Miller Dieker Syndrome as a Cause of Refractory Seizures

Address for correspondence: Dr. Sanamda Pati E-mail: sanandapati@gmail.com 1Dr. Sananda Pati, MBBS, MD, RMO Cum Clinical Tutor, Department of Paediatrics, Burdwan Medical College and Hospital, 2Dr. Sangita De, MBBS, MD, PGT, Department of Paediatrics, Burdwan Medical College and Hospital, 3Dr. Sankha Subhra Nag, MBBS, MD, RMO Cum Clinical Tutor, Department of Paediatrics, North Bengal Medical College and Hospital, 4Dr. K Nayek, Professor, MBBS, MD, Department of Paediatrics, Burdwan Medical College and Hospital. Abstract


Introduction
M iller-Dieker syndrome is a very rare gene dele on syndrome 1,2 characterized by neuronal migra on disorder lissencephaly and characteris c facial dysmorphism.Here we report a case of a one year old boy who presented to our emergency with convulsion and respiratory distress and was diagnosed as Miller Dieker syndrome based on clinical examina on and inves ga on.Here we highlight that rare diseases can have common presenta ons, the iden fi ca on of which helps in management, an cipa ng prognosis and planning gene c counselling.

The Case
A one year old boy born presented to our emergency with severe respiratory distress and recurrent convulsions.The child was born out of nonconsanguinous marriage in a rural tribal family of West Bengal.He was treated on and off since birth by local doctors , paramedics and quacks before coming to our medical college and hospital.Apart from the presen ng complaints the child had dysmorphic facies, grossly delayed milestones and failure to thrive.The characteris c facial appearance was due to a prominent forehead, narrow palpebral fi ssure, bilateral convergent squint, midface hypoplasia, bitemporal hollowing, a small, upturned nose, low-set ears and abnormally fl a ened pinna, thin vermillion border, small jaw and long philtrum.There was no sugges ve birth history or family history.
The child was managed symptoma cally with moist oxygen, i.v.fl uids, an epilep cs.Seizures were refractory to treatment with phenytoin, phenobarbitone, leve racetam, midazolam (shi ed to PICU), blood glucose and electrolyte [Na+, K+, Ca++, Mg++] correc on.Empirical intravenous pyridoxine was started.Pentobarbitol coma and general anaesthesia were being considered.Arterial blood gas revealed impending Type  -1 respiratory failure following which child was put to ven lator.
CT Brain showed loss of convula ons of brain, a characteris c fi gure of eight appearance consistent with classical or type-1 lissencephaly with hypoplasia of corpus callosum.
A diagnosis of Miller Diecker syndrome was made consistent with typical clinical features and inves ga ons.However the condi on of the child deteriorated by second day.He succumbed on the third day of admission.This was the fi rst and only child and the parents were counselled about the nature of the disease, prognosis, and very low chances of recurrence in the siblings and informed about chorionic villus sampling and other antenatal imaging available for early diagnosis of the condi on.

