
 chromosome 22q13.3 deletion syndrome is a well - recognized cause of global developmental delay ( gdd ) [ 1 , 2 ] while duplication of the same chromosome is a rare occurrence [ 35 ] .
the presence of both abnormalities in the same family has never been reported , to our knowledge .
we report the presence of 22q13.3 deletion and 22q13.3 duplication in two siblings , with the mother carrying an inversion of chromosome 22 ( 46 , xx , inv ( 22 ) ( p13q13.32 ) ) a 6 year - old male was noted in infancy to have mild global developmental delay without dysmorphic features .
his 4 year - old brother was noted in early infancy to have severe global developmental delay and dysmorphic features related to 22q13.3 deletion to the terminus .
the mother 's inversion may rearrange to form 22q duplication or deletion when passed on to children .
the chance of a child born with a chromosome imbalance is as high as 50% .
he had calcaneo - valgus deformity of the right foot which improved with manipulation with each diaper change . at 9-month - old
, his mother noticed that he would not engage with her and would stare into space .
he was referred to a neurodevelopmental pediatrician at age 18 months because all developmental milestones were delayed .
his height and weight were at 50th percentile , and fronto - occipital circumference ( foc ) was at 98th percentile ( large head ) .
neuropsychological evaluation revealed significant difficulty in social skills and adaptive functioning , consistent with a diagnosis of  pervasive developmental disorder nos  .
it further revealed that receptive language was better than expressive language skills . a metabolic disorder screen ( plasma for amino acids , urine for organic acids , smith - lemli opitz , thyroid ) and fragile - x screening were normal .
chromosomal analysis revealed 46 , xy , rec ( 22 ) dup ( 22q ) inv ( 22 ) ( p13 ; q13.32 ) mat ( figures 1 and 2 ) .
jc is the younger sibling who was born by normal vaginal delivery , after a term gestation , when his mother was 38  yrs old .
his birth weight was 9  lb . 3  oz . he had transient tachypnea of the newborn which responded to oxygen administration .
jc was referred to a neurodevelopmental pediatrician at the age of 13  mos . because of delayed language and motor development .
height and weight were in the 90th percentile , and foc was between 70 and 90th percentile .
he had downslanting palpebral fissures , fleshy hands , dysplastic toe nails , and clinodactyly .
he has generalized coarse facial features , broad nasal bridge , relatively flat midface , and prominent chin and ears .
he has heat intolerance ( because of decreased perspiration ) , a high pain threshold , and a wobbly gait ( because of hypotonia ) .
behavior characteristics included mouthing and chewing of nonfood items and autistic - like behavior and affect , typical of the 22q13.3 deletion syndrome .
newborn genetic screening ( amino academia , congenital adrenal hyperplasia , congenital hypothyroidism , smith - lemli opitz , galactosemia , hemoglobinopathy ) was normal .
chromosomal analysis revealed 46 , xy , rec ( 22 ) dup ( 22p ) inv ( 22 ) ( p13q13.32 ) mat ( figures 1 and 2 ) .  
medication management for his disruptive behaviors was strongly recommended , but the family refused this option because of the potential sideeffects . the mother ( hc )
has an inversion in one of her number 22 chromosomes : 46 , xx , inv(22 ) ( p13 ; q13.32)indicating that one of the mother 's number 22 chromosomes contains a large piece that is inverted or flipped backwards ( figure 3 ) .
her mother 's first paternal cousin has an intellectual disability but went on to have 3 children , and one of them is intellectually disabled . the father ( tc ) has entirely normal chromosomes .
