Primary immunodeficiency associated with hypopigmentation: A differential diagnosis approach

Main Article Content

Raha Zamani
Sepideh Shahkarami
Nima Rezaei

Keywords

Chediak–Higashi syndrome, differential diagnosis, Griscelli syndrome type 2, Hermansky–Pudlak syndrome, hypopigmentation syndromes, inborn errors of immunity, P14 deficiency, primary immunodeficiency, Vici syndrome

Abstract

Primary immunodeficiency diseases (PIDs) are a group of more than 400 disorders representing aberrant functioning or development of immune system. Hypopigmentation syndromes also characterize a distinguished cluster of diseases. However, hypopigmentation may also signify a feature of genetic diseases associated with immunodeficiency, such as Chediak–Higashi syndrome, Griscelli syndrome type 2, Hermansky–Pudlak syndrome type 2 and type 10, Vici syndrome, and P14/LAMTOR2 deficiency, all of which are linked with dysfunction in vesicular/endosomal trafficking. Regarding the highly overlapping features, these disorders need a comprehensive examination for prompt diagnosis and effective management. As an aid to clinician, distinguishing the pathophysiology, clinical phenotype, and diagnosis as well as treatment options of the six mentioned PID disorders associated with hypopigmentation are described and discussed in this review.

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References

1. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40:24–64. https://doi.org/10.1007/s10875-019-00737-x, https://doi.org/10.1007/s10875-020-00763-0

2. Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40:66–81. https://doi.org/10.1007/s10875-020-00758-x

3. Piirila H, Valiaho J, Vihinen M. Immunodeficiency mutation databases (IDbases). Hum Mutat. 2006;27:1200–8. https://doi.org/10.1002/humu.20405

4. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, et al. Primary immunodeficiency diseases worldwide: More common than generally thought. J Clin Immunol. 2013;33:1–7. https://doi.org/10.1007/s10875-012-9751-7

5. Kobrynski L, Powell RW, Bowen S. Prevalence and morbidity of primary immunodeficiency diseases, United States 2001–2007. J Clin Immunol. 2014;34:954–61. https://doi.org/10.1007/s10875-014-0102-8

6. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018;38:96–128. https://doi.org/10.1007/s10875-017-0464-9

7. Delmonte OM, Castagnoli R, Calzoni E, Notarangelo LD. Inborn errors of immunity with immune dysregulation: From bench to bedside. Front Pediatr. 2019;7:353. https://doi.org/10.3389/fped.2019.00353

8. Ham H, Billadeau DD. Human immunodeficiency syndromes affecting human natural killer cell cytolytic activity. Front Immunol. 2014;5:2. https://doi.org/10.3389/fimmu.2014.00002

9. Beguez-Cesar A, JB Scdp. Familial chronic malignant neutropenia with atypical granulations in the leukocytes. 1943;15:900.

10. Steinbrinck WJDAfkM. * UBER EINE NEUE GRANULATIONSANOMALIE DER LEUKOCYTEN. 1948;193:577–81.

11. Chediak MJRH. Nouvelle anomalie leucocytaire de caractère constitutionnel et familial. 1952;7:362–7.

12. Higashi OJTTjoem. Congenital gigantism of peroxidase granules. 1954;59:315–32.
https://doi.org/10.1620/tjem.59.315

13. Sato AJTTjoem. Chediak and Higashi's disease. Probable identity of “a new leucocytal anomaly (Chediak)” and “congenital gigantism of peroxidase granules (Higashi)”. 1955;61:201–10. https://doi.org/10.1620/tjem.61.201

14. Barrat FJ, Auloge L, Pastural E, Lagelouse RD, Vilmer E, Cant AJ, et al. Genetic and physical mapping of the Chediak–Higashi syndrome on chromosome 1q42-43. Am J Hum Genet. 1996;59:625–32.

