X-linked lymphoproliferative disease

X-linked lymphoproliferative disease
Classification and external resources
Specialty	hematology
ICD-10	D82.3
OMIM	308240 300635
DiseasesDB	3998
eMedicine	med/1370
MeSH	D008232
GeneReviews	Lymphoproliferative Disease, X-Linked

X-linked lymphoproliferative disease (also known as "Duncan's disease"^[1]^:86 or "Purtilo syndrome"^[2]) is a lymphoproliferative disorder.^[3]

Causes

XLP1

There is a mutation on the X-chromosome that has been found to be associated with a T- and NK-cell lymphoproliferative disorder. The mutation is on the long arm of the chromosome, at position 25, which is denoted as Xq25. At this position, there is a deletion in the SH2D1A gene, which codes for an SH2 domain on a signal transducing protein called SLAM-associated protein (SAP).

The term "SH2" domain stands for src-homology 2 domain, which is a three-dimensional domain structure of about 100 amino acid residues. These domains are present in many signalling proteins because they permit specific, non-covalent bonding to proteins that contain phosphotyrosines. The amino acid residues adjacent to the phosphotyrosine on the target protein are what determine the unique binding specificity.^[4]

The SAP protein is important in the signalling events that activate T- and NK-cells^[5] due to its adaptor function. Normally, the SAP protein is expressed in the cytoplasm of T- and NK-cells, where it binds to the cytoplasmic domain of the surface receptor called signaling lymphocyte activation molecule (SLAM). This binding initiates a signal transduction pathway, which results in the modulation of IFN-γ. A deletion in the SH2D1A gene leads to a non-functional SH2 domain on the SAP protein, making it unable to bind to SLAM. This leads to aberrant IFN-γ modulation, causing uncontrolled cell proliferation.

XLP2

A second form is associated with XIAP.^[6]

Some sources recommend classifying this condition as "X-linked familial hemophagocytic lymphohistiocytosis" instead of X-linked lymphoproliferative disease.^[7]

Presentation

Strangely, in boys with X-linked lymphoproliferative disorder, there is an inability to mount an immune response to the Epstein-Barr virus (EBV),^[8] which often leads to death from bone marrow failure, irreversible hepatitis, and malignant lymphoma. However, the connection between EBV and X-linked lymphoproliferative disorder is yet to be determined.^[9]

Patients produce insufficient numbers of CD27 memory B cells.^[10]

References

↑ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
↑ http://ghr.nlm.nih.gov/condition/x-linked-lymphoproliferative-disease
↑ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 808. ISBN 1-4160-2999-0.
↑ Abbas, A.K; Lichtman, A.H. (2005). Cellular and Molecular Immunology (5th ed.). Philadelphia: Elsevier Saunders.
↑ X-linked Lymphoproliferative Syndrome at Merck Manual of Diagnosis and Therapy Professional Edition
↑ Rigaud S, Fondanèche MC, Lambert N, et al. (November 2006). "XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome". Nature 444 (7115): 110–4. doi:10.1038/nature05257. PMID 17080092.
↑ Marsh RA, Madden L, Kitchen BJ, et al. (August 2010). "XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease". Blood 116 (7): 1079–82. doi:10.1182/blood-2010-01-256099. PMC 2938130. PMID 20489057.
↑ Kumar,Vinay; Cotran, Ramzi S.; Robbins, Stanley L. (2003). Robbins Basic Pathology, 7th Edition. Philadelphia: Elsevier. p. 418. ISBN 1-4160-2534-0.
↑ Lymphoproliferative Disorders at eMedicine
↑ Ma CS, Pittaluga S, Avery DT, et al. (February 2006). "Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease". J. Clin. Invest. 116 (2): 322–33. doi:10.1172/JCI25720. PMC 1332028. PMID 16424938.

External links

Sex linkage: X-linked disorders

X-linked recessive

Immune	Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency

Hematologic	Haemophilia A Haemophilia B X-linked sideroblastic anemia

Endocrine	Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita

Metabolic	Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry's disease Mucopolysaccharidosis: Hunter syndrome Purine-pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: Menkes disease/Occipital horn syndrome

Nervous system	X-linked mental retardation: Coffin–Lowry syndrome MASA syndrome X-linked alpha thalassemia mental retardation syndrome Siderius X-linked mental retardation syndrome Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2

Skin and related tissue	Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy

Neuromuscular	Becker's muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1

Urologic	Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus

Bone/tooth	AMELX Amelogenesis imperfecta

No primary system	Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome

X-linked dominant

X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

Hematological malignancy/leukemia histology (ICD-O 9590–9989, C81–C96, 200–208)
Lymphoid/Lymphoproliferative, Lymphomas/Lymphoid leukemias (9590–9739, 9800–9839)

