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$Unique_ID{BRK04052}
$Pretitle{}
$Title{Nezelof's Syndrome}
$Subject{Nezelof's Syndrome Cellular immunodeficiency with abnormal
immunoglobulin synthesis Purine nucleoside phosphorylase (PNP) deficiency}
$Volume{}
$Log{}

Copyright (C) 1986, 1988 National Organization for Rare Disorders, Inc.

75:
Nezelof's Syndrome

** IMPORTANT **
It is possible that the main title of the article (Nezelof's Syndrome) is
not the name you expected.  Please check the SYNONYM listing to find the
alternate names and disorder subdivisions covered by this article.

Synonyms

     Cellular immunodeficiency with abnormal immunoglobulin synthesis

DISORDER SUBDIVISIONS:

     Purine nucleoside phosphorylase (PNP) deficiency

General Discussion

** REMINDER **
The information contained in the Rare Disease Database is provided for
educational purposes only.  It should not be used for diagnostic or treatment
purposes.  If you wish to obtain more information about this disorder, please
contact your personal physician and/or the agencies listed in the "Resources"
section of this report.

Nezelof's syndrome is a disorder of the immune system.  There are two
important forms of immunity.  The T-cells maintain "cellular" immunity,
consisting of protection against many viruses, fungi, and related
microorganisms; long-term immunity, such as that developed in response to
vaccinations or childhood infections; and allergic reactions.  The B-cells
represent humoral immunity; they produce antibodies against many bacteria,
some viruses, and other pathogens.  In Nezelof's syndrome, cellular immunity
is impaired; there may be abnormalities of humoral immunity in addition.
Affected individuals are unable to ward off or overcome many infections,
including infections by organisms that cannot cause illness in persons with
intact immune systems (opportunistic infections).

Nezelof's syndrome is very rare.  It affects both males and females.  (A
subgroup of about 12 patients has been found in whom a lack the enzyme purine
nucleoside phosphorylase (PNP) appears to explain the immunodeficiency.)  The
prognosis for survival beyond childhood in this disorder is poor unless
matched sibling bone marrow transplants are successful.

Symptoms

Infections are extremely frequent and severe from birth.  Among the
potentially fatal infections are pulmonary infections, oral candidiasis
(thrush), diarrhea, skin infections, septicemia (blood poisoning), urinary
tract infections, measles, and cow pox (vaccinia).  Pneumonia due to the
opportunistic organism Pneumocystis carinii is a characteristic and
particularly serious manifestation.  Infections may also be caused by such
agents as cytomegalovirus, rubeola, pseudomonas, and mycobacteria.  Growth
retardation and general wasting are evident.  Chronic diarrhea is a
characteristic problem.

Cellular immunity impairment is associated with a lack of
hypersensitivity reactions (delayed cutaneous anergy) to appropriate antigens
applied to the skin, with an inability to reject foreign tissue grafts,
potentially fatal reactions to immunization with live vaccines, and a high
incidence of malignant tumors.  Related to the inability to reject foreign
tissue is the susceptibility to graft-versus-host disease (GVHD).  This
occurs when the graft contains immunocompetant cells which react against the
recipient's tissues, causing fever, skin reactions, gastrointestinal
disturbances such as diarrhea, vomiting, intestinal obstruction and
malabsorption, and hepatitis.  Associated with Nezelof syndrome with PNP
deficiency are a progressive neurological deterioration characterized by
spastic paralysis of all the limbs, autoimmune hemolytic anemia, and a
tendency to bleed subcutaneously because of a deficiency of platelets
(thrombocytopenic purpura).

Laboratory findings include very few T-cells and consequently,
lymphopenia.  Other white blood cell counts may be abnormal, too, with reduced
numbers of neutrophils and high concentrations of eosinophils.  Lymph glands
are reduced in size.  The thymus gland, where T-cells are produced, is small
and histologically abnormal.  All classes of antibodies are present, often in
normal concentrations.  Sometimes, there is a selective IgA deficiency.
Substantial elevations of IgE and/or IgD antibodies may also occur.  In PNP
deficiency, uric acid levels in the blood and urine are very low.

Causes

Nezelof's syndrome is thought to be hereditary, but it is unclear whether it
follows an autosomal or a sex linked mode of transmission.  The mechanism of
disease is also poorly understood.  In PNP deficiency, it is thought that the
substrate for PNP accumulates due to the enzyme deficiency, and is
preferentially taken up by T-lymphocytes; within these cells, the high
concentration of the substrate molecule inhibits DNA synthesis, and thus
impairs the cells' functioning.  An unidentified dysfunction of the thymus
gland is suspected to cause the remaining cases of Nezelof's syndrome.

