DiGeorge Syndrome (DGS)

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DiGeorge Syndrome
Body Parts: Whole Body
Medical Subjects: Children's Health Blood Genetic disease
Overview

What Is DiGeorge Syndrome?

What is DiGeorge syndrome?

In 1965, Dr. Angelo DiGeorge reported a group of diseases with congenital deficiency of thymus and thyroid, thus named DiGeorge syndrome, or DGS for short.

The typical triad of DGS is truncus arteriosus of the heart, thymus hypoplasia, and hypocalcemia, with varying degrees of disease. Treatment requires the participation of multidisciplinary experts, including correction of hypocalcemia, correction of heart and other organ malformations, thymus transplantation, hematopoietic stem cell transplantation, etc.

What are the types of DiGeorge syndrome?

In the 1980s, studies found that most patients with DGS and patients with other similar syndromes such as velocardiofacial syndrome, VCFS) had loss of heterozygosity on chromosome 22q11.2 (i.e., DGS 1 locus). Therefore, DGS can be divided into two categories:

  • DGS with chromosome 22q11.2 deletion: It accounts for the majority of DGS. The specific manifestation of the patient is related to the function of genes such as TBX1.
  • DGS without chromosome 22q11.2 deletion: accounts for a small portion of DGS.

In addition to chromosome 22q11.2, 2% to 5% of patients with loss of heterozygosity on chromosome 10p13-14 (i.e., DGS 2 locus) are more likely to have sensorineural hearing loss. Some patients do not have any chromosomal abnormalities but are caused by simple mutations of genes such as TBX1.

Is DiGeorge syndrome common?

A study in the United States confirmed that one out of every 5,950 live births has a chromosome 22q11.2 deletion. The other two studies found a chromosome 22q11.2 deletion in 1/4,000 live births and 1/1,000 fetuses, respectively.

However, these data do not fully represent the incidence of DGS because some fetuses with chromosome 22q11.2 deletions were aborted before birth.

Studies also have been performed in a low-risk pregnancy population and have revealed a chromosome 22q11.2 deletion in 1 in 400 fetuses.

Cause

What Is The Cause Of DiGeorge Syndrome?

DGS is caused by an abnormal developmental sequence of the embryonic pharyngeal system, which leads to a differential in the formation and morphogenesis of the thymus, thyroid, parathyroid, maxilla, mandible, aortic arch, cardiac outflow tract, and outer/middle ear.

Abnormal developmental sequence of the embryonic pharyngeal system associated with chromosomal abnormalities or gene mutations in the diseased fetus:

  • Most patients with DGS have a loss of heterozygosity on chromosome 22q11.2 (DGS 1 locus).
  • 2% to 5% of patients with DGS have loss of heterozygosity (DGS 2 locus) on chromosome 10p13-14.
  • There is also a small percentage of patients with DGS who do not have any chromosome deletions but only have simple gene mutations such as TBX1.

Is DiGeorge syndrome hereditary?

DiGeorge syndrome is hereditary. Most DGS are caused by chromosome 22q11.2 deletions and follow an autosomal dominant inheritance pattern. If the father or mother has a chromosome 22q11.2 deletion, the risk of future transmission to the child is 50%.

However, in actual cases, 90% of the deletions on chromosome 22q11.2 are not inherited from the parents, but occur newly in the fetal period.

Symptom

What Are The Symptoms Of DiGeorge Syndrome?

What are the symptoms of DiGeorge syndrome?

Typical triad manifestations of DGS are the following:

  • Trunk malformation of conical artery of heart.
  • Thymic agenesis.
  • Hypocalcemia caused by abnormal parathyroid.
  • The symptoms and manifestations vary greatly among patients with DGS. Even within the same family.

What cardiac abnormalities can DiGeorge syndrome cause?

  • Interrupted aortic arch: differential cyanosis with pink upper body part and blue lower body part.
  • Persistent truncus arteriosus: cyanosis of the newborn may occur and is caused by hypoxia.
  • Tetralogy of fallot: cyanosis of the newborn may occur.
  • Atrial septal defect (ASD).
  • Ventricular septal defect (VSD).
  • Vascular ring.
  • Severe compression may result in critical airway obstruction, wheezing, and feeding problems.
  • Congenital coronary anomalies.

What are the manifestations of hypocalcemia in DiGeorge syndrome?

Hypocalcemia is due to hypoplastic parathyroidism. This is a potentially life-threatening problem. Hypocalcemia occurs in 60% of neonates with DiGeorge syndrome and may present as tremors, tetany, seizures, decreased serum calcium, increased serum phosphorus, and extremely low parathyroid hormone levels.

