DiGeorge Syndrome

 

INTRODUCTION

Background: The syndrome that now is understood to be the chromosome 22q11 deletion syndrome actually grew out of 3 syndromes described on 2 continents. The first of these was DiGeorge syndrome (DGS), which was described by Angelo DiGeorge, MD, in 1965, although the description was not published until 1968, 2 years after the syndrome was named for him.

DiGeorge was the first to provide clinical examples in humans demonstrating that the thymus was involved in immune function, lending credence to the then new theory that the immune system was composed of 2 distinct elements: the humoral (B-cell) element and the cell-mediated (T-cell) element. He demonstrated this by describing the cases of 4 infants with thymic hypoplasia, hypoparathyroidism, and recurrent infection. This triad of findings grew over time, and DiGeorge association (DGA) came to include congenital cardiac anomalies, craniofacial dysmorphology, and learning dysfunction, all of which were traced to a defect in the third and fourth pharyngeal pouches during embryogenesis.

About 10 years later, in Japan, Kinouchi et al described the conotruncal anomalies face (CTAF) syndrome, composed of congenital conotruncal cardiac anomalies, characteristic facies, learning dysfunction, and developmental delay. Two years after that, Shprintzen et al described their experiences in a craniofacial clinic with a syndrome of congenital conotruncal cardiac anomalies, characteristic facies, velopharyngeal dysfunction with or without cleft palate, and learning dysfunction, which they termed the velocardiofacial syndrome (VCFS).

Two things prompted the discovery of a common genetic link between these supposedly distinct phenotypes. The first came from a comparison of DGA with VCFS. The children DiGeorge described all presented (and died) in infancy, while those with VCFS presented at an older age. As understanding of DGA improved, care of affected children improved as well. This, along with the new diagnosis of partial DGA, allowed many children with DGA to survive into the second decade of life, when they clearly resembled the older patients with VCFS. The theory was entertained that children with VCFS may have a form of DGA without the immune dysfunction common in the diagnosis of DGA in infancy.

Genetic support for this came in 1981 when de la Chapelle reported a family with a balanced translocation t(20;22)(q11;q11) in individuals with an unbalanced karyotype resulting in monosomy 22q11 and phenotypic features of DGA. Based on this finding and the similarity between DGA and VCFS phenotypically, similar genetic studies were performed on individuals with DGA, VCFS, and CTAF.

A common area of deletion, known as the DiGeorge syndrome critical region (DGCR), was found on band 22q11.2. As a result, these 3 syndromes have been combined into one genetic entity with variable phenotypic presentations. Some have suggested the name CATCH 22 be used for this group, since it describes the findings of cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia on chromosome 22; however, given its literary connotations, this terminology is apt to cast the prognosis of this syndrome in a pessimistic light to the patients' parents and caregivers and thus probably should be avoided. Chromosome 22q11 deletion syndrome is probably better employed in the description of this condition.

Pathophysiology: As the name implies, this syndrome is the result of a deletion on the long arm of chromosome 22. The usual deletion is quite long (2-3 Mb), found in 95% of patients with DGA and 75% of patients with VCFS, and defined as the DGCR. This area is believed to have a predilection for such mutations during meiosis as a result of the many repetitive DNA sequences found there. A minimal critical region of 250-500 kb appears to exist within the DGCR and has been identified as DGCR5, which, although it does not transcribe any particular RNA, may function as a regional transcription controller. Support for this theory has come from recent studies of the mouse transcription factor gene Tbx1, which maps to the murine equivalent of the DGCR. Genetically engineered mice have been used to demonstrate that haplo-insufficiency of this gene produces DGA-like cardiovascular abnormalities (but not extracardiac ones).

The result of this deletion is a developmental field defect involving the third and fourth pharyngeal pouches, caused by defective migration of the neural crest cells during the fourth week of embryogenesis. Portions of the heart, head and neck, thymus, and parathyroids derive from these pouches, and the clinical manifestations arise from them as well.

Frequency:

  • In the US: Incidence of chromosome 22q11 deletion syndrome initially was estimated at 1:20,000 live births, but as the syndrome has become better understood and the technology for detecting submicroscopic deletions more sensitive, the estimates are now closer to 1:4,000. It is found in 8% of cleft palates, making it the most commonly associated genetic defect, and in 25% of congenital cardiac defects, placing it second only to Down syndrome as a genetic cause of neonatal heart malformation.
  • Internationally: Incidence of chromosome 22q11 deletion syndrome is the same internationally as it is in the United States.

