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Dedicator of cytokinesis 8 deficiency: A predisposition to sclerosing cholangitis
Clinical Immunology (2014) 155, 71–73
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
LETTER TO THE EDITOR Dedicator of cytokinesis 8 deficiency: A predisposition to sclerosing cholangitis KEYWORDS DOCK8; Sclerosing cholangitis; Cryptosporidium
Dear Editor
Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive combined immunodeficiency, caused by a heterogeneous group of defects in the DOCK8 gene. The molecular basis of this disease was described in 2009 [1,2]. Immunological features include impaired T cell expansion, T and B cell lymphopenia, low IgM, variable IgG, functional antibody abnormalities, hyper-immunoglobulin E and eosinophilia. The clinical picture is typically one of recurrent viral infections particularly affecting the skin, sino-pulmonary bacterial infections, atopy and increased susceptibility to malignancy. In addition, autoimmunity and neurological abnormalities have been observed [3,4]. Sclerosing cholangitis associated with DOCK8 deficiency was described in two unrelated Turkish children in 2012 [5]. We describe two further children with DOCK8 deficiency and sclerosing cholangitis, providing additional evidence to support this clinical association (Table 1). The first child (A) aged 7 presented with cough, faltering growth and paronychia. He had a history of eczema from the age of 2 years, and recurrent cough from the age of 4 years. On presentation he had bronchiectasis. His clinical course was complicated by recurrent herpes simplex virus, bacterial and fungal skin infections, eczematous flares, food intolerances, reactive airway disease and type 1 hypersensitivity reactions with no cause identified. He had CD4 lymphopenia, low IgM, normal IgA, and normal IgG but with increased IgG1 and low IgG2 subclasses, eosinophilia and elevated IgE. At the age of 13, eleven years after his first symptoms, he presented with weight loss, reduced appetite and abdominal pain, exacerbated by eating. He had mildly elevated inflammatory markers and liver enzymes and ultrasound revealed a thickened gallbladder with filling defects. Magnetic resonance
http://dx.doi.org/10.1016/j.clim.2014.09.001 1521-6616/© 2014 Elsevier Inc. All rights reserved.
imaging, endoscopic retrograde cholangio-pancreatography (ERCP) and liver biopsy were all consistent with a diagnosis of sclerosing cholangitis. Cryptosporidium, which had not been identified previously, was isolated from bile fluid obtained at ERCP. His symptoms resolved with conservative management and he is currently awaiting hematopoietic stem cell transplantation (HSCT). The second child (B) presented with Haemophilus influenzae septicemia and septic arthritis at 2 years. Subsequent problems included bronchiectasis, Pneumocystis jiroveci pneumonitis, a further H. influenzae septicemia, severe molluscum contagiosum and chronic diarrhea secondary to Cryptosporidium. He was severely atopic, with eczema, asthma and numerous allergies including anaphylaxis to peanuts. He had CD4 lymphopenia, low IgM, increased IgA, and normal IgG including subclasses. He did not have eosinophilia but had elevated IgE. At 8 years of age discussion about transplantation was initiated, and he underwent ERCP and liver biopsy in light of previous Cryptosporidium infection. At the time, he had no gastrointestinal symptoms, normal liver function and no evidence of infection. Intrahepatic cholangiopathy was demonstrated, which was mild and predominantly involved the third and fourth order ducts. He was commenced on ursodeoxycholic acid, and continued azithromycin as prophylaxis for Cryptosporidium. Sclerosing cholangitis slightly worsened until age 10 when he successfully underwent HSCT and thereafter improved over 5 years. He has a younger sibling with an identical mutation who also had Cryptosporidium in the stool but had no evidence of liver pathology. Immunodeficiency was suspected earlier than in her brother and supportive care commenced and 4 years after her initial presentation she successfully underwent HSCT. Taking these two cases together with those reported previously, there is no common mutation and they represent three ethnicities. Three of the four had Cryptosporidium identified. In one child there was a significant clinical presentation with acute weight loss and abdominal cramps and Cryptosporidium was only isolated from bile duct fluid. However the other had no symptoms at the time of diagnosis of sclerosing cholangitis, but had a known history of diarrhea associated with Cryptosporidium. Interestingly the younger sibling of Child B, who has an identical mutation and was infected with Cryptosporidium, did not develop sclerosing cholangitis. She, however, had a prompt ERCP and started azithromycin and ursodeoxycholic acid within 1 year of her
72 Table 1
Letter to the Editor Relevant clinical and laboratory findings in two children with DOCK8 deficiency and sclerosing cholangitis.
