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DiGeorge Syndrome

CATCH 22

DiGeorge syndrome (DGS) belongs to a group of phenotypically similar disorders which share a microdeletion at band 22q11.2.


Presentation

One of the most common reasons to suspect DGS is the presence of a conotruncal cardiac anomaly. Neonatatal hypocalcemia will also bring about suspicion of this syndrome especially in cases where the heart defect or hypocalcemia is coupled with a cleft palate [7]. This is often seen in affected individuals. Equally, pediatric severe immune deficiency is good reason to suspect this syndrome as well.

The characteristics of this syndrome are not obvious in infancy as they are not fully manifested until the child is a bit older. The distinctive facial features many be subtle or even absent especially in people who are not ethnic whites.

Delay in development may not be overly visible in infancy. It can also remain unnoticed until the child has attained school age.
In nearly 40% of patients, feeding difficulty is present. These difficulties may be due to nasal regurgitation arising from a submucous cleft palate. Swallowing difficulties often clear up with the first year leaving the child with hypernasal speech as manifestation. Dysmotility and abnormality of the oropharyngeal and cricoesophagheal swallowing phase may bring about abnormal swallowing (with aspiration in many cases).

Neonatal tetany, nephrocalcinosis and hypocalcemia are some of the endocrinologic problems that are associated with parathyroid deficiency.

Recurrent Infection
  • Its symptoms vary greatly between individuals but commonly include a history of recurrent infection, heart defects, and characteristic facial features. Few cases of DiGeorge syndrome have been reported in adults.[ncbi.nlm.nih.gov]
  • Abstract BMT was carried out on a patient with DiGeorge syndrome who suffered recurrent infections after birth.[ncbi.nlm.nih.gov]
  • METHODS: Patients underwent standard clinical and epidemiological protocol and tests to detect heart diseases, facial abnormalities, dimorphisms, neurological or behavioral disorders, recurrent infections and other comorbidities.[ncbi.nlm.nih.gov]
  • Although recurrent infections can be observed in patients with deletion of chromosome 22 syndrome, the immune pathogenesis of this condition is yet not fully understood.[ncbi.nlm.nih.gov]
  • As would be appropriate for any child who presents with recurrent infections at 2 years of age, an immunologic evaluation should be performed.[ncbi.nlm.nih.gov]
Down Syndrome
  • […] with Down syndrome and the children with VCFS.[doi.org]
  • The present patient is the second case of mosaic type of Down syndrome associated with 22q11.2 microdeletion. In addition the patient also had clinical and laboratory features of DiGeorge syndrome.[ncbi.nlm.nih.gov]
  • Next to Down syndrome, DiGeorge syndrome is the most common genetic cause of congenital heart disease. DiGeorge syndrome is caused by a microdeletion in chromosome band 22q11.2.[medicinenet.com]
Splenectomy
  • Relapses are not uncommon and are treated with splenectomy or rituximab. There is a paucity of reports in the literature regarding treatment options beyond this stage.[ncbi.nlm.nih.gov]
Streptococcal Infection
  • This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection.[ncbi.nlm.nih.gov]
Failure to Thrive
  • […] to thrive Faltering weight Weight faltering [ more ] 0001508 Feeding difficulties in infancy 0008872 Foot polydactyly Duplication of bones of the toes 0001829 Gastroesophageal reflux Acid reflux Acid reflux disease Heartburn [ more ] 0002020 Gastrointestinal[rarediseases.info.nih.gov]
  • Symptoms and signs can consist of some mixture of the following: Tiring easily or weaknesses Bluish skin because of poor circulation of oxygen-rich blood Failure to gain weight Failure to thrive Muscle tone that is poor Infections that are frequent Problems[byebyedoctor.com]
  • […] to Thrive can result and most of these infants will die within a month from severe cardiac abnormalities or infections Infants must be isolated once immune deficiency is identified Survivors face increased susceptibility to respiratory infections Uneven[bilinguistics.com]
  • Congenital anomalies of any organ system, classically cardiac defects, particularly interrupted aortic arch type B, septal defects, tetralogy of Fallot pulmonary atresia, truncus arteriosus, and vascular ring Failure to thrive/dysphagia/gastroesophageal[unboundmedicine.com]
Diarrhea
  • […] ear fold Small jaw A narrow, short groove in the upper lip Other signs and symptoms of DiGeorge syndrome include: Cleft palate Recurrent infections, such as chronic runny nose or multiple bouts of pneumonia, oral thrush (candidiasis), diaper rash or diarrhea[chd-uk.co.uk]
  • Patients may experience chronic runny nose, recurrent pneumonia, oral thrush (yeast infection of the mouth), and diarrhea. Patients are generally weak and may also be susceptible to sudden death.[naturallivingcenter.net]
  • Discussion Some 12 million infants and young children die each year in developing countries from complications of marasmus (protein-calorie deficiency) and kwashiorkor (severe protein deficiency).[ 8 ] Diarrhea, dehydration, and infection are generally[nutritionj.biomedcentral.com]
  • DIG012 was hospitalized for diarrhea and low calcium; however, it was the low calcium that made the admission necessary.[bloodjournal.org]
Seizure
  • At the age of 13 years, he experienced a seizure for the first time. At this time, the calcium concentration was normal. An electroencephalogram (EEG) proved that the seizure was due to epilepsy. Antiepileptic medications controlled the seizure.[ncbi.nlm.nih.gov]
  • Hypoparathyroidism and hypocalcemia cause recurrent seizures if patients are not properly treated. We present two patients with poorly controlled epileptic seizures that turned out to be caused by DiGeorge syndrome with hypocalcemia.[ncbi.nlm.nih.gov]
  • The patient developed generalized tonic-clonic seizures when she was 9 years old and these were associated with hypocalcemia. Despite treatment with calcium, seizures persisted and the patient required antiepileptic medications.[ncbi.nlm.nih.gov]
  • A large cohort study showed that 21% of the patients with chromosome 22q11.2 deletion syndrome (62/290) had seizures, and at least 68% (42/62) of the seizures were hypocalcemic in origin [ 8 ].[doi.org]