Mortality/Morbidity: The aspects of the deletion syndrome that lead to the greatest morbidity and mortality are cardiac. Cardiac defects are observed in 80-90% of patients who carry this genetic defect. Only a small fraction of patients experience recurrent infection secondary to immunodeficiency, which involves primarily the T-cell lineage. Failure to thrive may be observed during early infancy in those with cleft palates and swallowing difficulties.

Race: No racial or ethnic predisposition has been identified.

Sex: Males and females appear to be affected equally.

Age: This is a congential condition; therefore, the genetic defect exists at birth. Age of presentation depends largely on the severity and nature of the defect, thus those with more serious cardiac defects and/or hypocalcemia observed in classic DGA are diagnosed in the neonatal period. Recurrent infections usually present in patients older than 3-6 months. Some individuals without hypocalcemia who have normal immune function, mild cardiac defects, and minimal facial anomalies may not be diagnosed until late childhood.

 

CLINICAL

History: The most common reason to suspect chromosome 22q11 deletion syndrome is a cardiac anomaly, especially a conotruncal one. Neonatal hypocalcemia also should raise suspicion for this syndrome, especially if the hypocalcemia or heart defect is coupled with the cleft palate that frequently is observed in affected individuals. The characteristic facies of this syndrome are often subtle in infancy and not fully manifested until the child is older; therefore, they are not common causes of genetic investigation. The same is true of developmental delays, which often are not noticed until the child is of school age. A recent review of a large series reported involvement as follows: cardiac system (49%), developmental delay (16%), behavioral disturbance (7%), otolaryngologic system (6%), psychiatric symptoms (3%), and mental retardation (2%).

  • Cardiac defects are observed in 49-90% of patients with this genetic defect.
    • The resulting cardiac defect is usually, but not always, an obstructive lesion involving the left ventricular outflow tract. This type of defect, as well as others, arises from a branchial arch mesenchymal tissue defect, of which the most frequently observed anomaly is, by far, the type B interrupted aortic arch, followed by a right aortic arch.
    • Other defects in this family include bicuspid aortic valve, membranous ventricular septal defects, aberrant right subclavian artery, and atrial septal defects.
    • Other anomalies include truncus arteriosus, the tetralogy of Fallot (consisting of pulmonic stenosis, overriding aorta, ventricular septal defect, and right ventricular hypertrophy), pulmonary valve stenosis, double outlet right ventricle, transposition of the great arteries, and the absent pulmonary vein syndrome.
    • In the neck, approximately 25% of affected persons have anomalies of the internal carotid artery, which, although rarely an intrinsic cause for concern, can be problematic if anomalies are encountered unexpectedly during a surgical procedure.
  • Patients usually have characteristic facies, which become more pronounced as the children grow into the second decade.
    • The most common malformation in this region is velopharyngeal insufficiency, often associated with a cleft second palate.
    • Many affected children present when aged 1-2 months with poor suck as a result of the velopharyngeal insufficiency alone and/or in combination with the generalized hypotonia that sometimes is observed in these infants.
    • The swallowing problem usually resolves by the end of the first year, leaving the child with hypernasal speech as the main remaining manifestation.
    • A degree of midface hypoplasia also is present, which produces narrowed nasal passages and eustachian tubes and leads to recurrent episodes of otitis media, which, in turn, causes the conductive hearing loss observed in 75% of patients with this deletion.
  • Recurrent infection occurs secondary to immune deficiency.
    • The characteristic immunodeficiency is a mild-to-moderate defect in T-cell lineage as a consequence of thymic hypoplasia. Only approximately 25% of patients with DGA have clinically significant immune dysfunction, also known as complete DGA, while most patients with this syndrome do not suffer from opportunistic infections observed in other patients with severe T-cell immunodeficiencies. Only a small fraction of patients present with marked impairment of T-cell function associated with complete absence of thymus and T cells and severe systemic infections.
    • Variable secondary humoral defects can be present, including hypogammaglobulinemia, selective antibody deficiency, and polysaccharide antigens.