22q13 would not be considered a classic  hot spot  for genomic rearrangements , which are generally regions flanked by highly homologous segmental duplications which predispose to nonhomologous allelic recombination during meiosis in one of the parental lines , yielding identical and recurrent deletions or the reciprocal duplication .
although such individuals are completely healthy , a certain proportion of their gametes will contain a rearranged form of the inverted 22 chromosome .
a parent with an inversion or a balanced translocation could transmit the unbalanced form of the translocation to the offspring , or deletions and duplications may occur through recombination between the normal allele and the inverted allele .
a child with this unbalanced rearrangement would be expected to have developmental delay and possible birth defects .
this rearrangement can be in the form of deletion or duplication of the chromosomal segment in question . in the remaining off - springs , where the rearrangement remains balanced
alternately , the mother may pass on her normal number 22 chromosome , and the child will be normal .  
cc , the older sibling ( 46 , xy , rec ( 22 ) dup ( 22q ) inv ( 22 ) ( p13 ; q13.32 ) mat , ) has no dysmorphic features , yet has significant developmental delay .
the 22 chromosome duplications are very rare , and the ones cited in the literature have breakpoints on 22q12 rather than 22q13 .  
jc , with monosomy of 22q13.3 , has findings typical of 22q13.3 deletion syndrome patients including global developmental delay , generalized hypotonia , absent or severely delayed speech , and normal or accelerated growth .
the true prevalence of 22q13.3 deletion may be underestimated because routine karyotyping may only detect a fraction of the cases . when this condition is suspected based on clinical features or there is a history of mild gdd in an older sibling , early genetic testing should be instituted employing new and more assertive methods like genomic microarray and fluorescent in situ hybridization ( fish ) .
it is worth noting that our case ( jc ) acquired the deletion from his mother .
in addition , jc also received music therapy , picture exchange communication , and sign language instruction .
it is believed that these interventions contributed to improving behavioral issues ( autistic features ) in jc and global developmental delay in both . to facilitate communication and decrease frustration within the family ,
all family members should be encouraged to learn sign language [ phelan , personal communication ] . as is true for most chromosomal abnormalities , and as was done with the presented cases , individuals with 22q13.3 deletion or duplication
should also undergo base - line investigations like renal ultrasound ( for renal cysts and other structural problems ) , echocardiogram ( for septal defects ) , eeg ( for seizure activity ) , audiology tests ( to r / o hearing deficits ) , and brain imaging studies ( arachnoid cysts , etc . ) . as these individuals are expected to have a reasonably normal life expectancy [ phelan , personal communication ]
, they should receive the recommended health maintenance preventive services ( pap smears , colon cancer screening , prostate exam , cholesterol check , etc . ) .
some screening tests like colon cancer screening may need to be expedited , as there may be an increased predisposition towards colon cancer .  
amniocentesis for prenatal testing in pregnancies at increased risk for chromosomal abnormalities may not be diagnostic , as in jc 's case [ dr . grati , european genetics conf .
2008 ] , and fish , chorionic villus sampling , or micro - array testing should be considered , as they are more specific .  
behavioral interventions and medication management such as atypical neuroleptics are often recommended to control behavior problems .
 chromosome 22q13.3 deletion syndrome is a well - recognized cause of global developmental delay , while duplication of the same chromosome is a rare occurrence . 
 the presence of both abnormalities in the same family has never been reported , to our knowledge . 
 we report a rare occurrence of 22q13.3 duplication and 22q13.3 deletion in siblings , as a consequence of a mother 's inversion on her 22nd chromosome ( p13;q13.32 ) . 
 a 6  year old male was noted in infancy to have mild global developmental delay without dysmorphic features . 
 his genetic testing revealed he had 22q13.3 duplication to the terminus . 
 his 4  year old brother was noted in early infancy to have severe global developmental delay and dysmorphic features related to 22q13.3 deletion to the terminus . 
 their mother had a long inversion on her 22nd chromosome . 
 genetic tests for their father and eldest brother were unremarkable . 
 the mother 's inversion may rearrange to form 22q duplication or deletion when passed on to children . 
 the chance of a child born with a chromosome imbalance is as high as 50% . 
1. Introduction
2. Case Report
3. Discussion