our patient was an 8-month - old male child of indian origin and the first issue of a nonconsanguineous marriage .
he presented to our center with the complaints of cough , cold , progressively increasing breathlessness , and refusal to feed over the past 3 days .
past history was elicited that the child was a full - term baby weighing 2.4 kg .
his important clinical course is summarized in table 1 . on presentation to us , he had tachycardia ( 160 beats per minute ) , tachypnea ( 64 breaths per minute ) , capillary refill time of 3 s , and blood pressure of 76/60 mmhg in the right arm supine position .
the child had increased work of breathing , as evidenced by the subcostal and intercostal retractions .
cardiac examination revealed a pansystolic murmur ( grade iii ) , in the third and fourth intercostal spaces .
his weight , length , and head circumference were below the third percentile for his age ( weight 3.5 kg , length 61 cm , head circumference 37 cm ) .
he had narrow and upslanting palpebral fissures , epicanthal folds , and prominent ears [ figure 1 ] .
past clinical course of the patient hgt = hemoglucotest ; pcv = packed cell volume ; cbc = complete blood count ; tlc = total leucocyte counts ; dlc = differential leucocyte count ; anc = absolute neutrophil count ; alc = absolute lymphocyte count ; crp = c - reactive protein ; tof = tetralogy of fallot ; ps = pulmonary stenosis ; vsd = ventricular septal defect ; * dose of the iv calcium 2cc / kg / dose , tds for 3 days facial profile of the child . note the narrow and upslanting palpebral fissures , epicanthal folds , and prominent ears q1 : name some hereditary and nonhereditary conditions in which the facial dysmorphisms associated with the underlying heart disease can give a clue to the etiology of the condition . ans . :
table 2 elaborates the conditions in which facial dysmorphisms associated with underlying heart disease can give a clue to the etiology of the condition .
conditions in which facial dysmorphisms are associated with a heart disease ecd = endocardial cushion defect ; asd = atrial septal defect ; pda = patent ductus arteriosus ; ar = aortic regurgitation ; mr = mitral regurgitation ; cad = coronary artery disease ; as = aortic stenosis ; pa = pulmonary artery ; dgs = digeorge syndrome case details ( continued ) : in view of the association of conotruncal cardiac anomaly , hypocalcemia with hypoparathyroidism [ table 1 ] in the infantile period , and typical dysmorphic facies , we were prompted to suspect digeorge syndrome ( dgs ) .
: dgs is a 22q11.2 microdeletion syndrome , associated with the classic triad of conotruncal cardiac anomalies , hypoplastic thymus ( resulting in immunodeficiencies ) , and hypoplasia of the parathyroid glands ( resulting in hypoparathyroidism and hypocalcemia ) .
the other synonyms for dgs are 22q11.2 deletion syndrome ( preferred terminology ) , velocardiofacial syndrome , conotruncal anomaly face syndrome , sedlackova syndrome , and cayler cardiofacial syndrome . in less than 1% of all patients with dgs , there is complete athymia , resulting in severe combined immunodeficiency ( scid ) .
this is called  complete dgs ;  the remaining 99% are  partial  dgs , having some thymic function preserved . in our patient , repeated blood investigations failed to show lymphopenia [ table 1 ] .
detailed immunological tests could not be carried out in our patient . with a worldwide prevalence of between 1/2000 and 1/4000 live births ,
the actual prevalence may be higher due to high clinical expressivity , accounting for underrecognition .
: dgs is caused due to the deletion of the genes in the digeorge chromosomal region ( dgcr ) on chromosome 22q11.2 , secondary to a nonallelic meiotic recombination during spermatogenesis or oogenesis . a great percentage ( 93% ) of the probands
have a de novo deletion of 22q11.2 , while some ( 7% ) inherit the 22q11.2 deletion from a parent in an autosomal dominant fashion . rarely , less than 1% of the individuals with dgs have chromosomal rearrangements , such as a translocation between chromosome 22 and another autosome , involving 22q11.2 .