    • Patients with DGA tend to present with immune dysfunction more frequently than those diagnosed with VCFS. However, this is highly variable, even among those with similar genotypes.

    • Clinically significant immune problems appear to occur in individuals with CD3+ T-cell counts below500 and CD4+ below 350. Those who have no T-cell function can be thought to have essentially no thymus present, as surgical measurements of thymic size in patients with no clinical evidence of T-cell dysfunction have shown glands as small as 0.1 cm to be associated with normal T-cell immunity.
  • Hypoparathyroidism effects are observed.
    • The incidence of hypocalcemia is much higher in patients with DGA (60-90%) than that observed overall in patients with chromosome 22q11 deletion syndrome.

    • Approximately 10-20% of patients who have hypocalcemia and this syndrome present with hypocalcemia when aged 0-3 months. Approximately 10% present with seizures secondary to hypocalcemia, and another 10-20% seize at some time before calcium homeostasis is attained. This is frequently a self-limiting problem, and about one half of these children are no longer receiving calcium supplementation by age 1 year.
  • Developmental delay and learning disability are observed in virtually all patients with chromosome 22q11 deletion syndrome.
    • Initially, developmental milestones are achieved later than expected for age. Delayed language acquisition often is seen in older children. As they near school age, 40-50% of patients are found to be affected with mental retardation.
    • A frequent pattern of disability is observed in these children, consisting of a low performance intelligence quotient (IQ) compared to verbal IQ, which creates problems with nonverbal learning, abstract reasoning, and math.

    • Hypoxia secondary to hypocalcemic seizures or cyanotic cardiac lesions has been suspected as a cause of this retardation, but this theory has not been supported convincingly yet.
  • Some form of psychosis may occur in 3-60% of patients.
    • Paranoid schizophrenia is the most common psychosis in one series, and mood disorders are the most common in sibling controls.

    • A structural defect has been sought, but not conclusively found, to explain this behavior, and investigators have been unable to correlate a particular location or size of deletion to the type or degree of neurologic or psychiatric problem affecting the individual.

Physical: Physical examination findings vary depending on the organ systems involved.

  • Patients usually have characteristic facies, which become more pronounced as the child grows into the second decade.
    • The most common malformation in this region is velopharyngeal insufficiency, often associated with a cleft second palate.
    • Other frequent facial features include narrowed palpebral fissures with lateral displacement of the inner canthi, retrognathia, prominent nose and squared nasal root, long face with vertical maxillary excess, microcephaly, posteriorly rotated or low-set ears, minor auricular anomalies, and midface hypoplasia.
  • Cardiac findings may be present, depending on the nature of the cardiac lesion.

Causes: The 21q11 deletion syndrome can be transmitted in an autosomal-dominant manner or arise from an unbalanced translocation from a balanced parent. One large series reported only 12% incidence of familial deletion, and of those, 29% had a paternally originated deletion. Other patients appeared to have de novo deletions (although 25% of parents of children with supposedly de novo deletions are found to carry the same deletions themselves). Environmental factors, such as maternal alcohol use, retinoid exposure, or uncontrolled diabetes during pregnancy, also have been implicated.

 

DIFFERENTIALS

Velocardiofacial Syndrome


Other Problems to be Considered:

CTAF syndrome


WORKUP

Lab Studies:

  • Test for gene mutation: Making the diagnosis of chromosome 22q11 deletion syndrome requires performing fluorescent in situ hybridization (FISH) probe for the 22q11 deletion with high-resolution chromosome analysis.
  • Immune function tests
    • Enumeration of lymphocyte subpopulation using surface marker staining and flow cytometric analysis: Typical patients with DGS with immune dysfunction have decreased number of T-cell lineage, such as CD3+, CD4+, and CD8+, but normal B cells and natural killer (NK) cells. The CD3+ and CD4+ T-cell quantifications and the phytohemagglutinin (PHA) proliferation response should be performed. Of the 3 tests, the latter 2 are more predictive of poor immune function either now or in the future, and results are of concern when the CD4+ T-cell count is less than 400 or the PHA proliferation index is less than 10. This immune deficiency can be transitory, and, as these children approach age 1 year, they should undergo a reevaluation of their immune histories and laboratory tests prior to deciding whether to use the measles-mumps-rubella (MMR) or varicella vaccines.
    • In vitro lymphocyte stimulation with PHA: Earlier reports suggested that poor in vitro proliferative response to PHA (stimulation index <10) was predictive of clinical immunodeficiency.
  • Parathyroid evaluation: Measure serum parathyroid hormone and ionized calcium levels. If the results are normal, further testing with sodium ethylenediaminetetraacetic acid (EDTA) often reveals subclinical hypoparathyroidism, since the parathyroid hormone secretory reserve often is low in these children, despite normal parathyroid hormone and ionized calcium levels in the serum. Once calcium levels normalize and therapy is stopped, levels still need to be checked because a return to hypoparathyroidism and hypocalcemia is possible.

