array - comparative genomic hybridization ( a - cgh ) assay has made the genome - wide screening of genomic copy - number variations ( cnvs ) possible , enabling to assign genetic diagnoses to phenotypes , which could not be accounted for in the past .
microcephaly , disproportionate pontine and cerebellar hypoplasia ( micpch ) syndrome [ online mendelian inheritance in man ( omim ) number 300749 ] , a rare clinico - radiological phenotype , was first described by najm et al . and linked to calcium / calmodulin - dependent serine protein kinase ( cask ) gene mutations .
the core phenotype comprises severe neurodevelopmental delay , microcephaly , and disproportionate pontine and cerebellar hypoplasia .
neuroradiological features associated with cask mutations have been refined by takanashi . to date , forty five or so female patients with characteristic phenotype and two male patients with lethal form have been reported .
we report a girl with clinico - radiologic features of micpch syndrome , whose conventional cytogenetic analysis was normal and a subsequent a - cgh analysis discovered microduplication in cask gene at xp11.4 .
a 2-year - old asian girl was referred to pediatric neurology service with global developmental delay and growth restriction .
she could sit unaided and roll over , but was unable to stand without support .
she was born at term by normal vaginal delivery to un - related healthy parents .
pregnancy was unremarkable for infection , exposure to known teratogens , polyhydramnios or decreased fetal movements .
she was both breast and bottle fed . during the weaning period , she struggled with lumpy food and failed to gain weight beyond 6 months .
clinical assessment revealed microcephaly , low weight ( < 0.4 centile ) , an open mouthed appearance with thickened alveolar ridges , prominent maxilla , bilateral epicanthic folds , short nose , long philtrum , large ears , hypoplastic 5 toe nails , delayed neurodevelopmental milestones , low axial tone , and slightly increased peripheral tone , more so in the lower limbs .
as a part of her diagnostic work - up , she underwent extensive investigations . magnetic resonance imaging ( mri ) showed prominent lateral ventricles , mega cisterna magna , small cerebellum , and normal corpus callosum [ figure 1 ] .
neurometabolic investigations were normal and toxoplasmosis , rubella , cytomegalovirus , herpes simplex ( torch ) studies were negative .
note the hypoplastic pons and cerebellum with normal appearance of the corpus callosum she was referred to clinical genetics team with a view to assigning a syndromic diagnosis .
subsequently , an a - cgh analysis was carried out , which revealed cask gene duplication at xp11.4 .
micpch syndrome is a rare x - linked genetic disorder caused by cask gene mutations and is characterized by neurodevelopmental delay and specific brain malformations .
cask , a multi - domain scaffolding protein , is a member of membrane associated guanylate kinase protein family , which regulates presynaptic neurotransmitter release , postsynaptic ion - channel function , and expression of genes associated with brain development .
evidence suggests that loss - of - function cask gene mutations lead to x chromosome inactivation , causing severe phenotype , whereas hypomorphic missense cask mutations produce less severe phenotypes . deletions and intragenic mutations have been associated with micpch syndrome more commonly than duplications .
almost invariably , the cask genetic aberrations are de novo , resulting most commonly from the mutational mechanism of non - allelic recombination .
najm studied four females and one male who died in neonatal period to describe the core phenotype and found cnvs , gene inversion and single nucleotide polymorphism as the possible mutational mechanisms .
hayashi in his ten cases discovered nonsense mutations , 2-bp deletions , exon - intron junction mutations , interstitial duplications , and heterozygous deletions with almost equal frequency .
moog reported 20 patients of which 11 showed submicroscopic cnvs , including nine deletions and two duplications in the cask gene .
recently , burglen have reported 13 patients ( 11 females and 2 males ) with de novo cask gene mutations , 10 being intragenic mutations and 3 xp11.4 deletions .
the core micpch syndrome clinical phenotype , originally described by najm , was further defined by moog , and confirmed by burglen .
