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Reticular dysgenesis

MedGen UID:
124417
•Concept ID:
C0272167
•
Disease or Syndrome
Synonyms: ALEUKOCYTOSIS; Congenital aleukia; DeVaal disease; HEMATOPOIETIC HYPOPLASIA, GENERALIZED; RETICULAR DYSGENESIA; Severe combined immunodeficiency with leukopenia
SNOMED CT: Reticular dysgenesis (111584000); De Vaal disease (111584000); Immunoerythromyeloid hypoplasia (111584000); Congenital aleukia (111584000); Reticular dysgenesia (111584000); Generalized hematopoietic hypoplasia (111584000); SCID - Severe combined immunodeficiency, neutropenia and thrombocytopenia (111584000); Severe combined immunodeficiency, neutropenia and thrombocytopenia (111584000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Gene (location): AK2 (1p35.1)
 
Monarch Initiative: MONDO:0009973
OMIM®: 267500
Orphanet: ORPHA33355

Definition

Reticular dysgenesis, the most severe form of inborn severe combined immunodeficiency (SCID), is characterized by absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immune functions, leading to fatal septicemia within days after birth (summary by Pannicke et al., 2009). [from OMIM]

Clinical features

From HPO
Lymphoproliferative disorder
MedGen UID:
6162
•Concept ID:
C0024314
•
Neoplastic Process
A disorder characterized by proliferation of lymphocytes at various stages of differentiation. Lymphoproliferative disorders can be neoplastic (clonal, as in lymphomas and leukemias) or reactive (polyclonal, as in infectious mononucleosis).
See: Feature record | Search on this feature
Erythroid hypoplasia
MedGen UID:
488912
•Concept ID:
C0542035
•
Disease or Syndrome
Decreased count of erythroid precursor cells, that is, erythroid lineage cells in the bone marrow.
See: Feature record | Search on this feature
Leukopenia
MedGen UID:
6073
•Concept ID:
C0023530
•
Disease or Syndrome
An abnormal decreased number of leukocytes in the blood.
See: Feature record | Search on this feature
Lymphopenia
MedGen UID:
7418
•Concept ID:
C0024312
•
Disease or Syndrome
A reduced number of lymphocytes in the blood.
See: Feature record | Search on this feature
Sepsis
MedGen UID:
48626
•Concept ID:
C0036690
•
Disease or Syndrome
Systemic inflammatory response to infection.
See: Feature record | Search on this feature
Hypoplasia of the thymus
MedGen UID:
146347
•Concept ID:
C0685891
•
Congenital Abnormality
Underdevelopment of the thymus.
See: Feature record | Search on this feature
Lack of T cell function
MedGen UID:
336597
•Concept ID:
C1849426
•
Finding
Complete inability of T cells to perform their functions in cell-mediated immunity.
See: Feature record | Search on this feature
Impaired T cell function
MedGen UID:
395415
•Concept ID:
C1860127
•
Cell or Molecular Dysfunction
Abnormally reduced ability of T cells to perform their functions in cell-mediated immunity.
See: Feature record | Search on this feature
Combined immunodeficiency
MedGen UID:
751396
•Concept ID:
C2711630
•
Disease or Syndrome
A group of phenotypically heterogeneous genetic disorders characterized by profound deficiencies of T- and B-cell function, which predispose the patients to both infectious and noninfectious complications.
See: Feature record | Search on this feature
Congenital agranulocytosis
MedGen UID:
1631650
•Concept ID:
C4551555
•
Congenital Abnormality
Congenital onset of a marked decrease in the number of granulocytes.
See: Feature record | Search on this feature
Decreased circulating IgG level
MedGen UID:
1720114
•Concept ID:
C5234937
•
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
See: Feature record | Search on this feature
Absent leukocyte alkaline phosphatase
MedGen UID:
870282
•Concept ID:
C4024724
•
Finding
Alkaline phosphatase levels measured within leukocytes is below detectable levels.
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVReticular dysgenesis
Follow this link to review classifications for Reticular dysgenesis in Orphanet.