Ethnicity Consanguinity Age of onset of symptoms (years) Time to diagnosis of SC (years) DOCK8 mutation Gastrointestinal infections Poor growth Abdominal pain Reduced appetite Clinical examination Liver function prior to diagnosis of sclerosing cholangitis a
Virology Gallbladder & biliary tree imaging
Liver biopsy
Outcome
Child A
Child B
Asian No 2 11 Failure of amplification of exon 11 Helicobacter pylori antibody positive Cryptosporidium from bile fluid Yes Yes Yes No cutaneous stigmata of liver disease. Mild splenomegaly. Bilirubin: 7 μmol/L AST: 59 IU/L (↑) ALT: 77 IU/L (↑) GGT: 65 IU/L (↑) ALP: 216 IU/L EBV, hepatitis B & C negative, CMV — low level viremia on PCR MRI: Thickened gallbladder with filling defects Dilated common bile duct and beading of the intra-hepatic ducts Biliary features, mild inflammation, peri-portal and early bridging fibrosis, orcein focally positive Awaiting HSCT
Caucasian No 2 6 Heterozygous deletion of exons 9 and 11 Chronic diarrhea with Cryptosporidium Giardia No No No No cutaneous stigmata of liver disease. Mild hepatomegaly Bilirubin: 4 μmol/L AST: 32 IU/L GGT: 13 IU/L ALP: 233 IU/L CMV, EBV, hepatitis B & C negative ERCP: Mild intrahepatic cholangiopathy predominantly involving the third and fourth order ducts Mild inflammatory features
Successful matched unrelated donor HSCT; gradual improvement in biliary abnormalities
EBV — Epstein–Barr virus. CMV —cytomegalovirus. a Normal ranges: bilirubin: 3–20 μmol/L, aspartate transaminase (AST): 7–36 IU/L, alanine transaminase (ALT): 5–55 IU/L, gamma-glutamyl transferase (GGT): 1–55 IU/L, and alkaline phosphatase (ALP): 178–455 IU/L.
immunodeficiency being recognized. Her interval to transplant was also one year less than her sibling. Chronic infection with Cryptosporidium is associated with sclerosing cholangitis in other primary immunodeficiencies with CD4 lymphopenia, for example MHC class II deficiency, or when CD4 lymphocytes are dysfunctional, for example CD40 ligand deficiency [6,7]. Patients with DOCK8 deficiency also have CD4 lymphopenia, suggesting a common mechanistic link for susceptibility to Cryptosporidium infection and sclerosing cholangitis. In light of these four cases the possibility of sclerosing cholangitis should be borne in mind in children affected by DOCK8 deficiency, even in the absence of clinical symptomatology or known infection with Cryptosporidium. As for other combined immunodeficiencies, precautions to avoid cryptosporidial infection, such as boiling drinking water and avoiding public swimming pools, are important. Evidence of Cryptosporidium infection should prompt investigation for liver disease and supportive care. Its presence should contribute to discussion regarding timing of hematopoietic stem cell transplantation which can be curative of the underlying immune deficiency and may prevent lifethreatening complications.
Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] K.R. Engelhardt, S. McGhee, S. Winkler, A. Sassi, C. Woellner, G. Lopez-Herrera, A. Chen, H.S. Kim, M.G. Lloret, I. Schulze, et al., Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome, J. Allergy Clin. Immunol. 124 (6) (2009) 1289–1302 (e1284). [2] Q. Zhang, J.C. Davis, I.T. Lamborn, A.F. Freeman, H. Jing, A.J. Favreau, H.F. Matthews, J. Davis, M.L. Turner, G. Uzel, et al., Combined immunodeficiency associated with DOCK8 mutations, N. Engl. J. Med. 361 (21) (2009) 2046–2055. [3] H.C. Su, Dedicator of cytokinesis 8 (DOCK8) deficiency, Curr. Opin. Allergy Clin. Immunol. 10 (6) (2010) 515–520. [4] H.C. Su, H. Jing, Q. Zhang, DOCK8 deficiency, Ann. N. Y. Acad. Sci. 1246 (2011) 26–33. [5] O. Sanal, H. Jing, T. Ozgur, D. Ayvaz, D.M. Strauss-Albee, S. ErsoyEvans, I. Tezcan, G. Turkkani, H.F. Matthews, G. Haliloglu, et al., Additional diverse findings expand the clinical presentation of DOCK8 deficiency, J. Clin. Immunol. 32 (4) (2012) 698–708.
Letter to the Editor [6] C. Klein, B. Lisowska-Grospierre, F. LeDeist, A. Fischer, C. Griscelli, Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome, J. Pediatr. 123 (6) (1993) 921–928. [7] F. Rodrigues, E.G. Davies, P. Harrison, J. McLauchlin, J. Karani, B. Portmann, A. Jones, P. Veys, G. Mieli-Vergani, N. Hadzic, Liver disease in children with primary immunodeficiencies, J. Pediatr. 145 (3) (2004) 333–339.
Tejshri Shah Catherine Cale Immunology Department, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK E-mail addresses: [email protected] (T. Shah), [email protected] (C. Cale).
73
Nedim Hadzic Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, London SE5 9RS, UK E-mail address: [email protected].
Alison Jones* Immunology Department, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK E-mail address: [email protected]. *Corresponding author. 24 June 2014
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
LETTER TO THE EDITOR Dedicator of cytokinesis 8 deficiency: A predisposition to sclerosing cholangitis KEYWORDS DOCK8; Sclerosing cholangitis; Cryptosporidium
Dear Editor
Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive combined immunodeficiency, caused by a heterogeneous group of defects in the DOCK8 gene. The molecular basis of this disease was described in 2009 [1,2]. Immunological features include impaired T cell expansion, T and B cell lymphopenia, low IgM, variable IgG, functional antibody abnormalities, hyper-immunoglobulin E and eosinophilia. The clinical picture is typically one of recurrent viral infections particularly affecting the skin, sino-pulmonary bacterial infections, atopy and increased susceptibility to malignancy. In addition, autoimmunity and neurological abnormalities have been observed [3,4]. Sclerosing cholangitis associated with DOCK8 deficiency was described in two unrelated Turkish children in 2012 [5]. We describe two further children with DOCK8 deficiency and sclerosing cholangitis, providing additional evidence to support this clinical association (Table 1). The first child (A) aged 7 presented with cough, faltering growth and paronychia. He had a history of eczema from the age of 2 years, and recurrent cough from the age of 4 years. On presentation he had bronchiectasis. His clinical course was complicated by recurrent herpes simplex virus, bacterial and fungal skin infections, eczematous flares, food intolerances, reactive airway disease and type 1 hypersensitivity reactions with no cause identified. He had CD4 lymphopenia, low IgM, normal IgA, and normal IgG but with increased IgG1 and low IgG2 subclasses, eosinophilia and elevated IgE. At the age of 13, eleven years after his first symptoms, he presented with weight loss, reduced appetite and abdominal pain, exacerbated by eating. He had mildly elevated inflammatory markers and liver enzymes and ultrasound revealed a thickened gallbladder with filling defects. Magnetic resonance
http://dx.doi.org/10.1016/j.clim.2014.09.001 1521-6616/© 2014 Elsevier Inc. All rights reserved.