However, hypocalcemia is less common after neonatal period, probably because of compensatory hyperplasia of existing parathyroid tissue. However, excessive stress (such as severe infection, major surgery, burns, huge mental stimulation, etc.) can still promote hypocalcemia. Some patients with DGS who fail to be diagnosed early may present with hypocalcemia at a hospital after adulthood and thus be diagnosed.

What are the manifestations of thymic dysplasia in DiGeorge syndrome?

In some patients with DiGeorge syndrome, the thymus is completely absent, while in some patients the thymus is simply reduced in size. Either way, will lead to immunodeficiency, low resistance, only the degree of weight.

According to the degree of thymic dysplasia, DGS can be divided into the following three types:

Complete DGS

Complete DGS is a severe combined immunodeficiency (SCID) that can be fatal. Our patient's T-cell count was more than three standard deviations below normal for the same age group and the initial CD3+T cells were generally < 50/mm3. Diseased infants can be diagnosed after repeated severe infections, chronic diarrhea, and growth retardation.

In DGS with chromosome 22q11.2 deletion, less than 1% of patients have complete DGS; Forty-eight percent of patients with complete DGS did not have any chromosomal abnormalities, which may be associated with TBX1 genetic abnormalities.

Atypical completeness DGS

Although patients with atypical complete DGS have thymus deficiency, lymphadenopathy and eczema-like dermatitis, oligoclonal T cell populations can be detected in peripheral blood, so their T cell counts can be higher than those of typical complete DGS patients. Patients with atypical complete DGS may present with erythroderma, oligoclonal expansion of T cells, enlarged lymph nodes, and elevated serum IgE levels.

Partial DGS

Seventy-five percent of DGS with chromosome 22q11.2 deletions were due to thymic insufficiency rather than complete absence of thymic function. They had only a certain degree of immunologic hypofunction, not severe combined immunodeficiency (SCID). Therefore, most patients with partial DGS do not develop opportunistic infections and have few life-threatening infections.

Partial DGS is immunodeficient in that it is characterized by IgA deficiency and antibody dysfunction (i.e., polysaccharide antibody deficiency).

However, many patients with partial DGS have a history of repeated sinus and lung infections, which predispose them to bronchitis, pneumonia, sinusitis, and otitis media.

What are the manifestations of autoimmune/atopic lesions in DiGeorge syndrome?

Patient with DiGeorge syndrome is susceptible to autoimmune hemolytic anemia (AIHA), autoimmune cytopenia, arthritis, inflammatory bowel disease, autoimmune thyroid disease, eczema, and asthma. Surprisingly, however, the incidence of allergic rhinitis has not increased for reasons that are not well known.

What are the major head and face anomalies in DiGeorge syndrome?

Cephalic and facial malformations are not unique to DiGeorge syndrome and are present in other patients with a chromosome 22q11.2 deficiency.

Craniofacial malformations included low posterior rotation of the ear, widening of the orbital distance, spherical tip of the nose, dominant cleft palate and submucous cleft palate, and rhinocnesmus and nasal regurgitation caused by velopharyngeal insufficiency. However, facial features may become less apparent in patients with DGS as they age.

What developmental and behavioral problems can DiGeorge syndrome cause?

The vast majority of patients have developmental delay, especially in language. May have moderate mental retardation but may also be normal. There may also be affective dysfunction, behavioral inhibition disorder, attention disorder, and psychosis (schizophrenia, major depression, etc.).

Detect

How To Check For DiGeorge Syndrome

What are the conditions for a definitive diagnosis of DiGeorge syndrome?

  • The number of CD3+T cells was reduced to < 500/mm3 (required).
  • Conical heart defect (arterial trunk, Tetralogy of Fallot, interrupted aortic arch, or right subclavian anomaly).
  • Hypocalcemia persists for more than three weeks and requires treatment.
  • Chromosome 22q11.2 was found missing.
  • In addition to the necessary conditions, there are three other conditions that satisfy at least two of them in order to confirm the diagnosis of DiGeorge syndrome.

What are the conditions for the initial diagnosis of DiGeorge syndrome?

  • The numb of CD3+T cells decrease to < 1500/mm3.
  • Chromosome 22q11.2 is missing.
  • DiGeorge syndrome can be diagnosed if the above two conditions are met simultaneously.

What are the conditions for a suspected diagnosis of DiGeorge syndrome?