Professional guidelines

PubMed

TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan.
Wakamatsu M, Kojima D, Muramatsu H, Okuno Y, Kataoka S, Nakamura F, Sakai Y, Tsuge I, Ito T, Ueda K, Saito A, Morihana E, Ito Y, Ohashi N, Tanaka M, Tanaka T, Kojima S, Nakajima Y, Ito T, Takahashi Y
J Clin Immunol 2022 Nov;42(8):1696-1707. Epub 2022 Jul 28 doi: 10.1007/s10875-022-01335-0. PMID: 35902420
Recent advances in understanding the pathogenesis and management of reticular dysgenesis.
Hoenig M, Pannicke U, Gaspar HB, Schwarz K
Br J Haematol 2018 Mar;180(5):644-653. Epub 2017 Dec 21 doi: 10.1111/bjh.15045. PMID: 29270983
Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience.
Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, Griffith LM, Kohn DB, O'Reilly RJ, Fleisher TA, Pai SY, Martinez CA, Buckley RH, Cowan MJ
J Allergy Clin Immunol 2014 Apr;133(4):1092-8. Epub 2013 Nov 28 doi: 10.1016/j.jaci.2013.09.044. PMID: 24290292Free PMC Article

Recent clinical studies

Etiology

Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.
Alsultan A, Essa M, Aljefri A, Ayas M, Alharbi M, Alkhayat N, Al-Anzi F, Yassin F, Alkasim F, Alharbi Q, Abdullah S, Jastaniah W
Pediatr Blood Cancer 2020 Jul;67(7):e28340. Epub 2020 May 2 doi: 10.1002/pbc.28340. PMID: 32359129
Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India.
Aluri J, Desai M, Gupta M, Dalvi A, Terance A, Rosenzweig SD, Stoddard JL, Niemela JE, Tamankar V, Mhatre S, Bargir U, Kulkarni M, Shah N, Aggarwal A, Lashkari HP, Krishna V, Govindaraj G, Kalra M, Madkaikar M
Front Immunol 2019;10:23. Epub 2019 Feb 4 doi: 10.3389/fimmu.2019.00023. PMID: 30778343Free PMC Article
Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.
Heimall J, Logan BR, Cowan MJ, Notarangelo LD, Griffith LM, Puck JM, Kohn DB, Pulsipher MA, Parikh S, Martinez C, Kapoor N, O'Reilly R, Boyer M, Pai SY, Goldman F, Burroughs L, Chandra S, Kletzel M, Thakar M, Connelly J, Cuvelier G, Davila Saldana BJ, Shereck E, Knutsen A, Sullivan KE, DeSantes K, Gillio A, Haddad E, Petrovic A, Quigg T, Smith AR, Stenger E, Yin Z, Shearer WT, Fleisher T, Buckley RH, Dvorak CC
Blood 2017 Dec 21;130(25):2718-2727. Epub 2017 Oct 11 doi: 10.1182/blood-2017-05-781849. PMID: 29021228Free PMC Article
Neutropenia associated with primary immunodeficiency syndromes.
Cham B, Bonilla MA, Winkelstein J
Semin Hematol 2002 Apr;39(2):107-12. doi: 10.1053/shem.2002.31916. PMID: 11957193
Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience.
Knutsen AP, Wall DA
J Clin Immunol 2000 Nov;20(6):466-76. doi: 10.1023/a:1026463900925. PMID: 11202237