B cell
(lymphoma,
leukemia)
(most CD19

CD20)

By
development/
marker

TdT+	ALL (Precursor B acute lymphoblastic leukemia/lymphoma)

CD5+	naive B cell (CLL/SLL) mantle zone (Mantle cell)

CD22+	Prolymphocytic CD11c+ (Hairy cell leukemia)

CD79a+	germinal center/follicular B cell (Follicular Burkitt's GCB DLBCL Primary cutaneous follicle center lymphoma) marginal zone/marginal zone B-cell (Splenic marginal zone MALT Nodal marginal zone Primary cutaneous marginal zone lymphoma)

RS (CD15+, CD30+)	Classic Hodgkin's lymphoma (Nodular sclerosis) CD20+ (Nodular lymphocyte predominant Hodgkin's lymphoma)

PCDs/PP (CD38+/CD138+)	see immunoproliferative immunoglobulin disorders

By infection

KSHV (Primary effusion)
EBV (Lymphomatoid granulomatosis
Post-transplant lymphoproliferative disorder)
HIV (AIDS-related lymphoma)
Helicobacter pylori (MALT lymphoma)

Cutaneous

T/NK

T cell
(lymphoma,
leukemia)
(most CD3

CD4
CD8)

By
development/
marker

TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma)

prolymphocyte (Prolymphocytic)

Cutaneous

MF+variants	indolent: Mycosis fungoides Pagetoid reticulosis Granulomatous slack skin aggressive: Sézary disease Adult T-cell leukemia/lymphoma

Non-MF	CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma Pleomorphic T-cell lymphoma Lymphomatoid papulosis type B CD30+: CD30+ cutaneous T-cell lymphoma Secondary cutaneous CD30+ large-cell lymphoma Lymphomatoid papulosis type A

Other
peripheral

By infection

HTLV-1 (Adult T-cell leukemia/lymphoma)

NK cell/
(most CD56)

T or NK

Lymphoid+
myeloid

Acute biphenotypic leukaemia

Lymphocytosis

Cutaneous lymphoid hyperplasia

Deficiencies of intracellular signaling peptides and proteins

GTP-binding protein regulators

GTPase-activating protein	Neurofibromatosis type I Watson syndrome Tuberous sclerosis

Guanine nucleotide exchange factor	Marinesco–Sjögren syndrome Aarskog–Scott syndrome Juvenile primary lateral sclerosis X-Linked mental retardation 1

G protein

Heterotrimeic	cAMP/GNAS1: Pseudopseudohypoparathyroidism Progressive osseous heteroplasia Pseudohypoparathyroidism Albright's hereditary osteodystrophy McCune–Albright syndrome CGL 2

Monomeric	RAS: HRAS Costello syndrome KRAS Noonan syndrome 3 KRAS Cardiofaciocutaneous syndrome RAB: RAB7 Charcot–Marie–Tooth disease RAB23 Carpenter syndrome RAB27 Griscelli syndrome type 2 RHO: RAC2 Neutrophil immunodeficiency syndrome ARF: SAR1B Chylomicron retention disease ARL13B Joubert syndrome 8 ARL6 Bardet–Biedl syndrome 3

MAP kinase

Cardiofaciocutaneous syndrome

Other kinase/phosphatase

Tyrosine kinase	BTK X-linked agammaglobulinemia ZAP70 ZAP70 deficiency

Serine/threonine kinase	RPS6KA3 Coffin-Lowry syndrome CHEK2 Li-Fraumeni syndrome 2 IKBKG Incontinentia pigmenti STK11 Peutz–Jeghers syndrome DMPK Myotonic dystrophy 1 ATR Seckel syndrome 1 GRK1 Oguchi disease 2 WNK4/WNK1 Pseudohypoaldosteronism 2

Tyrosine phosphatase	PTEN Bannayan–Riley–Ruvalcaba syndrome Lhermitte–Duclos disease Cowden syndrome Proteus-like syndrome MTM1 X-linked myotubular myopathy PTPN11 Noonan syndrome 1 LEOPARD syndrome Metachondromatosis

Signal transducing adaptor proteins

Other

NF2
- Neurofibromatosis type II
NOTCH3
- CADASIL
PRKAR1A
- Carney complex
PRKAG2
- Wolff–Parkinson–White syndrome
PRKCSH
- PRKCSH Polycystic liver disease
XIAP
- XIAP2

See also intracellular signaling peptides and proteins

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