DiGeorge Syndrome: A Case Report of a Child with Attention Deficit and Socialization Problems

DiGeorge Syndrome which is also known as chromosome 22q11.2 deletion syndrome is a primary immunodeficiency caused by the deletion of chromosome 22. Its main features include dysmorphia, hypoparathyroidism, hypocalcemia, hypoplasia or aplasia of the thymus, cardiac anomalies, renal anomalies


Introduction Background
DiGeorge Syndrome (DGS), as described in 1968 by Angelo DiGeorge is a primary immunodeficiency caused by abnormal development of 3 rd and 4 th pharyngeal pouches in the embryonic state

Etiology and Epidemiology
DGS is the commonest of human genetic microdeletion syndromes.
It can be seen in both males and females equally.Its occurrence is one in every 3000-6000 live births.Its diagnosis is done in early childhood, but with the unavailability of genetic testing before the 1990s there can be undiagnosed adults of age > 40yrs.Though there

Case Presentation
A 5-year-old boy born to unrelated healthy parents was seen at a psychiatric hospital with attention deficit and socialization problems.
Following psychiatric assessment, the patient was referred pediatric endocrinology department at the pediatric hospital for evaluation of possible hypothyroidism.The patient's mother reported that he was inattentive and asocial.The boy had a medical history of mild recurrent numbness in his hands in the past 2 years.During the physical examination, mild facial dysmorphism was seen -prominent nose with a bulbous tip, smallmouth and eyes, ocular hypertelorism, and long face.

Clinical Findings and Analysis
According to the case study, the patient is a 5-year-old boy born to unrelated healthy parents.He has been following psychiatric assessment for attention deficit and socialization problems.It was also reported that he was inattentive and asocial.During the physical examination, it has been able to find mild facial dysmorphismprominent nose with a bulbous tip, smallmouth and eyes, ocular hypertelorism, and long face.All these symptoms illustrate the characteristic features of DGS.Deletion of chromosome 22q11.2leads to the absence of the T-box1 (TBX1) gene which is involved in the development of 3 rd and 4 th pharyngeal pouches in the fetus which later gives rise to different parts of the head and neck, and hence, results in abnormalities in those parts and cause facial dysmorphism.TBX1 also causes the development of brain mesoderm, hence its absence may lead to neuropsychiatric issues.Small vermis and reduction in the gray matter will have resulted from the absence of TBX1 and causes socialization problems as it's controlled by the posterior vermis and psychiatric issues, respectively [11].
Since the patient's parents are unrelated and healthy, it confirms that the case is due to a de novo mutation and hasn't been inherited.
The boy has a 2yrs medical history of mild recurrent numbness in his hands which can be due to hypocalcemia which is another feature of DGS [1].The urine Calcium/ Creatinine ratio tends to increase in children with deficient vitamin D [10].Since this patient has a normal urine calcium/ creatinine ratio it tells that the patient has sufficient vitamin D.

Laboratory Findings and Analysis
CD3+ (CD16+56+) 48-58% 58-82% CD3+ (CD16+56+) value is slightly low which can lead to immunodeficiency in the patient but there is no significant evidence shown in the case for immunodeficiency.

Thyroid Hormones Normal
Sometimes thyroid hormones can be decreased due to low PTH levels and cause hypothyroidism.
But since this patient has normal levels of thyroid hormones, he doesn't have hypothyroidism.
Laboratory investigations have revealed a low level of parathormone Prenatal ultrasound can be used to diagnose an affected fetus.
Screening can be done through fetal echocardiography, chronic villi sampling, and amniocentesis [11].

Treatments and Prognosis
The mortality rate in DGS is unknown and though the rate of childhood deaths is rare, most of it has been due to cardiac diseases  Treatments for a few other complications are explained in Table-2.

Disease Complications Treatments
Hypoparathyroidism Hypocalcemia and hyperphosphatemia arise due to hypoparathyroidism.
Therefore, hypoparathyroidism can be treated by treating hypocalcemia.
Treatment is giving supplements of calcium together with oral calcitriol which is active vitamin D. But should make sure not to do overtreatment because if so will lead to several other problems such as renal failure, hypercalciuria, nephrolithiasis, and nephrocalcinosis.

