnosed with neonatal diabetes have mild resolving diabetes that is undetected or, despite the fluctuation of glucose levels seen in FBS, do not meet the diagnostic criteria for diabetes.19 Overall, prognosis of FBS patients for survival to adulthood seems favorable. Even successful pregnancy has been reported in a patient with FBS.20 However, there is no specific treatment for this disorder of carbohydrate metabolism. Symptomatic replacement of phosphate, bicarbonate, and vitamin D along with avoidance of fasting and small frequent meals provide relief to patients. Symptomatic improvement was noted in our patients on oral phosphate replacement through Joulie’s solution and 1,25- dihydroxy vitamin D3 at the 5 month follow-up.
References 1 Santer R, Schneppenheim R, Dombrowski A, Götze H, Steinmann B,
2
3
4 5
6
7
Schaub J Jr. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 1997;17(3):324–326 Online Mendelian Inheritance in Man. OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 227810. 2006. World Wide Web URL: http://omim.org/ Sakamoto O, Ogawa E, Ohura T, et al. Mutation analysis of the GLUT2 gene in patients with Fanconi-Bickel syndrome. Pediatr Res 2000;48(5):586–589 Pascual JM. [Glucose transport hereditary diseases]. Med Clin (Barc) 2006;127(18):709–714 Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect 2014;3(1):R13–R30 Fanconi G, Bickel H. Chronic aminoaciduria (amino acid diabetes or nephrotic-glucosuric dwarfism) in glycogen storage and cystine disease. Helv Paediatr Acta 1949;4(5):359–396 Santer R, Schneppenheim R, Suter D, Schaub J, Steinmann B. Fanconi-Bickel syndrome—the original patient and his natural Journal of Pediatric Genetics
Vol. 5
No. 3/2016
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Table 2 Summary of recently-identified SLC2A2 mutations in Pakistan and India
Fanconi–Bickel Syndrome
8 9
10 11
12
13 14
Afroze, Chen
history, historical steps leading to the primary defect, and a review of the literature. Eur J Pediatr 1998;157(10):783–797 Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: 2008 update. Genome Med 2009;1(1):13 Santer R, Groth S, Kinner M, et al. The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome. Hum Genet 2002; 110(1):21–29 Al-Haggar M. Fanconi-Bickel syndrome as an example of marked allelic heterogeneity. World J Nephrol 2012;1(3):63–68 Gopalakrishnan A, Kumar M, Krishnamurthy S, Sakamoto O, Srinivasan S. Fanconi-Bickel syndrome in a 3-year-old Indian boy with a novel mutation in the GLUT2 gene. Clin Exp Nephrol 2011;15(5):745–748 Ekbote AV, Mandal K, Agarwal I, Sinha R, Danda S. Fanconi-Bickel Syndrome: mutation in an Indian patient. Indian J Pediatr 2012; 79(6):810–812 Kehar M, Bijarnia S, Ellard S, et al. Fanconi-Bickel syndrome - mutation in SLC2A2 gene. Indian J Pediatr 2014;81(11):1237–1239 Kehar M, Bijarnia S, Ellard S, et al. Fanconi-Bickel syndrome— mutation in SLC2A2 gene. Indian J Pediatr 2014;81(11):1237–1239
Journal of Pediatric Genetics
Vol. 5
No. 3/2016
15 Tsuda M, Kitasawa E, Ida H, Eto Y, Owada M. A newly recognized
16
17
18
19
20
missense mutation in the GLUT2 gene in a patient with FanconiBickel syndrome. Eur J Pediatr 2000;159(11):867 Habeb AM, Al-Magamsi MSF, Eid IM, et al. Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia. Pediatr Diabetes 2012;13(6):499–505 Mochida GH, Mahajnah M, Hill AD, et al. A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am J Hum Genet 2009;85(6): 897–902 Mir A, Kaufman L, Noor A, et al. Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-β-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet 2009;85(6):909–915 Sansbury FH, Flanagan SE, Houghton JAL, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia 2012;55(9): 2381–2385 Pena L, Charrow J. Fanconi-Bickel syndrome: report of life history and successful pregnancy in an affected patient. Am J Med Genet A 2011;155A(2):415–417
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
166
