Dr.Venkatesh Kumar, Dr.Vinayan(Pediatric Neurology ), Dr.Sheela Nampoorthi(Genetics), Dr.C.Jayakumar, AIMS Kochi.
Six year old male child, 4th out of 5 children, born of non-consanguineous marriage presented with paroxsymal events since 9 months of age with semiology of up rolling of eye ball with multiple episodes of oral automatism ,clonic stiffening of left upper and lower limbs. MRI Brain showed mild periventricular gliosis and periventricular cystic changes, chronic lacunar infarcts in the b/lbasal ganglia and thalami.
CT brain showed multiple punctate calcifications in the B/L basal ganglia and thalami.
EEG was normal, treated as possible Intrauterine infection /hypothyroidism and started on levetiracetam .Even after levetiracetam there is history of recurrent paroxysmal events with different semiology including myoclonic jerks,occasional head deviation to one side with consciousness during the event.
Parents also noticed to have behavioural issues-aggressive behaviour, reduced eye contact,reduced attention during speech, speaks on his own, not interested in surroundings in addition to developmental delay in the language and personal social domains.
Perinatal history of delayed cry and hypoglycemia was present.
On examination, vitals were stable. Head to toe examination did not reveal any findings. Auxology revealed normal growth parameters.Neurological examination did not reveal any focal deficits and other systemic examination findings were unremarkable.
Differentials considered at this point are:
1. Congenital TORCH infections.
2. Congenital HIV encephalopathy.
3. Interferonopathies like Aicardi-Goutiere’s syndrome.
4. Genetic microangiopathies with leukoencephalopathy and calcifications( Labrunes or Cerebroretinal microangiopathies with calcifications and cysts)
5. Band like calcification polymicroglia( BLC-PMG)
6. Leukoencephalopathy with calcification.
INVESTIGATIONS:
Hemogram: TC- 13.58 ku/ml, N-30.7%, L-57.1%, Hb- 13.6 gm/dl, Plt- 3.80 lakh.
LFT,RFT- normal.
CRP: 0.69 mg/L.
Na+: 139.1 mEq/L , K+: 4 mEq/L , Ca2+: 9.25 mg/dl, Mg: 2.3 mg/dl, Phosphorous: 5.5 mg/dl.
Ammonia:38.4 umol/L, Lactate: 1.57 mmol/L
CPK: 187 U/L, S.T4: 1.64 ng/dl , TSH: 2.61 IU/ml.
MRI Brain : Symmetric and confluent periventricular white matter signal changes with hyperintensity along thalami,internal capsules,cerebellum, old lacunar infracts/gliosis and scattered punctate calcifications were noted.Focal mass like areas on the right frontal region,cortical based with gradient blooming ? Calcified and peripheral contrast enhancement- exact nature of this is not evident.No imaging features to suggest an underlying vascular anomaly.
Prolonged VEEG: (VideoEEG)
Revealed runs off occipital spikes on right side.
He was started on Clobazam and Leviteracetam was continued.
VEP and NCV: normal.
Ophthal consultation: Normal disc and macula.
Clinical pyschology
Vineland social maturity scaling -VSSM), social quotient of 57 was obtained and on Child hood Autism rating score(CARS) of 32.5 was obtained indicating mild to moderate symptoms of ASD.He was advised speech, behavioural and occupational therapy.
Serial MRI’s from the past were compared and noted to have progression.
The possibilities considered were:
1.Genetic vasculopathy
2.Interfernopathies- Aicardi-Goutiere’s syndrome
3.Possibility of Intrauterine infection was less likely as there was progression and no other stigmata elsewhere.
The lesion in right frontal lobe shows slow progression, possibility of slow growing lesion such as Glioneural tumour/ DNET is not excluded.
Genetics consult was sought and advised WES medgenome.
WES: showed mutation of a variant in COL4A1 gene suggestive of HANAC syndrome( Hereditary Angiopathy with Nephropathy,Aneurysms and Muscle Cramps ).
Retrospective history suggests complaints of intermittent calf muscle pain which gets relieved after rest.
USG abdomen- No renal cysts.
MR angiogram- No aneurysms of intracranial vessels.
ECHO- Normal.
DISCUSSION:
HANAC Syndrome: Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is a genetic condition that causes blood vessels to become fragile. Signs and symptoms include muscle cramps, Raynaud phenomenon, kidney cysts, blood in the urine (typically not visible to the eye), leukoencephalopathy (a change in brain tissue that can be seen on MRI), arteries in the back of the eye that twist and turn abnormally, headaches, and supraventricular arrhythmia. These signs and symptoms do not often cause serious complications, however temporary vision loss due to bleeding in the back of the eye, minor ischemic stroke, and bleeding complications with blood thinner use has been described. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. HANAC syndrome is caused genetic changes in the COL4A1 gene. It is passed through families in a autosomal dominant fashion.
Take home message:
Any children presenting with paroxysmal event and slowly growing lesions in the brain with progressive changes in the MRI should not always be considered and worked up as intracranial tumour ,but extensive workup including genetics should be done to rule out rare genetic disorderslike HANAC Syndrome.