TSC2/PKD1 Contiguous Gene Deletion Syndrome

Introduction: Tuberous Sclerosis (TS) is an autosomal dominant disorder due to mutations in either TSC1 encoding hamartin or TSC2 encoding tuberin. Both genes play important roles in normal functioning of the mammalian target of rapamycin (mTor pathway) and mutations in this pathway causes abnormal cellular proliferation and differentiation producing hamartomatous lesions. PKD 1 and TSC2 genes lie tail to tail on Chromosome 16p13.3. Deletions in this region lead to TSC2/ADPKD1 contiguous gene syndrome. We report two cases of de novo TSC2/PKD1 contiguous gene deletion syndrome

Case1: A male infant presented at 13 weeks with focal seizures, global developmental delay, macrocephaly and bilateral ballotable kidneys. Abdominal ultrasound confirmed extensive cystic replacement of renal parenchyma. MRI Brain showed multiple subependymal nodules and tubers.

He had a de novo large deletion of the TSC2 gene from exon 1-41 to at least exon 46 of the PKD 1 gene. He has refractory focal epilepsy and chronic Hypertension with normal renal function. At nine months he has an evolving right hemiplegia and significant Developmental Delay.

Case 2: Case 2 presented at 3 months with supraventricular tachycardia and has upper lobe congenital emphysema. He had a large deletion of TSC2/ADPKD gene. CT brain was suggestive of TS. At 5 months he had focal seizures with EEG showing temperoparietal discharges. At 8 months he developed clinical and electrographic spasms and responded to Vigabatrin .He is on Everolimus for multicystic kidney disease.

Conclusion: Only 33 cases of TS and ADPKD have been described in the literature.

Renal complications are common in TS, however the coexistence of these two genes leads to increased rate of malignancy and development of ESRF at an earlier age. Our cases highlight the treatment challenges that these patients pose including seizure control and antihypertensive management.