DiGeorge Syndrome

Background

Conditions associated with DiGeorge syndrome are 22q11 deletion syndromes, velocardiofacial syndrome (VCFS or Shprintzen syndrome), conotruncal anomaly face syndrome, Cayler syndrome, Opitz-GBBB syndrome, and CHARGE (coloboma [eye], heart anomaly, atresia [choanal], retardation [mental and growth], genital anomaly, ear anomaly) syndrome.

DiGeorge anomaly (DGA) is a congenital immunodeficiency characterized by abnormal facies; congenital heart defects; hypoparathyroidism with hypocalcemia; cognitive, behavioral, and psychiatric problems; and increased susceptibility to infections. Pathological hallmarks include conotruncal abnormalities and absence or hypoplasia of thymus and parathyroid glands. Although this condition is commonly known as DiGeorge syndrome, the term DiGeorge anomaly is more appropriate. The constellation of defects is not a syndrome resulting from a single cause, but rather the failure of an embryological field to develop normally.

Harrington first noted the absence of the thymus gland in 1929. This condition was later associated with congenital hypoparathyroidism by Lobdell in 1959. Angelo DiGeorge first noted the immunological consequences associated with the above conditions and was the first to propose that the concurrent absence of the thymus and parathyroid glands might result from a perturbation in the development of the third and fourth pharyngeal pouches.

Kelly in Philadelphia and de la Chapelle in France described partial monosomy of chromosome 22 associated with DiGeorge anomaly, providing the first clue to its genetic origin. Since then, a number of phenotypically similar syndromes have been described. Today, these are collectively grouped under the acronym CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia resulting from 22q11 deletions); however, this acronym does not recapitulate the full spectrum of symptoms. This disorder varies greatly in expressivity. While some patients are mildly affected with learning disabilities and subtle craniofacial malformations, others die after birth with thymic aplasia and major cardiovascular defects.

Pathophysiology

DiGeorge anomaly is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The common thread among all the organs involved in DiGeorge anomaly is that their development is dependent on migration of neural crest cells to the region of pharyngeal pouches.

Lammer and Opitz described DiGeorge anomaly as a field defect in which a group of tissues (field or neural crest and pharyngeal pouches in DiGeorge anomaly) that are interdependent on each other for normal development develop in an abnormal fashion. Although DiGeorge anomaly has traditionally been described as abnormal development of the third and fourth pharyngeal pouches, defects involving the first to sixth pouches are known to occur. Animal studies have shown that acute ethanol exposure in mice at a time when neural crest cells are migrating results in a craniofacial phenotype similar to that noted in DiGeorge anomaly. Features of DiGeorge anomaly have been described in children with evidence of fetal alcohol syndrome. Thus, it is postulated that any intrauterine insult to the facial neural crest can result in features of DiGeorge anomaly.

Frequency

United States

Autopsy studies for DiGeorge anomaly accounted for 0.7% of 3469 postmortem examinations in the Seattle, Washington, area over a period of 25 years.

International

In the past, incidence of DiGeorge anomaly was estimated to be 1 case per 20,000 persons in Germany and 1 case per 66,000 persons in Australia. With the advent of fluorescent in situ hybridization (FISH) techniques to detect monosomy 22 and the inclusion of related syndromes, more recent estimates place the incidence of DiGeorge anomaly and VCFS in the range of 1 case per 3000 persons.

Mortality/Morbidity

• A congenital heart defect is the main cause of morbidity and mortality. Ryan et al reported an 8% mortality rate in a series of 558 patients, with heart disease accounting for all but one of the cases. Most deaths occur within 6 months after birth.

• Infections due to severe immune deficiency are the second most common cause of mortality.

Sex

• No major difference is noted in the incidence of DiGeorge anomaly between males and females.

Age

• DiGeorge anomaly usually is diagnosed shortly after birth because of abnormal facies or cardiac manifestations.

Treatment

Medical Care

• Hypoparathyroidism and hypocalcemia are managed with calcium supplements and vitamin D administration.

• Treatment of immunodeficiency
• • Use the usual prophylactic regimens for T- and B-cell deficiency.