Workup

To evaluate DiGeorge syndrome, some of the laboratory studies carried out include multiplex ligation-dependent probe amplification (MLPA), TBX1 gene sequencing or TBX1 deletion/duplication analysis, fluorescent in situ hybridization (FISH) and array comparative genomic hybridization (aCGH) [8].

Radiography and MRI, CT scanning, Echocardiography and Angiography are some of the imaging studies carried out.

Multiple Renal Cysts
  • renal cysts Multiple kidney cysts 0005562 Multiple suture craniosynostosis 0011324 Narrow mouth Small mouth 0000160 Obesity Having too much body fat 0001513 Optic atrophy 0000648 Patellar dislocation Dislocated kneecap 0002999 Patent ductus arteriosus[rarediseases.info.nih.gov]

Treatment

Treatment depends on the associated abnormalities and may include heart surgery, speech therapy, nasogastric feeding, calcium supplementation, and thymus transplantation or adoptive transfer of mature T cells.

Prognosis

The prognosis for this condition varies a great deal depending on the nature and level of involvement of the different organs. Majority of adults with this condition live a long and productive life [9].

The major cause mortality with this condition is severe immune deficiency and congenital heart defect. This explains why mortality is higher in infants. Infants with thymus aplasia suffer severe immunodeficiency. They typically die of sepsis, which is usually due to bacterial or fungal infections.

Etiology

As stated earlier, the condition is triggered by part of chromosome 22. Every individual has two copies of this chromosome with one coming from each parent. The chromosome has 500 to 800 genes on average.

With DGS, a copy of the chromosome 22 will be short a segment housing an average of 40 genes. Many of these genes are yet to be clearly identified or well understood [5]. The deletion of genes from the chromosome 22 occurs randomly in the father’s sperm or mother’s egg. In some cases it occurs early into development. This means that deletion will be repeated in all of the cells in the body as the fetus continues to develop.

Epidemiology

According to estimates, DGS occurs between 1 per 2000 to 1 per 4000 individuals in the general population of the world. It is one of the most common causes of cleft palate and most congenital heart defects.