? ans . : the clinical features of dgs [ table 3 ] , are exceedingly variable , with over 190 features described in the literature , involving almost every organ system    thus underlining the need for sensitization among physicians and surgeons from all specialties . of note ,
no phenotype occurs in 100% of the patients , as the penetrance of each clinical feature is diverse .
thus , one should be wary of excluding differential of dgs solely on the basis of absence of a particular feature .
the presence of congenital heart disease ( chd ; especially conotruncal anomalies ) , neonatal hypocalcemia ( with hypoparathyroidism ) , and palatal defects can usually be picked up in the neonatal period , and should serve as red flags for early diagnosis .
authorities in this subject recommend that , given the high frequency of dgs among individuals with conotruncal anomalies , newborns with these heart anomalies should be routinely screened with fluorescence in situ hybridization ( fish ) for 22q11.2 deletion , once other causes ( down syndrome , trisomy 13 ) have been ruled out .
other pointers for this condition , such as dysmorphisms , intellectual disability , and psychiatric disorders may appear only years later , often delaying the diagnosis .
an emerging area of great interest is the high predilection of psychotic disorders ( including schizophrenia and bipolar disorders ) in adolescents and adults with dgs ( 25 times higher than the general population ) .
other than serving as a reminder to psychiatrists , this also underlines that pediatricians and geneticists dealing with dgs / suspected dgs should diligently excavate the psychiatric history of the pedigree in detail , along with the other relevant particulars .
clinical features of digeorge syndrome scid = severe combined immunodeficiency ; chd = congenital heart disease ; jra = juvenile rheumatoid arthritis case details ( continued ) : in view of suspected dgs , fish was performed using tuple1 probes on 200 interphase nuclei and 7 metaphases of the cultured blood .
all the cells analyzed showed a heterozygous deletion in the 22q11.2 region [ figures 2a and b ] .
presence of two green signals ( control arsa probe , locus 22q13 ) one orange signal ( tuple1 , locus 22q11.2 ) denotes hemizygous deletion in the 22q11.2 region ( b ) fish image of the patient : metaphase cell , each cell has two chromatids .
presence of two pairs of green signals ( control arsa probe , locus 22q13 ) and only one pair of orange signals ( tuple1 locus 22q11.2 ) denotes hemizygous deletion in the 22q11.2 region q5 : what is the diagnostic modality for digeorge syndrome ?
: the most regularly and widely used diagnostic test for detecting the 22q11.2 deletion is fish using probes for the commonly deleted region .
however , around 5% of the cases may require more sophisticated and costlier methods such as multiplex ligation - dependent probe amplification ( mlpa ) and array comparative genomic hybridization ( acgh ) to detect the underlying genetic aberration .
the presence of a chd in association with one or more of the following should serve as an important red flag for considering an underlying chromosomal imbalance as the possible genetic etiology : growth failure , intellectual disability , other malformations affecting a second organ , multiple anomalies , and dysmorphic features .
in such cases , when the conventional karyotype fails to pick up the underlying genetic condition , an acgh can lead to increased detection of the underlying causal chromosomal imbalance .
the major advantage of this acgh technique is its increased resolution , which surpasses that of conventional karyotyping by at least fivefold . in an excellent study by breckpot et al .
, 150 children with an underlying chd and one or more of the red flags mentioned above were subjected to acgh , after a genetic diagnosis could not be reached despite a conventional karyotype and ruling out well - defined genetic disorders . of these 150 children , 24 ( 17.3% )
were detected as having an underlying copy number variation ( cnv ) , that is , a deletion or duplication , as responsible for their syndromic chd , as detected by acgh .
some examples of the cnvs detected in this study include 1p36 deletion , 1q21.1 duplication , 8q deletion , 14q32 deletion , and 16p13.3 duplication .
acgh can also diagnose , among many other cnv conditions , williams syndrome and some cases of charge syndrome .
case details ( continued ) : on admission in our center , the child had leukocytosis ( total leukocyte count = 32  10/l ) and radiological evidence of bronchopneumonia .
however , the child 's condition worsened on day 9 , due to congestive cardiac failure precipitated by the infection . in spite of ionotropic support and mechanical ventilation , the child
timely diagnosis of this condition can alert the treating physician about the possibility of the associated comorbities known to occur with this disease .