15. Gil-Krzewska A, Wood SM, Murakami Y, Nguyen V, Chiang SCC, Cullinane AR, et al. Chediak–Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells. J Allergy Clin Immunol. 2016;137:1165–77. https://doi.org/10.1016/j.jaci.2015.08.039

16. Ward DM, Griffiths GM, Stinchcombe JC, Kaplan J. Analysis of the lysosomal storage disease Chediak–Higashi syndrome. Traffic (Copenhagen, Denmark). 2000;1:816–22. https://doi.org/10.1034/j.1600-0854.2000.011102.x

17. Kaplan J, De Domenico I, Ward DM. Chediak–Higashi syndrome. Curr Opin Hematol. 2008;15:22–9. https://doi.org/10.1097/MOH.0b013e3282f2bcce

18. Cullinane AR, Schaffer AA, Huizing M. The BEACH is hot: a LYST of emerging roles for BEACH-domain containing proteins in human disease. Traffic. 2013;14:749–66. https://doi.org/10.1111/tra.12069

19. Faigle W, Raposo G, Tenza D, Pinet V, Vogt AB, Kropshofer H, et al. Deficient peptide loading and MHC class II endosomal sorting in a human genetic immunodeficiency disease: The Chediak–Higashi syndrome. J Cell Biol. 1998;141:1121–34. https://doi.org/10.1083/jcb.141.5.1121

20. Ward DM, Shiflett SL, Huynh D, Vaughn MB, Prestwich G, Kaplan J. Use of expression constructs to dissect the functional domains of the CHS/beige protein: Identification of multiple phenotypes. Traffic (Copenhagen, Denmark). 2003;4:403–15. https://doi.org/10.1034/j.1600-0854.2003.00093.x

21. Burgess A, Mornon JP, de Saint-Basile G, Callebaut I. A concanavalin A-like lectin domain in the CHS1/LYST protein, shared by members of the BEACH family. Bioinformatics (Oxford, England). 2009;25:1219–22. https://doi.org/10.1093/bioinformatics/btp151

22. Jin Y, Zhang L, Wang S, Chen F, Gu Y, Hong E, et al. Whole genome sequencing identifies novel compound heterozygous lysosomal trafficking regulator gene mutations associated with autosomal recessive Chediak–Higashi syndrome. Sci Rep. 2017;7:41308. https://doi.org/10.1038/srep41308

23. Certain S, Barrat F, Pastural E, Le Deist F, Goyo-Rivas J, Jabado N, et al. Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak–Higashi syndrome. Blood. 2000;95:979–83.

24. Karim MA, Suzuki K, Fukai K, Oh J, Nagle DL, Moore KJ, et al. Apparent genotype–phenotype correlation in childhood, adolescent, and adult Chediak–Higashi syndrome. Am J Med Genet. 2002;108:16–22. https://doi.org/10.1002/ajmg.10184

25. Chiang SCC, Wood SM, Tesi B, Akar HH, Al-Herz W, Ammann S, et al. Differences in granule morphology yet equally impaired exocytosis among cytotoxic T cells and NK cells from Chediak–Higashi syndrome patients. Front Immunol. 2017;8:426. https://doi.org/10.3389/fimmu.2017.00426

26. Gil-Krzewska A, Saeed MB, Oszmiana A, Fischer ER, Lagrue K, Gahl WA, et al. An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak–Higashi syndrome. J Allergy Clin Immunol. 2018;142:914–27.e6. https://doi.org/10.1016/j.jaci.2017.10.040

27. Falkenstein K, De Lozanne A. Dictyostelium LvsB has a regulatory role in endosomal vesicle fusion. J Cell Sci. 2014;127:4356–67. https://doi.org/10.1242/jcs.138123

28. Ji X, Chang B, Naggert JK, Nishina PM. Lysosomal trafficking regulator (LYST). Adv Exp Med Biol. 2016;854:745–50. https://doi.org/10.1007/978-3-319-17121-0_99

29. Huynh C, Roth D, Ward DM, Kaplan J, Andrews NW. Defective lysosomal exocytosis and plasma membrane repair in Chediak–Higashi/beige cells. Proc Nat Acad Sci USA. 2004;101:16795–800. https://doi.org/10.1073/pnas.0405905101

30. Introne WJ, Westbroek W, Groden CA, Bhambhani V, Golas GA, Baker EH, et al. Neurologic involvement in patients with atypical Chediak–Higashi disease. Neurology. 2017;88:e57–e65. https://doi.org/10.1212/WNL.0000000000003622