Imaging Studies:

  • Cardiac: Cardiac assessment is accomplished readily by referral to a pediatric cardiologist with subsequent ECG, chest radiograph (CXR), cardiac echocardiography, and catheterization studies as necessary.
  • Thymus: Chest radiographs can demonstrate a decreased thymic silhouette but are unreliable. MRI is slightly better; however, thymic size is a poor predictor of immune function.
  • Head and neck: Magnetic resonance angiography (MRA) or conventional angiography is necessary before any neck surgery to identify abnormalities of the internal carotids.

Other Tests:

  • ECG may be used for cardiac assessment.

Procedures:

  • Cardiac catheterization studies are performed as needed for cardiac assessment.

 

TREATMENT

Medical Care:

  • Cardiac: If a lesion is present, further treatment, often surgical, can be directed depending on the type of lesion identified, and patients can be made aware of the need for bacterial endocarditis prophylaxis prior to certain procedures.
  • Immunologic

    • Immune function must be checked, and, while awaiting the results of these investigations, the patient must be treated as presumptively immunodeficient and receive cytomegalovirus-negative irradiated blood if transfusions are necessary. The immune deficiency can be transitory, and as these patients approach age 1 year, they should undergo reevaluation of their immune histories and laboratory tests prior to deciding whether to administer live attenuated vaccines such as the MMR or varicella vaccines.

    • Place patients with impaired immune function on Pneumocystis carinii pneumonia (PCP) prophylaxis with trimethoprim/sulfamethoxazole. Neither patients nor those in their households should receive live attenuated vaccines. Thymic and bone marrow transplantations are newer modalities that appear promising in normalizing the immune function of these children. Markert et al recently reported their experiences with thymic transplantation in 5 children with complete DGA and little or no circulating T lymphocytes, 2 of whom recovered normal immune function (the other 3 died of complications unrelated to their transplants).
  • Endocrine: If the patient is found to be hypocalcemic, begin calcium supplementation with subsequent frequent checks of ionized calcium levels to direct the dose and need for continued replacement therapy. Vitamin D supplementation and phosphate retention also may become necessary in refractory cases.
  • Failure to thrive: Feeding difficulties and failure to thrive are common in these patients, especially in those with significant cleft palates. Sometimes placement of a nasogastric tube is necessary for feeds during the first 6-12 months to provide adequate nutrition and thus avoid serious growth failure.
  • Other problems: Patients with other conditions, including developmental delay and psychosis, should receive appropriate care.

Surgical Care:

  • Cardiac: Surgical repair often is necessary to correct the frequently observed cardiac defects.
  • Head and neck: As patients with DGA grow older, correction of hypernasal speech becomes important; this can be performed initially with a combination of speech therapy followed later by surgery, often after the child is aged 3-4 years. Adenoidectomy in these children is absolutely contraindicated because this worsens the nasal escape by opening the velopharyngeal opening.

Consultations: Multidisciplinary follow-up care is usually necessary for optimum medical care of these patients; the following specialists can be consulted:

  • Geneticists for workup of chromosomal anomalies and for genetic counseling
  • Pediatric cardiologist for evaluation and management of cardiac disease
  • Pediatric thoracic surgeons when patient requires cardiac surgery
  • Craniofacial specialist for treatment of patients with cleft palate and feeding difficulties
  • Otolaryngologist because patients with chromosome 22q11 deletion syndrome must be observed and vigorously treated for otitis media to prevent conductive hearing loss. (Patients also should receive periodic hearing evaluations.)
  • Immunologist for evaluation of immune function

  • Pediatric endocrinologist for evaluation and management of hypocalcemia

  • Psychiatrists if necessary

Diet: No special diet is indicated.

