Purtilo syndrome D82.3

The name "Purtilo syndrome" refers to the author of the initial 1974 description D. T. Purtilo. Duncan is the name of the described family.

X-linked lymphoproliferative syndrome (XLP) is a rare, x-linked, recessively inherited primary immunodeficiency. It is caused by mutations of genes on the X chromosome.

• X-linked lymphoproliferative syndrome type 1 is the most common type (about 60% of all cases) is caused by a mutation in the SH2D1A gene at location Xq25. This gene encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP, also referred to as SH2 domain protein 1A or DSHP). Without SAP, lymphocytes proliferate in an uncontrolled response to Epstein-Barr virus(EBV/HHV-4) infection, while natural killer (NK) cells are deficient in function.

• X-linked lymphoproliferative syndrome type 2 is phenotypically similar to type 1; it predisposes to hemophagocytic lymphohistiocytosis(HLH). XLP2 is caused by mutations in a gene also located on Xq25 that encodes the X-linked inhibitor of apoptosis protein(XIAP gene).

Incidence: <1/ 100.000 persons

On the one hand, the defective SAP protein leads to the activation of certain cell functions being impaired. For example, natural killer (NK) cells or cytotoxic T cells can only insufficiently perform one of their essential tasks, the killing of virus-infected cells. Their task of supporting B lymphocytes in the formation of antibodies is also impaired.

Mutations of the 2nd gene(XIAP gene) also lead to XLP. This gene is also located on the X chromosome and codes for a protein involved in triggering apoptosis of immune cells.

Disease onset in early infancy (2 to 3 years of age), after infection with the Epstein-Barr virus (HHV-4).

Infectious mononucleosis leads to mostly harmless, flu-like symptoms in immunocompromised children. In XLP disease, it leads to a highly acute and often life-threatening Epstein-Barr virus infection (Gilmour KC et al. 2000).

Primary phase of the disease: severe sore throat, fatigue and exhaustion, accompanied by loss of appetite, headache and fever. The tonsils are covered with grayish dirty coatings. A transient skin rash is often seen. In the course, there is generalized lymphadenopathy, hepato- and splenomegaly.

Postinfectious: After a more or less severe course of infectious mononucleosis, XLP usually presents in school-age children as a secondary antibody deficiency syndrome, with a CVID (common variable immunodeficiency) like clinical picture. The consequence is frequent infections.

bacterial infections of the respiratory tract:

• Middle ear infections
• sinus infections
• bronchitis
• pneumonias

viral infections:

- e.g. herpes simplex infections

fungal infections:

- e.g. oral thrush or onychomycosis.

Chronic diarrheal diseases are more common.

Rarer signs of disease observed in XLP patients (3-5% of all patients) are:

• aplastic anemia
• vasculitis
• granulomatous changes in different organs
• bronchiectasis of the lung

Thrombocytopenia with the danger of an increased bleeding tendency. Many of the affected children develop a life-threatening haemophagocytosis syndrome (HLH) during the course of the disease, which leads to the destruction of the body's own blood cells and to a highly inflammatory disease of many organs.

hepatitis, myocarditis, encephalitis, nephritis, or pneumonia; B-cell lymphomas ( Woon ST et al. 2008)

The treatment of XLP consists in the transplantation of hematopoietic stem cells.

Unless haematopoietic stem cell transplantation is performed, about 75% of patients do not reach the age of 10 years! All patients die before the age of 40.

About 80% of patients who receive a transplant survive.

A transplant is curative if it is performed before Epstein-Barr virus infection or other disorders have induced irreversible damage.

A tentative diagnosis should be made in the case of:

decreased antibody responses to antigens (especially EBV nuclear antigen)

impaired T cell proliferative response to mitogens

decreased NK cell function

an inverted CD4: CD8 ratio

These findings are typical before and after Epstein-Barr virus infection . Bone marrow biopsy may help confirm HLH.

Note: Genetic testing of relatives is performed when a case or carrier has been identified in a family. Prenatal screening is recommended in individuals in whom a mutation causing XLP has been identified in the family.

1. Gilmour KC et al (2000) Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression. Eur J Immunol 30:1691-1697.
2. Lyu X et al (2018) Identification of a novel nonsense mutation in SH2D1A in a patient with X-linked lymphoproliferative syndrome type 1: a case report. BMC Med Genet 19:60.
3. Purtilo DT et al (1974) Letter: Fatal infectious mononucleosis in familial lymphohistiocytosis. New Engl J Med 291: 736
4. Skare JC et al (1987) Mapping the X-linked lymphoproliferative syndrome. Proc Natl Acad Sci U S A 84:2015-2018.
5. Woon ST et al (2008) Follicular lymphoma in a X-linked lymphoproliferative syndrome 1carrier female. Scand J Immunol 68:153-158.