31. Gunay-Aygun M, Huizing M, Gahl WA. Molecular defects that affect platelet dense granules. Sem Throm Hemost. 2004;30:537–47. https://doi.org/10.1055/s-2004-835674

32. Fukai K, Ishii M, Kadoya A, Chanoki M, Hamada T. Chediak–Higashi syndrome: Report of a case and review of the Japanese literature. J Dermatol. 1993;20:231–7. https://doi.org/10.1111/j.1346-8138.1993.tb03867.x

33. Sayanagi K, Fujikado T, Onodera T, Tano Y. Chediak–Higashi syndrome with progressive visual loss. Jap J Ophthal. 2003;47:304–6. https://doi.org/10.1016/S0021-5155(03)00018-2

34. Nagai K, Ochi F, Terui K, Maeda M, Ohga S, Kanegane H, et al. Clinical characteristics and outcomes of Chédiak–Higashi syndrome: A nationwide survey of Japan. Pediatr Blood Cancer. 2013;60:1582–6. https://doi.org/10.1002/pbc.24637

35. Rezaei N, Farhoudi A, Ramyar A, Pourpak Z, Aghamohammadi A, Mohammadpour B, et al. Congenital neutropenia and primary immunodeficiency disorders: A survey of 26 Iranian patients. J Pediatr Hematol Oncol. 2005;27:351–6. https://doi.org/10.1097/01.mph.0000172280.27318.80

36. White JG. Virus-like particles in the peripheral blood cells of two patients with Chediak–Higashi syndrome. Cancer. 1966;19:877–84. https://doi.org/10.1002/1097-0142(196606)19:6<877::AID-CNCR2820190621>3.0.CO;2-Q

37. Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak–Higashi syndrome. Mol Genet Metab. 1999;68:283–303. https://doi.org/10.1006/mgme.1999.2927

38. Toro C Fau - Nicoli E-R, Nicoli Er Fau - Malicdan MC, Malicdan Mc Fau - Adams DR, Adams Dr Fau - Introne WJ, Introne WJ. Chediak–Higashi syndrome BTI – Gene Reviews (R).

39. Faber IV, Prota JRM, Martinez ARM, Nucci A, Lopes-Cendes I, Junior MCF. Inflammatory demyelinating neuropathy heralding accelerated Chediak–Higashi syndrome. Muscle Nerve. 2017;55:756–60. https://doi.org/10.1002/mus.25414

40. Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak–Higashi syndrome. Blood. 2005;106:40–2. https://doi.org/10.1182/blood-2005-01-0319

41. Introne W, Boissy Re Fau - Gahl WA, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak–Higashi syndrome.

42. Brisse E, Matthys P, Wouters CH. Understanding the spectrum of haemophagocytic lymphohistiocytosis: Update on diagnostic challenges and therapeutic options. Br J Haematol. 2016;174:175–87. https://doi.org/10.1111/bjh.14144

43. Kanjanapongkul S. Chediak–Higashi syndrome: Report of a case with uncommon presentation and review literature. J Med Assoc Thai Chotmaihet Thangphaet. 2006;89:541–4.

44. Rubin CM, Burke BA, McKenna RW, McClain KL, White JG, Nesbit ME Jr., et al. The accelerated phase of Chediak–Higashi syndrome. An expression of the virus-associated hemophagocytic syndrome? Cancer. 1985;56:524–30. https://doi.org/10.1002/1097-0142(19850801)56:3<524::AID-CNCR2820560320>3.0.CO;2-Z

45. Helmi MM, Saleh M, Yacop B, El Sawy D. Chédiak–Higashi syndrome with novel gene mutation. BMJ Case Rep. 2017;2017. https://doi.org/10.1136/bcr-2016-216628

46. Lozano ML, Rivera J, Sanchez-Guiu I, Vicente V. Towards the targeted management of Chediak–Higashi syndrome. Orphanet J Rare Dis. 2014;9:132. https://doi.org/10.1186/s13023-014-0132-6