  • Several therapies have been used to treat immunodeficiency associated with DiGeorge anomaly. Cases of immune reconstitution have been reported following transplantation of HLA-identical bone marrow, peripheral blood mononuclear cells, and fetal thymus. However, some of these patients may have had partial DiGeorge anomaly, and improvement may have been coincidental.

  • Markert et al reported a study of 5 patients with complete DiGeorge anomaly who were treated with allogeneic, cultured, postnatal thymus tissue. Of these patients, 4 developed immune reconstitution with T-cell proliferative responses to mitogens.

  • Early thymus transplantation (ie, before the onset of infectious complications) may promote successful immune reconstitution. Although Goldsobel et al reported that the results of thymus transplantation are disappointing, a significant number of patients in their group were lost to follow-up, and if their results were corrected accordingly, the benefits of thymus transplantation would seem to be more impressive. T-cell function may improve in patients with partial DiGeorge anomaly; therefore, thymus transplantation is not indicated.

Surgical Care

Correct cardiac malformations per standard surgical techniques. Irradiated cytomegalovirus-negative blood products must be administered because of the risk of graft versus host disease with nonirradiated products. Because the risk of infection is very high, a low index of suspicion must be used with regards to starting antibiotics.

Consultations

Obtain early consultation with a cardiologist and immunologist to evaluate disease manifestations.

Medication

The goals of pharmacotherapy are to prevent calcium deficiency, reduce morbidity, and prevent complications.

Drug Category: Calcium salts

These agents are used to treat or prevent calcium deficiency.

Drug Name	Calcium gluconate (Kalcinate)
Description	Moderates nerve and muscle performance and facilitates normal cardiac function. Can be administered IV initially, and calcium levels maintained with high-calcium diet. Some patients require oral calcium supplementation. The 10% IV solution provides 100 mg/mL of calcium gluconate, which equals 9 mg/mL (0.46 mEq/mL) of elemental calcium.
Adult Dose	Doses expressed as calcium gluconate 2-3 g IV over 5-10 min; repeat q6h prn based on response and serum calcium levels; not to exceed 15 g/d Alternatively: Repeat doses administered as 167 mg/kg IV infusion over 4-6h prn Oral supplementation: 15 g/d PO divided tid/qid
Pediatric Dose	Doses expressed as calcium gluconate 100-200 mg/kg IV over 5-10 min; then 500 mg/kg/d IV continuous infusion or divided doses q6-8h Oral supplementation: 500-725 mg/kg/d PO divided qid
Contraindications	Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions	May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in digitalized patients and patients with respiratory failure, acidosis, or severe hyperphosphatemia

Drug Name	Calcium carbonate (Os-Cal, Titralac, Oystercal, Caltrate)
Description	Has higher oral bioavailability of calcium than other orally administered calcium salt products. Moderates nerve and muscle performance and facilitates normal cardiac function. Dose expressed as calcium carbonate.
Adult Dose	5-10 g/d PO divided tid/qid
Pediatric Dose	112.5-162.5 mg/kg/d PO divided qid
Contraindications	Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions	May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in digitalized patients and patients with respiratory failure, acidosis, or severe hyperphosphatemia

Drug Category: Vitamin D supplements

These supplements help treat, prevent, or manage hypocalcemia.

Drug Name	Ergocalciferol, vitamin D-2 (Drisdol)
Description	Vitamin D-2 analog converted in liver to an active intermediate and then further converted to most active form in kidneys. Effectively increases renal reabsorption of calcium, intestinal absorption of calcium, and calcium mobilization from bone to plasma.
Adult Dose	25,000-200,000 U/d PO along with calcium supplements
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hypercalcemia; malabsorption syndrome
Interactions	Colestipol, mineral oil, and cholestyramine may decrease absorption of ergocalciferol from small intestine; thiazide diuretics may increase effects of vitamin D
Pregnancy	A - Safe in pregnancy
Precautions	Pregnancy category C in doses >400 U/d; caution in patients with cardiac disease, arteriosclerosis, renal impairment, and renal stones; caution during breastfeeding