  • The number of CD3+T cells was reduced to < 1500/mm3 (required).
  • Heart deformity.
  • Hypocalcemia persists for more than three weeks and requires treatment.
  • Craniofacial deformity/palate and related issues.
  • Diagnosis of DiGeorge Syndrome may be suspected in at least one of the following, except for the mandatory ones.

Prevention

How To Prevent DiGeorge Syndrome?

DiGeorge syndrome is hard to prevent. There are no feasible prenatal genetic tests for the fetus. Prenatal examination methods such as fetal echocardiography can help doctors to screen out fetal heart abnormalities to some extent, thus indirectly inferring DGS, but it is not possible to detect all DGS fetuses.

When a DGS child is found, genetic testing can be performed on the parents. If the father or mother is found to have identical chromosomal or genetic changes, the risk of future generations is 50%. Parents may decide, after weighing the advantages and disadvantages, whether or not to give birth again, and monitoring during pregnancy should be strengthened and the pregnancy terminated if necessary.

Treatment

How To Treat DiGeorge Syndrome?

What clinic does DiGeorge syndrome belong to?

The treatment of DGS patients requires multi-disciplinary cooperation, including otorhinolaryngology, plastic surgery, oral and maxillofacial surgery, immunology, cardiac surgery, neurology, psychiatry, endocrinology, speech pathology experts, genetics experts, and preferably social workers, nutrition and diet experts, etc.

How to treat DiGeorge syndrome?

Treatment strategies vary in different disease periods. "Acute infant treatment" and "subsequent long-term treatment" are described below.

How to treat DiGeorge syndrome in an acute infant phase?

The following issues should be highlighted for the identification and treatment of DGS patients who meet the criteria for suspicion after birth:

Hypocalcemia

Congenital cardiac anomaly

Patients with severe congenital heart malformations such as interrupted aortic arch and Tetralogy of Fallot may need emergency surgical correction, requiring the intervention of cardiology and cardiac surgery experts.

Careful evaluation of maxillary and gastrointestinal defects in children with feeding and swallowing difficulties, slow weight gain, and susceptibility to reflux aspiration also requires the intervention of a specialist. Multidisciplinary collaboration is extremely important at this time.

Severe immunodeficiency

Children with complete DGS must be identified because it is a severe combined immunodeficiency disease that requires protective isolation from a fatal infection. For example, irradiated, leukocyte-removed, cytomegalovirus-negative blood products should be used in neonates requiring blood transfusion for cardiac surgery, instead of general blood products.

In addition to protective isolation, children with complete DGS require intravenous immunoglobulin and prophylactic anti-infective therapy.

Thymus and hematopoietic stem cell transplants were then performed, and very few children without transplant therapy survived past one year.

Why thymus transplantation and hematopoietic stem cell transplantation for DiGeorge syndrome?

Patients with complete DiGeorge syndrome have T-cell immune deficiency, so thymus transplantation is the best treatment to correct the immune deficiency. If thymus cannot be transplanted, hematopoietic stem cells+memory T cells can be transplanted together for treatment (i.e., T cells in the donor tissue are not removed).

Patients with incomplete DiGeorge syndrome, although humoral immune and cellular immune deficient, generally do not require hematopoietic stem cell transplantation or thymus transplantation.

What are the long-term outcomes of DiGeorge syndrome?

After the hypocalcemia and the heart malformation are corrected, the following conditions of the children need to be monitored emphatically and targeted treatment is carried out:

  • To carry out hearing assessment, especially for the case with loss of heterozygosity on chromosome 10p13-14.
  • Language ability assessment was conducted.
  • Monitor thyroid hormone, growth hormone.
  • Evaluate for learning, development, and behavioral disorders.
  • Pay attention to the recognition of schizophrenia, schizoaffective disorder, severe depression.
  • Check for defects in the palate.
  • Immune function was checked once every 6–12 months, including T cell function and humoral immune function.

Life

What Should Patients With DiGeorge Syndrome Pay Attention To In Life?

Can people with DiGeorge syndrome be vaccinated?

T cell abnormalities in patients with DGS were once considered prohibited from receiving live vaccines, but this view has been increasingly questioned. After all, there are differences in the degree of T cell dysfunction. In view of this, immunology experts should be consulted to decide the vaccination.

Because patients with DGS also have a humoral immune deficiency, the protective antibodies they produce after vaccination may not be as persistent as in the general population. As a result, they generally need to be vaccinated more frequently to reduce the risk of infection.

What precautions should patients with DiGeorge syndrome have in their diet and life?

Pay attention to clean sanitation, reduce the risk of infection. Food reflux and aspiration are easy to occur during early feeding, and the help of experts should be sought.

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