Saudi Journal of Kidney Diseases and Transplantation

: 2018  |  Volume : 29  |  Issue : 6  |  Page : 1475--1479

Mammalian target of rapamycin inhibitors in a patient with polycystic kidney disease-1-tuberous sclerosis-2 contiguous gene syndrome

Urmila Anandh1, Gayatri Chandrasekar2, Vikas Agarwal3,  
1 Department of Nephrology, Yashoda Hospitals, Secunderabad, Telangana, India
2 Department of Radiology, Yashoda Hospitals, Secunderabad, Telangana, India
3 Department of Neurology, Yashoda Hospitals, Secunderabad, Telangana, India

Correspondence Address:
Dr. Urmila Anandh
Department of Nephrology, Yashoda Hospitals, Secunderabad -500 003, Telangana


The mutations associated with polycystic kidney disease are closely aligned with that of tuberous sclerosis (TSC) in chromosome 16. Occasionally, the presence of these mutations in an individual can lead to a presence of a disease phenotype with a combination of polycystic kidney disease and TSC (contiguous gene syndrome). We present a case report of a young girl who presented with skin lesions, central nervous system tubers, and cystic disease of the kidneys. She was treated with mammalian target of rapamycin inhibitors with a favorable outcome.

How to cite this article:
Anandh U, Chandrasekar G, Agarwal V. Mammalian target of rapamycin inhibitors in a patient with polycystic kidney disease-1-tuberous sclerosis-2 contiguous gene syndrome.Saudi J Kidney Dis Transpl 2018;29:1475-1479

How to cite this URL:
Anandh U, Chandrasekar G, Agarwal V. Mammalian target of rapamycin inhibitors in a patient with polycystic kidney disease-1-tuberous sclerosis-2 contiguous gene syndrome. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2021 Sep 27 ];29:1475-1479
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Full Text


The inheritance of autosomal polycystic kidney disease is genetically heterogeneous. Two genes polycystic kidney disease (PKD)-1 (OMIM #601313) and PKD2 (OMIM#173910) are involved in the dominant inheritance of this disease.[1] The mutations of PKD1 are located in an intrachromosomally mutated region of chromosome 16. PKD1 has an unusual structure consisting of 46 exons. The last 45 exons made of 31 kb are present directly adjacent to tuberous sclerosis 2 (TSC2) gene. Large deletions in this segment often lead to PKD1/TSC2 contiguous gene syndrome.[2] Patients with PKD1/TSC2 deletions present with early-onset cystic disease of the kidneys in combination with various phenotypic manifestations of the TSC complex. We present a case of a young girl who presented with polycystic kidney disease, adenoma sebaceum, and intracranial tubers and her genetic analysis were suggestive of the presence of the PKD1/ TSC2 contiguous gene syndrome.

 Case Report

An 18-year old girl presented to us in our outpatient department with back pain, weakness and progressive skin rash all over her body. She denied any swelling of legs, puffiness of the face and any urinary complaints. She complained of an intermittent headache over the last one year. She was routinely evaluated at her hometown and was told to have bilateral kidney swelling. For these complaints, she sought a nephrology evaluation. Her clinical examination revealed a fairly built normotensive afebrile girl. She had extensive small raised papules on her face [Figure 1] and back. There were small hypo-melanotic papules all over her body. Systemic examination revealed bilateral enlarged kidneys which were non tender. Her routine investigations are outlined in [Table 1]. She had normal renal function and inactive urine sediment. A dermatology consultation was taken, and it was opined that the skin lesion was classical adenoma sebaceum. A plain computed tomography (CT) scan of the abdomen revealed bilateral bulky kidneys (right kidney 11.8 cm and left kidney 11.0 cm) showing multiple cysts of varying size. Few of the cysts had hyperdensity and foci of calcification. An intensely enhancing solid exophytic cyst in the lower pole suggestive of a hamartoma was noted [Figure 2]. Due to her persistent headache, a non-contrast CT brain was done. In this study, there were subependymal calcified nodules along the atrium of both the lateral ventricles and body of the left lateral ventricle. Rest of her brain parenchyma was normal [Figure 3]. These lesions were suggestive of TSC. Non-contrast MRI brain was suggestive of bilateral T1 hyperintense subependymal nodules most likely due to TSC [Figure 4]. Due to these clinical and radiologic findings, a diagnosis of contiguous gene syndrome secondary to possible mutations in the PKD1/TSC2 gene complex was considered. A mutation analysis revealed a large deletion in the chromosome 16p13.3 which confirmed our diagnosis [Figure 5].{Figure 1}{Table 1}{Figure 2}{Figure 3}{Figure 4}{Figure 5}