Diagnosis

TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan.
Wakamatsu M, Kojima D, Muramatsu H, Okuno Y, Kataoka S, Nakamura F, Sakai Y, Tsuge I, Ito T, Ueda K, Saito A, Morihana E, Ito Y, Ohashi N, Tanaka M, Tanaka T, Kojima S, Nakajima Y, Ito T, Takahashi Y
J Clin Immunol 2022 Nov;42(8):1696-1707. Epub 2022 Jul 28 doi: 10.1007/s10875-022-01335-0. PMID: 35902420
Reticular dysgenesis exacerbated by hemophagocytic lymphohistiocytosis and the presence of unusual histiocyte-like cells in bone marrow.
Sharma M, Tyagi R, Loganathan SK, Sreedharaunni S, Rawat A, Gupta A
Immunobiology 2021 Nov;226(6):152143. Epub 2021 Sep 24 doi: 10.1016/j.imbio.2021.152143. PMID: 34598034
Reticular Dysgenesis and Mitochondriopathy Induced by Adenylate Kinase 2 Deficiency with Atypical Presentation.
Ghaloul-Gonzalez L, Mohsen AW, Karunanidhi A, Seminotti B, Chong H, Madan-Khetarpal S, Sebastian J, Vockley CW, Reyes-Múgica M, Vander Lugt MT, Vockley J
Sci Rep 2019 Oct 31;9(1):15739. doi: 10.1038/s41598-019-51922-2. PMID: 31673062Free PMC Article
Recent advances in understanding the pathogenesis and management of reticular dysgenesis.
Hoenig M, Pannicke U, Gaspar HB, Schwarz K
Br J Haematol 2018 Mar;180(5):644-653. Epub 2017 Dec 21 doi: 10.1111/bjh.15045. PMID: 29270983
Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing.
Dzeja P, Terzic A
Int J Mol Sci 2009 Apr 17;10(4):1729-1772. doi: 10.3390/ijms10041729. PMID: 19468337Free PMC Article

Therapy

Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation.
Chou J, Alazami AM, Jaber F, Hoyos-Bachiloglu R, Jones J, Weeks S, Alosaimi MF, Bainter W, Cangemi B, Badran YR, Mohammed R, Alroqi F, Almutairi A, Al-Onazi N, AlAjaji S, Al-Saud B, Arnaout R, Elkins M, Devana S, Imperial J, Li B, Drexhage L, Abdel Rahman AM, Jacob M, Haddad H, Hanna-Wakim R, Dbaibo G, Massaad MJ, Dasouki M, Mikhael R, Baz Z, Geha RS, Al-Mousa H
J Allergy Clin Immunol 2020 Jul;146(1):192-202. Epub 2019 Dec 17 doi: 10.1016/j.jaci.2019.12.004. PMID: 31862378
Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.
Heimall J, Logan BR, Cowan MJ, Notarangelo LD, Griffith LM, Puck JM, Kohn DB, Pulsipher MA, Parikh S, Martinez C, Kapoor N, O'Reilly R, Boyer M, Pai SY, Goldman F, Burroughs L, Chandra S, Kletzel M, Thakar M, Connelly J, Cuvelier G, Davila Saldana BJ, Shereck E, Knutsen A, Sullivan KE, DeSantes K, Gillio A, Haddad E, Petrovic A, Quigg T, Smith AR, Stenger E, Yin Z, Shearer WT, Fleisher T, Buckley RH, Dvorak CC
Blood 2017 Dec 21;130(25):2718-2727. Epub 2017 Oct 11 doi: 10.1182/blood-2017-05-781849. PMID: 29021228Free PMC Article
Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome.
Hoenig M, Lagresle-Peyrou C, Pannicke U, Notarangelo LD, Porta F, Gennery AR, Slatter M, Cowan MJ, Stepensky P, Al-Mousa H, Al-Zahrani D, Pai SY, Al Herz W, Gaspar HB, Veys P, Oshima K, Imai K, Yabe H, Noroski LM, Wulffraat NM, Sykora KW, Soler-Palacin P, Muramatsu H, Al Hilali M, Moshous D, Debatin KM, Schuetz C, Jacobsen EM, Schulz AS, Schwarz K, Fischer A, Friedrich W, Cavazzana M; European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party
Blood 2017 May 25;129(21):2928-2938. Epub 2017 Mar 22 doi: 10.1182/blood-2016-11-745638. PMID: 28331055Free PMC Article
Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience.
Knutsen AP, Wall DA
J Clin Immunol 2000 Nov;20(6):466-76. doi: 10.1023/a:1026463900925. PMID: 11202237
Immunodeficiencies better treated by transplantation.
Hobbs JR, Hugh-Jones K
Tokai J Exp Clin Med 1985 Jun;10(2-3):85-97. PMID: 2939602