Immunological Aspects
The thymus is derived from the 3rd pharyngeal pouch and TBX1

Discussion
As discussed so far, DGS is caused by microdeletions of chromosome 22 located as 22q11.2and can be identified using FISH analysis [12].
Similarly, the patient in the presented case study has been identified to be having DGS, with the use of FISH analysis.Though CD3+ (CD16+56+) cell level is slightly low which may lead to immunodeficiency, since B cells and NK cells are also normal and there is no significant evidence of immunodeficiency, the patient can be confirmed to be having pDGS.

Conclusion
According to the details given in the case study and clinical and laboratory findings, it's able to conclude that the patient is having Partial DiGeorge Syndrome which has resulted due to a de novo mutation.His condition is not severe and can be treated for his disease complications such as with calcium and Calcitriol supplements for hypocalcemia, as discussed above.

[ 4 ]
Figure1.A child with DGS [3] Lowe C. DiGeorge Syndrome: A Case Report of a Child with Attention Deficit and Socialization Problems.J Med Case Rep Case Series 2(6): https://doi.org/10.38207/jmcrcs20210087 is no cure for DGS, early diagnosis and treatment of complications can increase the quality of life in patients [8].The etiology of DGS is due to the haploinsufficiency of one or more genes on chromosome 22 in humans [4].Though most of the DGS cases arise as de novo mutations, it can be inherited and shows an autosomal dominant inheritance pattern [12].
Lowe C. DiGeorge Syndrome: A Case Report of a Child with Attention Deficit and Socialization Problems.J Med Case Rep Case Series 2(6): https://doi.org/10.D helps in the absorption of Calcium.Test confirming the normal level of 25hydroxyvitamin D shows that a low level of serum Calcium isn't due to an effect of 25-

(Figure2.
Figure2.FISH analysis with the Vysis N25 probe specific to Di-George region, arrow shows a deletion of chromosome 22q11.2[7] diagnosis of disease complications and management will lead to a better prognosis.Management of DGS is dependent on the patient's age and phenotype, and treatment is personalized according to the complication severity.

Figure3.
Figure3.Hematoxylin and Eosin-stained biopsy of transplanted thymus viewed under low power.Thymic tissue is looking normal and is surrounded by striated muscle.A good corticomedullary distinction is observed.[2]
encodes transcription factors needed for the development of the thymus.Deletion of TBX1 due to 22q11.2 deletion causes hypoplasia or aplasia of the thymus.This will lead to primary immunodeficiency in DGS patients.Depending on the number of T-cells DGS can be either cDGS or pDGS.The aplastic thymus will lead to the absence of T-cells leading to complete immunodeficiency and will cause cDGS while the hypoplastic thymus can have T-cells numbers and functions from normal or near-normal to near-complete deficient leading to incomplete immunodeficiency causing pDGS.There can be conditions where T-cell numbers can be normal or near-normal in conditions where thymic tissues are placed ectopically [2].
Neuropsychiatric problems are resulted due to abnormal development of brain mesoderm due to deletion of TBX1 gene and also due to deletion of COMT gene.Socialization problems have resulted from the deletion of TBX1 leading to the development of a small vermis due to the reduction in gray matter, as psychiatric issues are Journal of Medical Case Reports and Case Series ISSN: 2692-9880 Citation: Lowe C. DiGeorge Syndrome: A Case Report of a Child with Attention Deficit and Socialization Problems.J Med Case Rep Case Series 2(6): https://doi.org/10.38207/jmcrcs20210087maintained by the posterior vermus [11].His laboratory reports revealed low levels of serum calcium and a high level of phosphorus together with a low level of PTH which further confirms DGS.One major feature of DGS is hypoparathyroidism which is revealed with patients having low PTH.Hypoparathyroidism causes hypocalcemia (low serum Calcium) and hyperphosphatemia (high phosphorus) and that can be clearly seen in the patient's laboratory findings [9].Therefore, he can be treated with calcium supplements together with active vitamin D. The patient has a medical history of recurrent numbness in the hands and that is due to hypocalcemia [1].The patient has a normal level of T-cells, but the thymus wasn't visualized in the scintigraphic evaluation and hence, that can be due to an ectopic thymus tissue placement [2].

Table 1 :
Interpretation of laboratory findings Phosphorus 8 mg/dL 2.4 -4.1 mg/dL Due to the low level of PTH, reabsorption of phosphorus from kidneys increases increasing the serum phosphorus level.Parathormone (PTH) 8 pg/mL 10 -65 pg/mL PTH is secreted by the parathyroid glands.The hypoplasia of parathyroid glands resulted from 22q11.2 deletion causes low levels of PTH.