Related Disorders

Other immunodeficiency diseases involving cell mediated immunity include
acquired immune deficiency syndrome (AIDS), severe combined immunodeficiency,
DiGeorge syndrome, Wiscott-Aldrich syndrome, and ataxia-telangiectasia.
AIDS in children may have very similar manifestations to Nezelof's syndrome.
Analysis of the ratios of the different T-cell subgroups to each other and of
the histologic characteristics of the thymus gland may serve to differentiate
the two.

For more information on the above disorders, choose the following words
as your search term in the Rare Disease Database:  immunodeficiency, AIDS,
SCID, DiGeorge, Wiscott, and ataxia.

Therapies:  Standard

In many cases, only symptomatic treatment of each infection as it arises is
possible.  Bone marrow transplants from immunologically compatible sibling
donors have been successful in several cases.  In PNP deficiency, attempts to
replace the missing enzyme, or at least to dilute the excess purine bases,
using blood transfusions, have met with little success.  So has
deoxycytitdine therapy, which was based on the possibility that this
substance might displace the toxic deoxyguanosine in the cells.

Infections must be treated vigorously with antifungal, antibiotic, and
supportive measures.  P. carinii pneumonia can be particularly difficult to
treat; the two drugs usually used are trimethoprim-sulfamethoxazole and the
orphan drug pentamidine isethionate.  (For more information on treatment, see
article on AIDS in the Rare Disease Database.)  Cytomegalovirus and
generalized herpes simplex infections are preferentially treated with
idoxuridine, floxuridine, or cytarabine.  Severe Candida and related fungi
usually respond to amphotericin B therapy.

Patients must be protected as much as possible from infectious agents.
They must not be immunized with live viral vaccines.  Corticosteroids and
immunosuppressant drugs, and removal of the spleen must be avoided.  Should
blood transfusions be necessary due to accidents or surgery, the blood must
be irradiated or "washed" to remove all viable lymphocytes that might cause
graft-versus-host disease.

Therapies:  Investigational

This disease entry is based upon medical information available through March
1987.  Since NORD's resources are limited, it is not possible to keep every
entry in the Rare Disease Database completely current and accurate.  Please
check with the agencies listed in the Resources section for the most current
information about this disorder.

Resources

For more information on Nezeloff's Syndrome, please contact:

     National Organization for Rare Disorders (NORD)
     P.O. Box 8923
     New Fairfield, CT  06812-1783
     [phone]

     Immune Deficiency Foundation
     3565 Ellicott Mill Drive, Unit B2
     Ellicott City, MD  21043
     [phone]
     [phone]

     NIH/National Institute of Allergy and Infectious Disease
     9000 Rockville Pike
     Bethesda, MD  20892
     [phone]

     American Cancer Society
     1599 Clifton Rd., NE
     Atlanta, GA  30329
     [phone]

     NIH/National Cancer Institute
     9000 Rockville Pike, Bldg. 31, Rm. 1A2A
     Bethesda, MD 20892
     1-800-4-CANCER

The National Cancer Institute has developed PDQ (Physician Data Query), a
computerized database designed to give doctors quick and easy access to many
types of information vital to treating patients with this and many other
types of cancer.  To gain access to this service, a doctor can contact the
Cancer Information Service offices at 1-800-4-CANCER.  Information
specialists at this toll-free number can answer questions about cancer
prevention, diagnosis, and treatment.

For information on genetics and genetic counseling referrals, please
contact:

     March of Dimes Birth Defects Foundation
     1275 Mamaroneck Avenue
     White Plains, NY  10605
     [phone]

     Alliance of Genetic Support Groups
     35 Wisconsin Circle, Suite 440
     Chevy Chase, MD  20815
     (800) 336-GENE
     [phone]

References

Immunodeficiency.  Buckley, R.H.  J Allergy Clin Immunol Dec 1983;
72(6):627-641.

Combined immunodeficiency and thymic abnormalities.  Webster, A.D.  J Clin
Pathol (Suppl) 1979; 13:10-14.

Metabolic defects in immunodeficiency diseases.  Webster, A.D.  Clin Exp
Immunol 1982 Jul; 49(1):1-10.