47. Chandravathi PL, Karani HD, Siddaiahgari SR, Lingappa L. Light microscopy and polarized microscopy: A dermatological tool to diagnose gray hair syndromes. Int J Trichol. 2017;9:38–41. https://doi.org/10.4103/ijt.ijt_21_16

48. Valente NY, Machado MC, Boggio P, Alves AC, Bergonse FN, Casella E, et al. Polarized light microscopy of hair shafts aids in the differential diagnosis of Chediak–Higashi and Griscelli–Prunieras syndromes. Clinics (Sao Paulo, Brazil). 2006;61:327–32. https://doi.org/10.1590/S1807-59322006000400009

49. Ridaura-Sanz C, Duran-McKinster C, Ruiz-Maldonado R. Usefulness of the skin biopsy as a tool in the diagnosis of silvery hair syndrome. Pediatr Dermatol. 2018;35:780–3. https://doi.org/10.1111/pde.13624

50. Eapen M, DeLaat CA, Baker KS, Cairo MS, Cowan MJ, Kurtzberg J, et al. Hematopoietic cell transplantation for Chediak–Higashi syndrome. Bone Marrow Transplant. 2007;39:411–5. https://doi.org/10.1038/sj.bmt.1705600

51. Bergsten E, Horne A, Arico M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: Long-term results of the cooperative HLH-2004 study. Blood. 2017;130:2728–38. https://doi.org/10.1182/blood-2017-06-788349

52. Wu XL, Zhao XQ, Zhang BX, Xuan F, Guo HM, Ma FT. A novel frameshift mutation of Chediak–Higashi syndrome and treatment in the accelerated phase. Braz J of Med Biol Res (Revista Brasileira de Pesquisas Medicas e Biologicas). 2017;50:e5727. https://doi.org/10.1590/1414-431x20165727

53. Sobh A, Bonilla FA. Vaccination in primary immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:1066–75. https://doi.org/10.1016/j.jaip.2016.09.012

54. Baldus M, Zunftmeister V, Geibel-Werle G, Claus B, Mewes D, Uppenkamp M, et al. Chediak–Higashi–Steinbrinck syndrome (CHS) in a 27-year-old woman -- Effects of G-CSF treatment. Ann Hematol. 1999;78:321–7. https://doi.org/10.1007/s002770050522

55. Colgan SP, Gasper PW, Thrall MA, Boone TC, Blancquaert AM, Bruyninckx WJ. Neutrophil function in normal and Chediak–Higashi syndrome cats following administration of recombinant canine granulocyte colony-stimulating factor. Exp Hematol. 1992;20:1229–34.

56. Cifaldi L, Pinto RM, Rana I, Caniglia M, Angioni A, Petrocchi S, et al. NK cell effector functions in a Chediak–Higashi patient undergoing cord blood transplantation: Effects of in vitro treatment with IL-2. Immunol Lett. 2016;180:46–53. https://doi.org/10.1016/j.imlet.2016.10.009

57. Griscelli C, Durandy A, Guy-Grand D, Daguillard F, Herzog C, Prunieras M. A syndrome associating partial albinism and immunodeficiency. Am J Med. 1978;65:691–702. https://doi.org/10.1016/0002-9343(78)90858-6

58. Menasche G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25:173–6. https://doi.org/10.1038/76024

59. Van Gele M, Dynoodt P, Lambert J. Griscelli syndrome: A model system to study vesicular trafficking. Pigment Cell Melanoma Res. 2009;22:268–82. https://doi.org/10.1111/j.1755-148X.2009.00558.x

60. Menasche G, Feldmann J, Houdusse A, Desaymard C, Fischer A, Goud B, et al. Biochemical and functional characterization of Rab27a mutations occurring in Griscelli syndrome patients. Blood. 2003;101:2736–42. https://doi.org/10.1182/blood-2002-09-2789

61. Tolmachova T, Ramalho JS, Anant JS, Schultz RA, Huxley CM, Seabra MC. Cloning, mapping and characterization of the human RAB27A gene. Gene. 1999;239:109–16. https://doi.org/10.1016/S0378-1119(99)00371-6