Prognosis

UK-5099, a mitochondrial pyruvate carrier inhibitor, recovers impaired neutrophil maturation caused by AK2 deficiency in human pluripotent stem cell models.
Wang J, Saiki N, Tanimura A, Noma T, Niwa A, Nakahata T, Saito MK
Biochem Biophys Res Commun 2023 Dec 20;687:149211. Epub 2023 Nov 3 doi: 10.1016/j.bbrc.2023.149211. PMID: 37949028
Reticular dysgenesis caused by an intronic pathogenic variant in AK2.
Ichikawa S, Prockop S, Cunningham-Rundles C, Sifers T, Conner BR, Wu S, Karam R, Walsh MF, Fiala E
Cold Spring Harb Mol Case Stud 2020 Jun;6(3) Epub 2020 Jun 12 doi: 10.1101/mcs.a005017. PMID: 32532877Free PMC Article
Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.
Alsultan A, Essa M, Aljefri A, Ayas M, Alharbi M, Alkhayat N, Al-Anzi F, Yassin F, Alkasim F, Alharbi Q, Abdullah S, Jastaniah W
Pediatr Blood Cancer 2020 Jul;67(7):e28340. Epub 2020 May 2 doi: 10.1002/pbc.28340. PMID: 32359129
Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome.
Hoenig M, Lagresle-Peyrou C, Pannicke U, Notarangelo LD, Porta F, Gennery AR, Slatter M, Cowan MJ, Stepensky P, Al-Mousa H, Al-Zahrani D, Pai SY, Al Herz W, Gaspar HB, Veys P, Oshima K, Imai K, Yabe H, Noroski LM, Wulffraat NM, Sykora KW, Soler-Palacin P, Muramatsu H, Al Hilali M, Moshous D, Debatin KM, Schuetz C, Jacobsen EM, Schulz AS, Schwarz K, Fischer A, Friedrich W, Cavazzana M; European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party
Blood 2017 May 25;129(21):2928-2938. Epub 2017 Mar 22 doi: 10.1182/blood-2016-11-745638. PMID: 28331055Free PMC Article
Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2.
Pannicke U, Hönig M, Hess I, Friesen C, Holzmann K, Rump EM, Barth TF, Rojewski MT, Schulz A, Boehm T, Friedrich W, Schwarz K
Nat Genet 2009 Jan;41(1):101-5. Epub 2008 Nov 30 doi: 10.1038/ng.265. PMID: 19043417

Clinical prediction guides

Reticular Dysgenesis and Mitochondriopathy Induced by Adenylate Kinase 2 Deficiency with Atypical Presentation.
Ghaloul-Gonzalez L, Mohsen AW, Karunanidhi A, Seminotti B, Chong H, Madan-Khetarpal S, Sebastian J, Vockley CW, Reyes-Múgica M, Vander Lugt MT, Vockley J
Sci Rep 2019 Oct 31;9(1):15739. doi: 10.1038/s41598-019-51922-2. PMID: 31673062Free PMC Article
Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India.
Aluri J, Desai M, Gupta M, Dalvi A, Terance A, Rosenzweig SD, Stoddard JL, Niemela JE, Tamankar V, Mhatre S, Bargir U, Kulkarni M, Shah N, Aggarwal A, Lashkari HP, Krishna V, Govindaraj G, Kalra M, Madkaikar M
Front Immunol 2019;10:23. Epub 2019 Feb 4 doi: 10.3389/fimmu.2019.00023. PMID: 30778343Free PMC Article
Altered functional balance of Gfi-1 and Gfi-1b as an alternative cause of reticular dysgenesis?
Barjaktarevic I, Maletkovic-Barjaktarevic J, Kamani NR, Vukmanovic S
Med Hypotheses 2010 Mar;74(3):445-8. Epub 2009 Nov 6 doi: 10.1016/j.mehy.2009.09.053. PMID: 19896777
Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2.
Pannicke U, Hönig M, Hess I, Friesen C, Holzmann K, Rump EM, Barth TF, Rojewski MT, Schulz A, Boehm T, Friedrich W, Schwarz K
Nat Genet 2009 Jan;41(1):101-5. Epub 2008 Nov 30 doi: 10.1038/ng.265. PMID: 19043417
Langerhans cell deficiency in reticular dysgenesis.
Emile JF, Geissmann F, Martin OC, Radford-Weiss I, Lepelletier Y, Heymer B, Espanol T, de Santes KB, Bertrand Y, Brousse N, Casanova JL, Fischer A
Blood 2000 Jul 1;96(1):58-62. PMID: 10891430

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