imaging, endoscopic retrograde cholangio-pancreatography (ERCP) and liver biopsy were all consistent with a diagnosis of sclerosing cholangitis. Cryptosporidium, which had not been identified previously, was isolated from bile fluid obtained at ERCP. His symptoms resolved with conservative management and he is currently awaiting hematopoietic stem cell transplantation (HSCT). The second child (B) presented with Haemophilus influenzae septicemia and septic arthritis at 2 years. Subsequent problems included bronchiectasis, Pneumocystis jiroveci pneumonitis, a further H. influenzae septicemia, severe molluscum contagiosum and chronic diarrhea secondary to Cryptosporidium. He was severely atopic, with eczema, asthma and numerous allergies including anaphylaxis to peanuts. He had CD4 lymphopenia, low IgM, increased IgA, and normal IgG including subclasses. He did not have eosinophilia but had elevated IgE. At 8 years of age discussion about transplantation was initiated, and he underwent ERCP and liver biopsy in light of previous Cryptosporidium infection. At the time, he had no gastrointestinal symptoms, normal liver function and no evidence of infection. Intrahepatic cholangiopathy was demonstrated, which was mild and predominantly involved the third and fourth order ducts. He was commenced on ursodeoxycholic acid, and continued azithromycin as prophylaxis for Cryptosporidium. Sclerosing cholangitis slightly worsened until age 10 when he successfully underwent HSCT and thereafter improved over 5 years. He has a younger sibling with an identical mutation who also had Cryptosporidium in the stool but had no evidence of liver pathology. Immunodeficiency was suspected earlier than in her brother and supportive care commenced and 4 years after her initial presentation she successfully underwent HSCT. Taking these two cases together with those reported previously, there is no common mutation and they represent three ethnicities. Three of the four had Cryptosporidium identified. In one child there was a significant clinical presentation with acute weight loss and abdominal cramps and Cryptosporidium was only isolated from bile duct fluid. However the other had no symptoms at the time of diagnosis of sclerosing cholangitis, but had a known history of diarrhea associated with Cryptosporidium. Interestingly the younger sibling of Child B, who has an identical mutation and was infected with Cryptosporidium, did not develop sclerosing cholangitis. She, however, had a prompt ERCP and started azithromycin and ursodeoxycholic acid within 1 year of her
72 Table 1
Letter to the Editor Relevant clinical and laboratory findings in two children with DOCK8 deficiency and sclerosing cholangitis.
Ethnicity Consanguinity Age of onset of symptoms (years) Time to diagnosis of SC (years) DOCK8 mutation Gastrointestinal infections Poor growth Abdominal pain Reduced appetite Clinical examination Liver function prior to diagnosis of sclerosing cholangitis a
Virology Gallbladder & biliary tree imaging
Liver biopsy
Outcome
Child A
Child B
Asian No 2 11 Failure of amplification of exon 11 Helicobacter pylori antibody positive Cryptosporidium from bile fluid Yes Yes Yes No cutaneous stigmata of liver disease. Mild splenomegaly. Bilirubin: 7 μmol/L AST: 59 IU/L (↑) ALT: 77 IU/L (↑) GGT: 65 IU/L (↑) ALP: 216 IU/L EBV, hepatitis B & C negative, CMV — low level viremia on PCR MRI: Thickened gallbladder with filling defects Dilated common bile duct and beading of the intra-hepatic ducts Biliary features, mild inflammation, peri-portal and early bridging fibrosis, orcein focally positive Awaiting HSCT
Caucasian No 2 6 Heterozygous deletion of exons 9 and 11 Chronic diarrhea with Cryptosporidium Giardia No No No No cutaneous stigmata of liver disease. Mild hepatomegaly Bilirubin: 4 μmol/L AST: 32 IU/L GGT: 13 IU/L ALP: 233 IU/L CMV, EBV, hepatitis B & C negative ERCP: Mild intrahepatic cholangiopathy predominantly involving the third and fourth order ducts Mild inflammatory features
Successful matched unrelated donor HSCT; gradual improvement in biliary abnormalities
EBV — Epstein–Barr virus. CMV —cytomegalovirus. a Normal ranges: bilirubin: 3–20 μmol/L, aspartate transaminase (AST): 7–36 IU/L, alanine transaminase (ALT): 5–55 IU/L, gamma-glutamyl transferase (GGT): 1–55 IU/L, and alkaline phosphatase (ALP): 178–455 IU/L.