62. Fukuda M. Rab27 effectors, pleiotropic regulators in secretory pathways. Traffic (Copenhagen, Denmark). 2013;14:949–63. https://doi.org/10.1111/tra.12083

63. Grandin V, Sepulveda FE, Lambert N, Al Zahrani M, Al Idrissi E, Al-Mousa H, et al. A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis. Hum Mut. 2017;38:1355–9. https://doi.org/10.1002/humu.23274

64. Meeths M, Bryceson YT, Rudd E, Zheng C, Wood SM, Ramme K, et al. Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr Blood Cancer. 2010;54:563–72. https://doi.org/10.1002/pbc.22357

65. Masri A, Bakri FG, Al-Hussaini M, Al-Hadidy A, Hirzallah R, de Saint Basile G, et al. Griscelli syndrome type 2: A rare and lethal disorder. J Child Neurol. 2008;23:964–7. https://doi.org/10.1177/0883073808315409

66. Kuskonmaz B, Ayvaz D, Gokce M, Ozgur TT, Okur FV, Cetin M, et al. Hematopoietic stem cell transplantation in children with Griscelli syndrome: A single-center experience. Pediatr Transplant. 2017;21. https://doi.org/10.1111/petr.13040

67. Trottestam H, Beutel K, Meeths M, Carlsen N, Heilmann C, Pasic S, et al. Treatment of the X-linked lymphoproliferative, Griscelli and Chediak–Higashi syndromes by HLH-directed therapy. Pediatr Blood Cancer. 2009;52:268–72. https://doi.org/10.1002/pbc.21790

68. Hermansky F, Pudlak PJB. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: Report of two cases with histochemical studies. 1959;14:162–9. https://doi.org/10.1182/blood.V14.2.162.162

69. Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky–Pudlak syndrome due to mutations in the β3A subunit of the AP-3 adaptor. Mol Cell. 1999;3:11–21. https://doi.org/10.1016/S1097-2765(00)80170-7

70. Gil-Krzewska A, Murakami Y, Peruzzi G, O'Brien KJ, Merideth MA, Cullinane AR, et al. Natural killer cell activity and dysfunction in Hermansky–Pudlak syndrome. Br J Haematol. 2017;176:118–23. https://doi.org/10.1111/bjh.14390

71. Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, et al. Innate immunity defects in Hermansky–Pudlak type 2 syndrome. Blood. 2006;107:4857–64. https://doi.org/10.1182/blood-2005-11-4398

72. Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, et al. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nature Immunol. 2003;4:1111–20. https://doi.org/10.1038/ni1000

73. Benson KF, Li FQ, Person RE, Albani D, Duan Z, Wechsler J, et al. Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase. Nature Genet. 2003;35:90–6. https://doi.org/10.1038/ng1224

74. Huizing M, Sarangarajan R, Strovel E, Zhao Y, Gahl WA, Boissy RE. AP-3 mediates tyrosinase but not TRP-1 trafficking in human melanocytes. Mol Biol Cell. 2001;12:2075–85. https://doi.org/10.1091/mbc.12.7.2075

75. Gochuico BR, Huizing M, Golas GA, Scher CD, Tsokos M, Denver SD, et al. Interstitial lung disease and pulmonary fibrosis in Hermansky–Pudlak syndrome type 2, an adaptor protein-3 complex disease. Mol Med (Cambridge, MA). 2012;18:56–64. https://doi.org/10.2119/molmed.2011.00198

76. Karampini E, Schillemans M, Hofman M, van Alphen F, de Boer M, Kuijpers TW, et al. Defective AP-3-dependent VAMP8 trafficking impairs Weibel–Palade body exocytosis in Hermansky–Pudlak syndrome type 2 blood outgrowth endothelial cells. Haematologica. 2019;104:2091–9. https://doi.org/10.3324/haematol.2018.207787

77. Huizing M, Scher CD, Strovel E, Fitzpatrick DL, Hartnell LM, Anikster Y, et al. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky–Pudlak syndrome type 2. Pediatr Res. 2002;51:150–8. https://doi.org/10.1203/00006450-200202000-00006

78. Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky–Pudlak syndrome type II. Blood. 2006;108:81–7. https://doi.org/10.1182/blood-2005-11-4413

79. Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, et al. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky–Pudlak syndrome, type 2. Blood. 2006;108:362–9. https://doi.org/10.1182/blood-2005-11-4377

80. Lorenzi L, Tabellini G, Vermi W, Moratto D, Porta F, Notarangelo LD, et al. Occurrence of nodular lymphocyte-predominant hodgkin lymphoma in Hermansky–Pudlak type 2 syndrome is associated to natural killer and natural killer T cell defects. PloS One. 2013;8:e80131. https://doi.org/10.1371/journal.pone.0080131

81. Hengst M, Naehrlich L, Mahavadi P, Grosse-Onnebrink J, Terheggen-Lagro S, Skanke LH, et al. Hermansky–Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood. Orphanet J Rare Dis. 2018;13:42. https://doi.org/10.1186/s13023-018-0780-z

82. Dell'Acqua F, Saettini F, Castelli I, Badolato R, Notarangelo LD, Rizzari C. Hermansky–Pudlak syndrome type II and lethal hemophagocytic lymphohistiocytosis: Case description and review of the literature. J Allergy Clin Immunol Pract. 2019;7:2476–8.e5. https://doi.org/10.1016/j.jaip.2019.04.001

83. Jessen B, Bode SF, Ammann S, Chakravorty S, Davies G, Diestelhorst J, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky–Pudlak syndrome type 2. Blood. 2013;121:2943–51. https://doi.org/10.1182/blood-2012-10-463166

84. Seward SL Jr, Gahl WA. Hermansky–Pudlak syndrome: Health care throughout life. Pediatrics. 2013;132:153–60. https://doi.org/10.1542/peds.2012-4003

85. Witkop CJ, Krumwiede M, Sedano H, White JG. Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky–Pudlak syndrome. Am J Hematol. 1987;26:305–11. https://doi.org/10.1002/ajh.2830260403

86. Avila NA, Brantly M, Premkumar A, Huizing M, Dwyer A, Gahl WA. Hermansky–Pudlak syndrome: Radiography and CT of the chest compared with pulmonary function tests and genetic studies. AJR Am J Roentgenol. 2002;179:887–92. https://doi.org/10.2214/ajr.179.4.1790887

87. Kantheti P, Qiao X, Diaz ME, Peden AA, Meyer GE, Carskadon SL, et al. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron. 1998;21:111–22. https://doi.org/10.1016/S0896-6273(00)80519-X

88. Ammann S, Schulz A, Krägeloh-Mann I, Dieckmann NM, Niethammer K, Fuchs S, et al. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky–Pudlak syndrome. Blood. 2016;127:997–1006. https://doi.org/10.1182/blood-2015-09-671636

89. Mohammed M, Al-Hashmi N, Al-Rashdi S, Al-Sukaiti N, Al-Adawi K, Al-Riyami M, et al. Biallelic mutations in AP3D1 cause Hermansky–Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder. Eur J Med Genet. 2019;62:103583. https://doi.org/10.1016/j.ejmg.2018.11.017

90. Seong E, Wainer BH, Hughes ED, Saunders TL, Burmeister M, Faundez V. Genetic analysis of the neuronal and ubiquitous AP-3 adaptor complexes reveals divergent functions in brain. Mol Biol Cell. 2005;16:128–40. https://doi.org/10.1091/mbc.e04-10-0892

91. Dionisi Vici C, Sabetta G, Gambarara M, Vigevano F, Bertini E, Boldrini R, et al. Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am J Med Genet. 1988;29:1–8. https://doi.org/10.1002/ajmg.1320290102

92. Halama N, Grauling-Halama SA, Beder A, Jäger D. Comparative integromics on the breast cancer-associated gene KIAA1632: Clues to a cancer antigen domain. Int J Oncol. 2007;31:205–10. https://doi.org/10.3892/ijo.31.1.205

93. Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z, et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature Genet. 2013;45:83–7. https://doi.org/10.1038/ng.2497

94. Tian Y, Li Z, Hu W, Ren H, Tian E, Zhao Y, et al. C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell. 2010;141:1042–55. https://doi.org/10.1016/j.cell.2010.04.034