acute management in neonates and during infancy is mainly focused on the evaluation and treatment of hypocalcemia and the underlying chd as in our case .
proactive prevention of the secondary complications and a watchful  system - wise  surveillance plan can go a long way in ensuring a healthy life for most of these individuals [ table 4 ] .
however , the lack of centers performing thymic transplantation in india and the immunosuppression following the transplant make that a difficult option .
prevention of secondary complications and the system - wise surveillance in patients with digeorge syndrome case details ( continued ) : the parents were offered genetic counseling , the main focus being on the future risk of recurrence , as our patient was the first issue .
ans . : following the detection of 22q11.2 deletion in the proband , it is of vital importance to screen both the parents for the same ( using fish or mlpa ) in order to ascertain the origin of the deletion , sporadic or inherited .
if either parent is detected with the deletion , then the risk of recurrence in the next pregnancy is 50% irrespective of the sex of the child ( autosomal dominant inheritance ) .
however , if the parents of an individual with 22q11.2ds have normal studies , the risk of recurrence in the subsequent pregnancy is low , though greater than that of the general population .
this is due to the possibility of germline or low - level somatic mosaicism in the parents .
report retrospectively detecting 30 relatives of probands having a deletion in the 22q 11.2 region , following a diagnosis in the proband . of note
, only 32% of the adults and 55% of the children in this case series ever had any major medical problems warranting care .
thus , the absence of obvious clinical features should not be a reason to exclude the screening for the 22q11.2 deletion in the parents , if their child has been proven to carry the same .
unfortunately , in our case the parents were unwilling to investigate themselves further . in the scenario of one child having dgs ,
prenatal testing by fish or mlpa can be offered in the next pregnancy , using fetal cells obtained by chorionic villus sampling ( 10 - 13 weeks of gestation ) or amniotic fluid analysis ( 15 - 18 weeks of gestation . ) in pregnancies without any family history of the disorder , the sonographic markers that should prompt one to request for prenatal diagnosis are : chd ( especially conotruncal anomalies ) and/or cleft lip and/or cleft palate , congenital diaphragmatic hernia , umbilical or inguinal hernia , tracheoesophageal fistula / esophageal atresia / laryngeal atresia , polydactyly , craniosynostosis , polymicrogyria , and renal anomalies .
the prognosis for patients with dgs depends mainly on whether the dgs is partial or complete and on the severity of the underlying cardiac defect .
most children with complete dgs who do not undergo a thymic transplant usually die in infancy .
in contrast , the overall mortality rate in children with partial dgs is reported to be <
10% , most of them due to the underlying heart disease . however , if the child with an underlying heart disease has a successful repair , then the prognosis may be much better , the majority of the immunological problems settling with time .
the endocrinological problems , too , do not tend to be devastating , most of them being treatable . learning disabilities , speech issues , and psychiatric manifestations respond well if remedial and supportive therapy is begun early .
dgs is the most common microdeletion syndrome , with a notoriety of being clinically varied .
timely diagnosis aids better management , more holistic counseling , and the opportunity for prenatal diagnosis in a subsequent pregnancy .
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has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
this research received no specific grant from any funding agency in the public , commercial , or not - for - profit sectors .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
this research received no specific grant from any funding agency in the public , commercial , or not - for - profit sectors .
 our patient presented with congenital heart disease ( chd : tetralogy of fallot ) , hypocalcemia , hypoparathyroidism , and facial dysmorphisms . 
 suspecting digeorge syndrome ( dgs ) , a fluorescence in situ hybridization ( fish ) analysis for 22q11.2 deletion was made . 
 the child had a hemizygous deletion in the 22q11.2 region , diagnostic of dgs . 
 unfortunately , the patient succumbed to the heart disease . 
 dgs is the most common microdeletion syndrome , and probably underrecognized due to the varied manifestations . 
 this case stresses the importance of a detailed physical examination and a high index of suspicion for diagnosing this genetic condition . 
 timely diagnosis can help manage and monitor these patients better and also offer prenatal diagnosis in the next pregnancy . 
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