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Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD(CVID9, FORMERLY; ALPS3)

MedGen UID:
816258
Concept ID:
C3809928
Disease or Syndrome
Synonym: Autoimmune lymphoproliferative syndrome, type III
 
Gene (location): PRKCD (3p21.1)
 
Monarch Initiative: MONDO:8000024
OMIM®: 615559

Definition

Autoimmune lymphoproliferative syndrome type III is an autosomal recessive disorder of immune dysregulation. The phenotype is variable, but most patients have significant lymphadenopathy associated with variable autoimmune manifestations. Some patients may have recurrent infections. Lymphocyte accumulation results from a combination of impaired apoptosis and excessive proliferation (summary by Oliveira, 2013). For a general description and a discussion of genetic heterogeneity of ALPS, see 601859. [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).
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Recurrent urinary tract infections
MedGen UID:
120466
Concept ID:
C0262655
Disease or Syndrome
Repeated infections of the urinary tract.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Obstruction of the superior vena cava
MedGen UID:
277776
Concept ID:
C1336532
Pathologic Function
Blockage of blood flow through the superior vena cava (SVC). Because the venous drainage from the upper extremities, upper thorax and head is obstructed, SVC obstruction presents with symptoms related to engorgement of these areas. Both the degree of SVC compromise and the extent of collateral veins determine the varied clinical presentation, which can be as mild as slight facial and upper extremity edema or as dire as intracranial swelling, seizures, hemodynamic instability and tracheal obstruction.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Arthritis
MedGen UID:
2043
Concept ID:
C0003864
Disease or Syndrome
Inflammation of a joint.
Recurrent sinusitis
MedGen UID:
107919
Concept ID:
C0581354
Disease or Syndrome
A recurrent form of sinusitis.
Recurrent upper respiratory tract infections
MedGen UID:
154380
Concept ID:
C0581381
Disease or Syndrome
An increased susceptibility to upper respiratory tract infections as manifested by a history of recurrent upper respiratory tract infections (running ears - otitis, sinusitis, pharyngitis, tonsillitis).
Recurrent lower respiratory tract infections
MedGen UID:
756211
Concept ID:
C3163798
Disease or Syndrome
An increased susceptibility to lower respiratory tract infections as manifested by a history of recurrent lower respiratory tract infections.
Autoimmune hemolytic anemia
MedGen UID:
1918
Concept ID:
C0002880
Disease or Syndrome
An autoimmune form of hemolytic anemia.
Autoimmunity
MedGen UID:
2136
Concept ID:
C0004368
Pathologic Function
The occurrence of an immune reaction against the organism's own cells or tissues.
Membranous nephropathy
MedGen UID:
42231
Concept ID:
C0017665
Disease or Syndrome
A type of glomerulonephropathy characterized by thickening of the basement membrane and deposition of immune complexes in the subepithelial space.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Antinuclear antibody positivity
MedGen UID:
101792
Concept ID:
C0151480
Laboratory or Test Result
The presence of autoantibodies in the serum that react against nuclei or nuclear components.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Autoimmune thrombocytopenia
MedGen UID:
116621
Concept ID:
C0242584
Disease or Syndrome
The presence of thrombocytopenia in combination with detection of antiplatelet antibodies.
Generalized lymphadenopathy
MedGen UID:
96909
Concept ID:
C0476486
Finding
A generalized form of lymphadenopathy.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargement (swelling) of a lymph node.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Decreased circulating complement C3 concentration
MedGen UID:
332469
Concept ID:
C1837512
Finding
Concentration of the complement component C3 in the blood circulation below the lower limit of normal.
Reduced natural killer cell activity
MedGen UID:
333452
Concept ID:
C1839969
Finding
Reduced ability of the natural killer cell to function in the adaptive immune response.