Discussion
Miller-Dieker syndrome is a gene c dele on syndrome characterized by neuronal migra on disorder lissencephaly where the exterior of the brain is abnormally smooth with fewer folds and grooves and characteris c facial dysmorphism 1,2 .
Pregnancy can be associated with a history of polyhydramnios, intrauterine growth retarda on and reduced fetal movements 3 .Children with MDS present with severe developmental delay.They usually do not a ain milestones beyond those of 3-6 month olds.Generalised hypotonia is a prominent feature early in life; with increasing spas city as the pa ents get older.Epilepsy can be present at birth, or usually within the fi rst 6 months of life, o en as infan le spasms.Feeding and swallowing problems are common, and can be complicated by aspira on pneumonia.There are life-threatening breathing problems.The head circumference is small to normal at birth, but older pa ents are usually microcephalic 1,2 .
In addi on to lissencephaly, pa ents with Miller-Dieker syndrome tend to have dis nc ve facial features that include a prominent forehead, a sunken appearance in the middle of the face (midface hypoplasia), a small, upturned nose, bi-temporal hollowing, low-set and abnormally shaped ears, a small chin, thin vermillion border and a thick upper lip 1,2,4 .
Rarely, aff ected individuals will have heart or kidney malforma ons, omphalocele or cryptoorchidism 1,2,4 .Most individuals with this condi on do not survive beyond child hood.
Brain imaging with clinical features is diagnos c.CT Brain consistent with lissencephaly type 1.The failure of the opercula to fold over the insula results in the "fi gure of eight" appearance seen on imaging 1,2 .The posterior fossa structures usually look normal.Antenatal diagnosis by chorionic villus sampling and imaging beyond 28 weeks is possible 3 .MD S is undoubtedly a rare condi on.Few published studies are present regarding its prevalence.A (1991) Dutch study showed prevalence of classical lissencephaly (lissencephaly type 1) to be 11.7 per million live births, of which 25-30% are es mated to have Miller Dieker syndrome 2 .
Miller-Dieker syndrome is caused by a dele on of gene c material near the end of the short (p) arm of chromosome 17 1,2 .The signs and symptoms of Miller-Dieker syndrome are probably related to the loss of mul ple genes in this region.The size of the dele on varies among aff ected individuals.All of the genes that contribute to the features of Miller-Dieker syndrome are yet to be iden fi ed.Dele on of a "cri cal region" comprising two or more gene c loci within band 17p13.3 is the cause of the MDS phenotype 1-2,4-5 .Addi onal genes in the deleted region probably contribute to the varied features of Miller-Dieke r syndrome 4,5 .
Most cases of Miller-Dieker syndrome are not inherited 4 .The dele on occurs most o en as a random event during the forma on of reproduc ve cells (eggs or sperm) or in early fetal development.Aff ected people typically have no history of the disorder in their family.
When Miller-Dieker syndrome is inherited, its inheritance pa ern is considered autosomal dominant because a dele on in one copy of chromosome 17 in each cell is suffi cient to cause the condi on 1,2,4,6 .About 12 percent of people with Miller-Dieker syndrome inherit a chromosome abnormality from an unaff ected parent.In these cases, the parent carries a chromosomal rearrangement called a balanced transloca on, in which no gene c material is gained or lost.Balanced transloca ons usually do not cause any health problems; however, they can become unbalanced as they are passed to the next genera on.Children who inherit an unbalanced transloca on can have a chromosomal rearrangement with extra or missing gene c material [4][5][6] .Individuals with Miller-Dieker syndrome who inherit an unbalanced transloca on are missing gene c material from the short arm of chromosome 17, which results in the health problems characteris c of this disorder.
Gene c counselling may be done.However since this is a gene c dele on syndrome chance of recurrence is low 4 .
Management of children with MDS is symptoma c.Nasogastric tubes and gastrostomies to avoid the complica ons of feeding and swallowing (like failure to thrive and aspira on pneumonia) and seizure control is important.

Conclusion
This case illustrates the need to iden fy gene c diseases which may have common presenta ons like convulsion and respiratory distress.The detec on of which not only helps in management but also an cipate prognosis, gene c counselling and reassurance of parents regarding possible recurrence of the disease in the family.

Fig 1 :
Fig 1: Pa ent with prominent forehead, hypertelorism, epicanthic fold, narrow palpebral fi ssure, convergent squint, bitemporal hollowing,low set ears, fl a ened helix of pinna, long philtrum, thin vermillion border, small jaw.Facial dysmorphism consistent with Miller Dieker Syndrome.Child in severe respiratory distress note the swea ng of forehead and upper lips (photo permission from parents taken).

Fig 2 :
Fig 2: CT Brain consistent with lissencephaly type 1 and hypoplasia of corpus callosum.Figure of eight confi gura on.Lissencephaly type I results from a complete arrest of cor cal neuronal migra on between 12-and 16-weeks gesta on.This appearance results from the smooth brain surface, large and ver cally placed Sylvian fi ssure, hypoplas c operculum, and enlarged ventricles.