95. Capolunghi F, Cascioli S, Giorda E, Rosado MM, Plebani A, Auriti C, et al. CpG drives human transitional B cells to terminal differentiation and production of natural antibodies. J Immunol (Baltimore, MD). 2008;180:800–8. https://doi.org/10.4049/jimmunol.180.2.800

96. Piano Mortari E, Folgiero V, Marcellini V, Romania P, Bellacchio E, D'Alicandro V, et al. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. Autophagy. 2018;14:22–37. https://doi.org/10.1080/15548627.2017.1389356

97. De Leo MG, Staiano L, Vicinanza M, Luciani A, Carissimo A, Mutarelli M, et al. Autophagosome–lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL. Nature Cell Biol. 2016;18:839–50. https://doi.org/10.1038/ncb3386

98. Baron O, Boudi A, Dias C, Schilling M, Nolle A, Vizcay-Barrena G, et al. Stall in canonical autophagy-lysosome pathways prompts nucleophagy-based nuclear breakdown in neurodegeneration. Curr Biol (CB). 2017;27:3626–42.e6. https://doi.org/10.1016/j.cub.2017.10.054

99. Zhao YG, Zhao H, Sun H, Zhang H. Role of Epg5 in selective neurodegeneration and Vici syndrome. Autophagy. 2013;9:1258–62. https://doi.org/10.4161/auto.24856

100. Byrne S, Jansen L, JM UK-I, Siddiqui A, Lidov HG, Bodi I, et al. EPG5-related Vici syndrome: A paradigm of neurodevelopmental disorders with defective autophagy. Brain J Neurol. 2016;139:765–81. https://doi.org/10.1093/brain/awv393

101. McClelland V, Cullup T, Bodi I, Ruddy D, Buj-Bello A, Biancalana V, et al. Vici syndrome associated with sensorineural hearing loss and evidence of neuromuscular involvement on muscle biopsy. Am J Med Genet A. 2010;152a:741–7. https://doi.org/10.1002/ajmg.a.33296

102. Filloux FM, Hoffman RO, Viskochil DH, Jungbluth H, Creel DJ. Ophthalmologic features of Vici syndrome. J Pediatr Ophthalmol Strabismus. 2014;51:214–20. https://doi.org/10.3928/01913913-20140423-02

103. Finocchi A, Angelino G, Cantarutti N, Corbari M, Bevivino E, Cascioli S, et al. Immunodeficiency in Vici syndrome: A heterogeneous phenotype. Am J Med Genet A. 2012;158a:434–9. https://doi.org/10.1002/ajmg.a.34244

104. Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H. Vici syndrome: A review. Orphanet J Rare Dis. 2016;11:21. https://doi.org/10.1186/s13023-016-0399-x

105. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nature Med. 2007;13:38–45. https://doi.org/10.1038/nm1528

106. Teis D, Taub N, Kurzbauer R, Hilber D, de Araujo ME, Erlacher M, et al. p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis. J Cell Biol. 2006;175:861–8. https://doi.org/10.1083/jcb.200607025

107. Sparber F, Tripp CH, Komenda K, Scheffler JM, Clausen BE, Huber LA, et al. The late endosomal adaptor molecule p14 (LAMTOR2) regulates TGFβ1-mediated homeostasis of Langerhans cells. J Invest Dermatol. 2015;135:119–29. https://doi.org/10.1038/jid.2014.324

108. Taub N, Nairz M, Hilber D, Hess MW, Weiss G, Huber LA. The late endosomal adaptor p14 is a macrophage host-defense factor against Salmonella infection. J Cell Sci. 2012;125:2698–708. https://doi.org/10.1242/jcs.100073

109. Bohn G, Hardtke-Wolenski M, Zeidler C, Maecker B, Sauer M, Sykora KW, et al. Lethal graft-versus-host disease in congenital neutropenia caused by p14 deficiency after allogeneic bone marrow transplantation from an HLA-identical sibling. Pediatr Blood Cancer. 2008;51:436–8. https://doi.org/10.1002/pbc.21643