it includes severe neurodevelopmental delay , varying degrees of congenital microcephaly , severe postnatal microcephaly ( occipitofrontal circumference < 3.5 sd ) by 1 year of age , commonly associated with feeding difficulties , postnatal growth restriction , axial hypotonia , peripheral hypertonia , and occasional optic nerve hypoplasia and/or other eye abnormalities and sensorineural hearing impairment . dysmorphic features comprised prominent and/or broad nasal bridge and tip , small or short nose , long philtrum , small chin , and/or large ears , hypoplastic toe nails etc .
takanashi described the radiological phenotypic spectrum associated with cask gene mutations , which confirmed the findings of najm and was , in turn , corroborated by observations recorded by moog mri revealed varying degrees of brainstem and cerebellar hypoplasia and in some cases , showed increase in the fourth ventricle size , subtle changes in gyral pattern in frontal cortex , and mild dilatation of lateral ventricles .
takanashi also concluded that a relatively normal corpus callosum with low cerebrum / corpus callosum ratio in a girl with microcephaly and neurodevelopmental delay , alludes to the possibility of cask gene mutation , as the pontocerebeller hypoplasia in non - cask gene mutations is associated with thinning of corpus callosum .
severe neurodevelopmental delay , marked microcephaly , small cerebellum , prominent lateral ventricles , and dysmorphic features such as short nose , long philtrum , prominent maxilla , and large ears fit in the clinico - radiologic phenotype described .
normal appearing corpus callosum ( cc ) in our patient is in line with observations made by takanashi .
minimal vermis involvement in our case was reported by moog in patient 10 , 11 , and 12 .
as seen in our case , hypoplastic toe nails were documented in patient 7 by moog and patient 10 by burglen .
fourth ventricle size was near normal in our case as was reported by moog in five of their patients . although , typically cerebellum and vermis are affected equally , our case , like patient 7 of moog and patients 10 , 11 and 12 of burglen had a subtly affected vermis .
cask gene duplication , found in our case , has been reported only in a small number of reported micpch syndrome cases and therefore , seems to be a less common mutational mechanism to produce michpch syndrome . despite extensive investigations in our case , the diagnosis remained elusive until a - cgh analysis uncovered micro - duplication , which was earlier reported in two cases by hayashi and in patients 21 and 25 reported by moog . based on the preceding discussion , it can be suggested that in girls presenting with severe neurodevelopmental delay and microcephaly , if neuroimaging depicts ponto - cerebellar hypoplasia with normal cc , a - cgh analysis may be carried out to ascertain genetic diagnosis .
micpch syndrome , mostly seen in girls , is caused by de novo loss - of - function cask gene mutations in x - chromosome in the xp11.4 region , producing null alleles .
clinicians assessing girls presenting with severe developmental delay and microcephaly can use the radiological features of ponto - cerebellar hypoplasia with normal corpus callosum and low cerebrum / cc ratio as a guide to look for cask gene mutations by using a - cgh analysis .
 microcephaly , disproportionate pontine and cerebellar hypoplasia ( micpch ) syndrome , a rare x - linked disorder , generally seen in girls , is characterized by neurodevelopmental delay , microcephaly , and disproportionate pontine and cerebellar hypoplasia . 
 it is caused by inactivating calcium / calmodulin - dependent serine protein kinase ( cask ) gene mutations . 
 we report a 2-year - old girl with severe neurodevelopmental delay , microcephaly , minimal pontine hypoplasia , cerebellar hypoplasia , and normal looking corpus callosum , with whom the conventional cytogenetic studies turned out to be normal , and an array - comparative genomic hybridization ( a - cgh ) analysis showed cask gene duplication at xp11.4 . 
 our case highlights the importance of using clinico - radiologic phenotype to guide genetic investigation and it also confirms the role of a - cgh analysis in establishing the genetic diagnosis of micpch syndrome , when conventional cytogenetic studies are inconclusive . 
Introduction
Case Report
Discussion
Conclusion