Even though DGS is a congenital condition, the age at which it becomes visible to diagnosis is dependent on the type of defect it causes and its severity [3]. Therefore, patients who have hypocalcemia and other more serious cardiac defects are diagnosed within the neonatal frame. In patients older than 3-6 months, recurrent infections are visible in patients that are older than 3-6months.

People who have normal immune function without hypocalcemia, mild cardiac defects, and very little facial anomalies may stay undiagnosed until late into childhood. There have been cases of diagnosis in adulthood and these are mostly reported in individuals with mild symptoms that are isolated [4]. There have been frequent prenatal diagnosis of fetuses with congenital heart conditions so pregnant women at risk of giving birth to children with this defect should be closely monitored.

Sex distribution
Age distribution

Pathophysiology

Deletion of this portion of the chromosome triggers a range of embryonic developmental disruptions which often involve the kidneys, skeleton, brain, neck and head. Parts of the heart, head and neck, thymus, and parathyroids arise from the third and fourth pharyngeal pouches and as a result of the chromosomal deletion, a developmental field defect occurs [6]. This leads to variable T-cell deficiency and hypocalcemia.

The size of the most common deletion seen in over 80% of cases is 3 million base pair. It encompasses 4 micro RNAs and 40genes. Among these genes is the TBX1 gene which is suspected to play a major role in the typical symptoms of this condition. There have not been any proofs of genotype-phenotype correlation.

Mode of inheritance

Since the condition is as a result of noninherited deletion its occurrence is sporadic in majority of cases (over 90%).

Only 10% of individuals have inherited this deletion from a parent as an autosomal dominant condition. The involvement of siblings has only been diagnosed when chromosome 22 deletion was found in a parent.

An affected individual has a 50% chance of transmitting this condition to his or her child. There have also been reports of wide intra and interfamily variability in the clinical manifestation of this condition.

Prevention

There are no guidelines for prevention of DiGeorge syndrome.

Summary

DiGeorge syndrome is a genetic condition known by other names such as DiGeorge anomaly, 22q11.2 deletion syndrome, velo-cardio-facial syndrome, Shprintzen syndrome, conotruncal anomaly face,strong syndrome, thymic hypoplasia and congenital thymic aplasia [1].

It is caused by the deletion of a small portion of chromosome 22. The deletion takes place towards the middle of the chromosome at a location designated as 22q11.2. The designation shows that the deletion occurs on region 1, band 1, sub-band 2 of the long arm of one of the pair of chromosomes 22.

This syndrome was first described in 1968 by Angelo DiGeorge, a pediatric endocrinologist. The condition is with truncus arteriosus also associated with truncus arteriosus [2].

Patient Information

Genetic counselling is vital so that parents will be fully aware of the recurrence risk of DiGeorge syndrome.

The families of individuals with significant immunodeficiency equally have to be educated on the potential complications that can arise due to exposure to poliovirus vaccine, MMR vaccine, and chicken pox vaccine that is live attenuated [10].

References

Article

  1. Tonelli AR, Kosuri K, Wei S, Chick D. Seizures as the first manifestation of chromosome 22q11.2 deletion syndrome in a 40-year old man: a case report. J Med Case Reports 2007 1: 167.
  2. Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
  3. James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
  4. Bassett AS, McDonald-McGinn DM, Devriendt K, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011; 159:332.
  5. McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore) 2011; 90:1.
  6. Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997; 34:798.
  7. Vantrappen G, Devriendt K, Swillen A, et al. Presenting symptoms and clinical features in 130 patients with the velo-cardio-facial syndrome. The Leuven experience. Genet Couns 1999; 10:3.
  8. Patel K, Akhter J, Kobrynski L, Benjamin Gathmann MA, Davis O, Sullivan KE. Immunoglobulin deficiencies: the B-lymphocyte side of DiGeorge Syndrome. J Pediatr. Nov 2012;161(5):950-3.
  9. Jawad AF, McDonald-Mcginn DM, Zackai E, Sullivan KE. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr. Nov 2001;139(5):715-23.
  10. Tison BE, Nicholas SK, Abramson SL, Hanson IC, Paul ME, Seeborg FO, et al. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol. Nov 2011;128(5):1115-7.e1-3.

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Last updated: 2018-06-22 07:24