Thymus Transplantation Dose in DiGeorge #932

DiGeorge anomaly is a congenital disorder in which infants are born with defects of the
thymus, heart, and parathyroid gland. Complete DiGeorge Anomaly is usually fatal within the
first two years of life. This trial evaluates the role of thymus tissue dose in thymus
transplantation in complete (typical) DiGeorge anomaly infants, and continues safety
assessments.

DiGeorge infants who have successful thymus transplants but remain with hypoparathyroidism
must go to the clinic for frequent calcium levels and to the hospital for calcium infusions;
these infants are at risk for seizures from low calcium. Approximately ½ of infants with
profound hypoparathyroidism will develop nephrocalcinosis. This protocol had a parental
parathyroid transplant arm for complete DiGeorge infants with athymia and profound
hypoparathyroidism.

Thymus Transplant Inclusion:

- Typical Complete DiGeorge Anomaly diagnosis

- On 2 separate tests must have < 50 CD3+ T cells/cumm (or < 50 CD3+ T cells/cumm that
are CD62L+ CD45RA+), or < 5% naïve phenotype T cells

- Must have < 20 fold response to PHA (or < 5,000 cpm) on 2 separate tests

- Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring
replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal
ears plus mother with diabetes (type I, type II, gestational)

Exclusion Criteria:

- Must not be anticipated to need heart surgery 4 weeks prior or 3 months
post-transplantation

- Present or past lymphadenopathy

- Rash associated with T cell infiltration of the dermis and epidermis

- Rejection by the surgeon or anesthesiologist as surgical candidate

- Lack of sufficient muscle tissue to accept transplant

- Prior attempts at immune reconstitution (e.g, BMT or thymus transplantation)

- HIV infection

- Ventilator Dependence

Additional Inclusion Criteria for Parathyroid Transplant Recipient:

- 2 tests showing: intact parathyroid hormone (PTH) < 5 pg/ml when ionized calcium < 1.1
mmol/L

- 2 involved parents

Exclusion for Parathyroid Transplant Recipient:

- Parents do not meet enrollment criteria.

- Parent(s) decline to be parathyroid donor(s).

Parental Parathyroid Donor Inclusion:

- > 18 years old

- Answers all questionnaire items and meets safety screening criteria

- Normal serum calcium

- Normal PTH function

- HLA typing consistent with parentage

- Parent chosen for donation will share HLA-DR allele in thymus donor; if not
applicable, then either parent will be selected (if meet all other criteria).

- Must not be on anticoagulation or can come off for donation/transplantation

Parental Parathyroid Donor Exclusion:

- Donor is only living involved parent or caretaker of the recipient

- Hypoparathyroidism - low parathyroid hormone (PTH) in presence of low serum calcium
and high serum phosphate

- Hyperparathyroidism (or history of) - elevated PTH in presence of high serum calcium
and low serum phosphate

- History of cancer

- Evidence of any of following: HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B,
hepatitis C, West Nile virus, or Trypanosoma Cruzi (Chagas disease)

- Elevated AST, ALT, alkaline phosphatase > 3 times upper limit of normal

- History including receipt of a xenograft or risk factors for SARS, Mad Cow - Disease
or smallpox. Note: if parent has Mad Cow Disease risk factors (but not active
disease), parent(s) may give permission for transplantation.

- CMV positive urine

- Positive CMV IgM antibodies

- Positive IgM anti-EBV VCA

- On blood thinners and cannot stop for the parathyroid donation

- Elevated PT or PTT (> ULN)

- Platelets < 100,000

- Positive Toxoplasma IgM

- The donor will receive a history and physical; may be excluded based on PI's medical
judgment

- Hemoglobin < 9 g/dl

- Infectious lesion on head or neck

- Goiter on ultrasound

- Abnormal fiberoptic laryngoscopy of vocal cords

- Pregnancy

- Positive HSV IgG is not an exclusion; however, post transplantation prophylaxis is
needed

- Positive VZV IgG is not an exclusion; however, post transplantation prophylaxis is
needed

- Medical concern of otolaryngologist

- Concern by medical psychologist or social worker including. Parents are interviewed
together and separately regarding following areas: medical history; health habits;
substance use; relationships and support; education/work history; mental
status/psychological history; readiness for donation.

- Questionnaire (safety screening) responses can lead to exclusion.

Biological Mother of DiGeorge Subject Inclusion Criteria:

- Competent to provide consent

- Willing to provide blood for testing (No other inclusion/exclusion for mother)