Her disease prognosis and treatment options were discussed with her. She was started on tablet sirolimus 1 mg twice daily, and the drug dose was titrated to reach a target drug level of 3-5 ng/mL. She has been on regular follow-up, and after one year of treatment, both her skin lesions and her tubers in the MRI brain [Figure 6] appear nonprogressive. The size of the kidneys on follow-up ultrasound did not show any significant increase (right kidney 10.6 cm and left 11.0 cm).{Figure 6}


Our case illustrates the presence of a combination of phenotypic characteristics of both TSC and polycystic kidney disease. This is due to the large deletion mutation in chromosome 16p13.3 affecting the adjacent genes of TSC2 and PKD1. Mutation in the TSC2 and PKD1 gene is enough to cause early onset cysts; however, it is unclear as to the contribution of the mutation in our patient and her unique phenotype.

Clinically, these patients have skin manifestations (adenoma sebaceum, shagreen patches, subungual fibromas, and hypopigmented macules), renal involvement and central nervous system (CNS) hamartomas (tubers). Renal manifestations are in the form cystic disease, angiomyolipomas and rarely renal cell carcinoma.[3] Renal manifestations are often early and severe and are responsible for early mortality.[4],[5] Our patient also presented with significant renal abnormalities in the second decade of her life consistent with the clinical presentation in such cases. The computed tomography of the abdomen showed multiple cysts with some showing hamartomatous changes. She also had CNS tubers consistent with the central nervous system manifestation of PKD1-TSC2 complex presentation.[6],[7] It was decided to consider treatment for her disease as she was expected to have rapid renal/CNS deterioration. The treatment with mTOR inhibitors showed no further deterioration in the CNS tubers. The kidney volumetric assessment was not done as the patient declined a CT scan fearing repeated radiation exposure.

Management of patients with PKD1-TSC2 contiguous gene syndrome patients involve regular monitoring of hypertension, renal functions and imaging to look for cyst complications. Hypertension is preferably managed with RAAS blockade as is done with patients with autosomal polycystic kidney disease. Vascular complications secondary to the hamartomas may need embolization as nephrectomy will lead to worsening of the progressive chronic kidney disease.

For the treatment of autosomal polycystic kidney disease (ADPKD), mTOR inhibitors have been evaluated and are being used since the beginning of this decade.[8] Some studies have shown to reduce the progression of the kidney volumes in the early stage ADPKD, but long-term benefits have not been impresssive.[9] However, mTOR inhibitors have been approved for the treatment of hamartomas in TSC complex and have shown promise in clinical trials.[10] Based on this background information, our patient was advised treatment with sirolimus. She was extensively counseled about the possible side effects including nephrotoxicity. On treatment for more than a year, her CNS, cutaneous and renal disease seems to be stable. She has reported no side effects which can be attributed to sirolimus.

Besides close monitoring and therapy, it is also important to counsel these patients regarding their overall prognosis and also consider early fetal genetic analysis if the patient conceives.


Sirolimus can be considered as a treatment option in patients of PKD1-TSC2 contiguous gene syndrome. However, long-term monitoring of side effects and assessment of the benefit of therapy is required.

Conflict of interest: None declared.


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