immunodeficiency being recognized. Her interval to transplant was also one year less than her sibling. Chronic infection with Cryptosporidium is associated with sclerosing cholangitis in other primary immunodeficiencies with CD4 lymphopenia, for example MHC class II deficiency, or when CD4 lymphocytes are dysfunctional, for example CD40 ligand deficiency [6,7]. Patients with DOCK8 deficiency also have CD4 lymphopenia, suggesting a common mechanistic link for susceptibility to Cryptosporidium infection and sclerosing cholangitis. In light of these four cases the possibility of sclerosing cholangitis should be borne in mind in children affected by DOCK8 deficiency, even in the absence of clinical symptomatology or known infection with Cryptosporidium. As for other combined immunodeficiencies, precautions to avoid cryptosporidial infection, such as boiling drinking water and avoiding public swimming pools, are important. Evidence of Cryptosporidium infection should prompt investigation for liver disease and supportive care. Its presence should contribute to discussion regarding timing of hematopoietic stem cell transplantation which can be curative of the underlying immune deficiency and may prevent lifethreatening complications.
Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] K.R. Engelhardt, S. McGhee, S. Winkler, A. Sassi, C. Woellner, G. Lopez-Herrera, A. Chen, H.S. Kim, M.G. Lloret, I. Schulze, et al., Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome, J. Allergy Clin. Immunol. 124 (6) (2009) 1289–1302 (e1284). [2] Q. Zhang, J.C. Davis, I.T. Lamborn, A.F. Freeman, H. Jing, A.J. Favreau, H.F. Matthews, J. Davis, M.L. Turner, G. Uzel, et al., Combined immunodeficiency associated with DOCK8 mutations, N. Engl. J. Med. 361 (21) (2009) 2046–2055. [3] H.C. Su, Dedicator of cytokinesis 8 (DOCK8) deficiency, Curr. Opin. Allergy Clin. Immunol. 10 (6) (2010) 515–520. [4] H.C. Su, H. Jing, Q. Zhang, DOCK8 deficiency, Ann. N. Y. Acad. Sci. 1246 (2011) 26–33. [5] O. Sanal, H. Jing, T. Ozgur, D. Ayvaz, D.M. Strauss-Albee, S. ErsoyEvans, I. Tezcan, G. Turkkani, H.F. Matthews, G. Haliloglu, et al., Additional diverse findings expand the clinical presentation of DOCK8 deficiency, J. Clin. Immunol. 32 (4) (2012) 698–708.
Letter to the Editor [6] C. Klein, B. Lisowska-Grospierre, F. LeDeist, A. Fischer, C. Griscelli, Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome, J. Pediatr. 123 (6) (1993) 921–928. [7] F. Rodrigues, E.G. Davies, P. Harrison, J. McLauchlin, J. Karani, B. Portmann, A. Jones, P. Veys, G. Mieli-Vergani, N. Hadzic, Liver disease in children with primary immunodeficiencies, J. Pediatr. 145 (3) (2004) 333–339.
Tejshri Shah Catherine Cale Immunology Department, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK E-mail addresses: [email protected] (T. Shah), [email protected] (C. Cale).
73
Nedim Hadzic Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, London SE5 9RS, UK E-mail address: [email protected].
Alison Jones* Immunology Department, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK E-mail address: [email protected]. *Corresponding author. 24 June 2014