Activity: Restrictions on activity depend on the nature and severity of the cardiac defect.

MEDICATION

Chromosome 22q11 deletion syndrome is not treated mainly with drugs. Treat immunodeficient patients prophylactically with trimethoprim/sulfamethoxazole. Calcium supplementation is necessary in those with hypocalcemia. In rare cases, calcium supplementation does not suffice, and vitamin D can be administered as well.

Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies

The overall consensus among clinical immunologists is that a dose of intravenous immunoglobulin (IVIG) of 400-600 mg/kg/mo or a dose that maintains trough serum immunoglobulin G (IgG) levels greater than 500 mg/dL is desirable. Patients (X-linked agammaglobulinemia) with meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy. Measurements of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, q2-3wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences in viral inactivation processes (eg, solvent detergent vs pasteurization, liquid vs lyophilized) are found. The choice of brands may depend on the hospital or home care formulary and the local availability and cost.

The dose, manufacturer, and lot number should be recorded for each infusion to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times yearly, also is recommended. The Food and Drug Administration (FDA) recommends that for patients at risk of renal failure (eg, those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, or paraproteinemia; those older than 65 y; those who use nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments is high, especially in patients with infections and those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose given the next day to achieve a full dose. Treatment should not be discontinued. After achieving normal serum IgG levels, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are much reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg q6-8h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, not to exceed 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring blood urea nitrogen and creatinine before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

Immunoglobulin E (IgE) antibodies to immunoglobulin A (IgA) have been reported to cause severe transfusion reactions in IgA-deficient patients. A few reports describe true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. However, in actual experience, this is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency disease (SCID). Caution should be exercised in IgA-deficient patients (<7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see Table 1).

Table 1. Intravenous Immunoglobulin

Brand
(Manufacturer)		 Manufacturing Process pH Additives* Parenteral
Form and Final
Concentrations		 IgA Content (mcg/mL)
Gammagard S/D
(Baxter Bioscience)		 Cohn-Oncley
cold ethanol
fractionation,
followed by
ultracentrafiltration
and ion exchange
chromatography;
solvent detergent
treated		 6.8 5% solution: 0.3%
albumin, 2.25%
glycine, 2% glucose		 Lyophilized
powder
5%, 10%		 1.6 (5%
solution)
Gamimune N
(Bayer)		 Cold ethanol
fractionation,
diafiltration, and
ultrafiltration;
solvent detergent
treated		 4-4.5 5% solution:
9-11%
maltose
10% solution: 0.16-
0.24M glycine		 Sterile solution
5%, 10%		 270
Gammar-P IV (Aventis) Heat-treated pasteurization 6.8 5% solution:
5% sucrose,
3% albumin,
0.5% NaCl		 Lyophilized powder
5%		 <20
Iveegam EN (Baxter Bioscience) Cohn fraction II/III;
DEAA Sephadex
adsorption; PEG
precipitation		 7 5% solution:
5% glucose,
0.3% NaCl		 Lyophilized powder
5%		 <10
Polygam S/D
(Baxter Bioscience
for the American
Red Cross)		 Cohn-Oncley
cold ethanol
fractionation,
followed by
ultracentrafiltration
and ion exchange
chromatography;
solvent detergent
treated		 6.8 5% solution:
0.3% albumin,
2.25% glycine,
2% glucose		 Lyophilized
powder
5%, 10%		 <1.6 (5%
solution)
Panglobulin
(Swiss Red Cross
for the American
Red Cross) 		Cold alcohol fractionation, filtration 6.6 Per gram of IgG:
1.67 g sucrose, <20 mg NaCl 		Lyophilized
powder
3%, 6%, 9%, 12%		 720
Sandoglobulin
(Swiss Red Cross for
Novartis)		 Cold alcohol fractionation, filtration 6.6 Per gram of IgG:
1.67 g sucrose, <20 mg NaCl		 Lyophilized
powder
3%, 6%,
9%, 12%		 720
Venoglobulin-S
(Alpha
Therapeutics)		 Cohn-Oncley cold
ethanol fractionation,
followed by polyethylene glycol (PEG)
fractionation and
ion exchange
chromatography;
solvent detergent
treated 		5.2-5.8 5% solution: 5%
sorbitol, 0.13%
albumin
10% solution: 5%
sorbitol, 0.26%
albumin		 Sterile
solution
5%, 10%		 11-14
*IVIG products containing sucrose are associated more often with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).
Contents of table adapted from manufacturers' literature, Thampakkul and Ballow, Schwartz, and Lacy et al.

Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.
Drug Name
 Sulfamethoxazole and trimethoprim (Bactrim, Septra) -- DOC for prophylaxis in DGA. Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Adult Dose 160 mg (based on trimethoprim component [ie, 1 double-strength tab]) PO bid administered 3 times/wk
Pediatric Dose Dose based on trimethoprim component
5-10 mg/kg/d or 150 mg/m2/d PO divided bid administered 3 times/wk; not to exceed 320 mg/d trimethoprim
Contraindications Documented hypersensitivity; porphyria; megaloblastic anemia due to folate deficiency; infants <2 mo
Interactions May decrease clearance of warfarin or phenytoin; may displace methotrexate from protein-binding sites, resulting in increased levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in G-6-PD deficiency (may cause hemolysis) and impaired renal or hepatic function; adjust dose in patients with renal impairment; discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides
Drug Category: Vitamin and mineral supplements -- Hypocalcemia may occur, requiring supplementation with calcium. In patients with symptoms refractory to calcium, supplementation with a vitamin D analog also may be necessary.
Drug Name
 Calcium carbonate (Oystercal, Caltrate) -- Treatment and prevention of calcium depletion. Calcium moderates nerve and muscle performance by regulating action potential excitation threshold. 1 g of calcium carbonate = 400 mg of elemental calcium.
Adult Dose 1-2 g/d (as elemental calcium) PO (or more), depending on degree of hypocalcemia
Pediatric Dose Neonates: 50-150 mg/kg/d (as elemental calcium) PO divided 4-6 times/d; not to exceed 1 g/d
Children: 45-65 mg/kg/d (as elemental calcium) PO divided qid
Contraindications Hypercalcemia; renal calculi; ventricular fibrillation
Interactions May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; large intakes of dietary fiber may decrease calcium absorption and levels
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Do not coadminister other calcium supplementation; measure serum calcium twice weekly during early dose adjustment period
Drug Name
 Calcitriol (Rocaltrol) -- Vitamin D analog. Increases calcium levels by promoting absorption of calcium in intestines and retention in kidneys.
Adult Dose 0.5-2 mcg PO qd
Pediatric Dose 1-5 years: 0.25-0.75 mcg (0.04-0.08 mcg/kg/d) PO qd
>6 years: 0.5-2 mcg PO qd
Contraindications Documented hypersensitivity; hypercalcemia; vitamin D toxicity; malabsorption syndrome
Interactions Thiazide diuretics increase risk of hypercalcemia; corticosteroids counteract effects of calcitriol; cholestyramine may decrease absorption; hypercalcemia may cause arrhythmias and exacerbate digoxin
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Adequate calcium supplementation is necessary for efficacy

FOLLOW-UP

Deterrence/Prevention:

  • Genetic counseling is advisable prior to making family-planning decisions.

Prognosis:

  • Prognosis depends largely on the nature and degree of involvement.

Patient Education:

  • Given the frequent learning disabilities observed in these children, they should undergo early developmental assessment and be placed in an early education program to help offset the expected educational delays. Such interventions have proven effective both academically and socially.
  • Families with patients with clinically significant immunodeficiency should be educated regarding the potential complication from exposure to live attenuated poliovirus vaccine, MMR vaccine, and chicken pox vaccine.

 

MISCELLANEOUS

Special Concerns:

  • Patients' families often feel alone when this diagnosis is made. Because of its rarity, most parents have not heard of the syndrome, nor do they know anyone who has it to whom they can turn for comfort. Support groups exist and are an invaluable help in this regard. One address is below.

    Velo-Cardio-Facial Syndrome Educational Foundation, Inc.
    Upstate Medical University
    University Hospital
    708 Jacobsen Hall (C.D.U.)
    750 East Adams Street
    Syracuse, NY 13210

    Telephone: (315) 464-6590
    FAX: (315) 464-6593
    E-mail: vcfsef@mail.upstate.edu