Increased B cell count
MedGen UID:
349067
Concept ID:
C1858972
Finding
An abnormal increase from the normal count of B cells.
Persistent EBV viremia
MedGen UID:
767466
Concept ID:
C3554552
Finding
Persistent presence of Epstein-Barr virus in the blood.
Follicular hyperplasia
MedGen UID:
863170
Concept ID:
C4014733
Finding
Lymphadenopathy (enlargement of lymph nodes) owing to hyperplasia of follicular (germinal) centers.
Decreased proportion of memory B cells
MedGen UID:
893145
Concept ID:
C4072913
Finding
A reduction in the normal proportion of memory B cells (CD19+/CD27+) in circulation relative to the total number of B cells. Memory B cells develop from naive B cells. Upon antigen rechallenge, memory B cells rapidly expand and differentiate into plasma cells under the cognate control of memory Th cells (Phase IV).
Decreased proportion of class-switched memory B cells
MedGen UID:
892709
Concept ID:
C4072925
Finding
A reduction in the normal proportion of class-switched memory B cells (CD19+/CD27+/IgM+/IgD+) relative to the total number of B cells. Marginal zone B cells undergo limited somatic hypermutation and produce high-affinity IgM and some IgG, whereas class-switched memory B cells synthetize IgG, IgM, and IgA.
Decreased circulating complement C4 concentration
MedGen UID:
893114
Concept ID:
C4073169
Finding
Concentration of the complement component C4 in the blood circulation below the lower limit of normal.
Absent isohemagglutinin level
MedGen UID:
1691361
Concept ID:
C5139456
Finding
Absent or undetectable level of isohemagglutinin. An isohemagglutinin refers to the naturally occurring antibodies in the ABO blood group system (i.e., anti-A in a group B person, anti-B in a group A person, and anti-A, anti-B, and anti-A,B in a group O person).
Anticardiolipin IgG antibody positivity
MedGen UID:
1696853
Concept ID:
C5209232
Laboratory or Test Result
The presence of circulating IgG autoantibodies to cardiolipin.
Increased circulating antibody concentration
MedGen UID:
1713383
Concept ID:
C5397581
Finding
An increased level of gamma globulin (immunoglobulin) in the blood.
Increased proportion autoreactive unresponsive CD21-/low B cells
MedGen UID:
1772613
Concept ID:
C5421684
Finding
Increased proportion relative to B-lymphocytes of a subset of B lymphocytes characterized by dim/low levels of CD21, i.e., CD21-/low, in flow cytometry, and additionally enriched in autoreactive clones as determined for instance by clonse showing rheumatoid factor (anti-IgG) reactivity and antibodies recognizing cytoplasmic and to a lesser extent nuclear structures.
Elevated erythrocyte sedimentation rate
MedGen UID:
57727
Concept ID:
C0151632
Finding
An increased erythrocyte sedimentation rate (ESR). The ESR is a test that measures the distance that erythrocytes have fallen after one hour in a vertical column of anticoagulated blood under the influence of gravity. The ESR is a nonspecific finding. An elevation may indicate inflammation or may be caused by any condition that elevates fibrinogen.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.
Elevated circulating C-reactive protein concentration
MedGen UID:
892906
Concept ID:
C4023452
Finding
An abnormal elevation of the C-reactive protein level in the blood circulation.
Mediastinal lymphadenopathy
MedGen UID:
451062
Concept ID:
C0520743
Disease or Syndrome
Swelling of lymph nodes within the mediastinum, the central compartment of the thoracic cavities that contains the heart and the great vessels, the esophagus, and trachea and other structures including lymph nodes.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
Erythematous macule
MedGen UID:
1390597
Concept ID:
C2228270
Finding
A macule (flat, distinct, discolored area of skin less than 1 cm wide that does not involve any change in the thickness or texture of the skin) with a red or reddish color often associated with inflammation or irritation.

Recent clinical studies

Therapy

Gu H, Chen Z, Ma J, Wang J, Zhang R, Wu R, Wang T
Int J Immunopathol Pharmacol 2021 Jan-Dec;35:20587384211025934. doi: 10.1177/20587384211025934. PMID: 34187243Free PMC Article

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