A child with TSC2/PKD1 contiguous gene deletion syndrome successfully treated with tolvaptan for rapidly enlarging renal cysts

Abstract

Tolvaptan, a vasopressin receptor antagonist, has been shown to be effective in the treatment of renal cysts in ADPKD. However, tolvaptan is not indicated for pediatric patients, and reports of its use are rare, making its efficacy and adverse reactions unclear. Herein, we present the case of an 11-year-old girl who had vitiligo from birth. She was diagnosed with West syndrome at 6 months of age and tuberous sclerosis at 2 years of age. At the age of 6 years, an abdominal magnetic resonance imaging (MRI) revealed multiple bilateral renal cysts, and she was diagnosed with ADPKD. Abdominal MRI scans performed at 10 years and 11 years showed rapid renal cyst enlargement, and the renal prognosis was judged to be poor. The patient was treated with tolvaptan to delay cyst exacerbation. There were no apparent adverse events after the initiation of treatment, and the MRI performed 12 months after treatment initiation showed that renal cyst enlargement was suppressed. The results suggest that tolvaptan may be effective in pediatric patients with severe ADPKD who have rapidly enlarging renal cysts, although evaluation of renal cyst enlargement and side effects should be continued.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is a condition characterized by the progressive development and enlargement of numerous cysts in both kidneys due to abnormalities in the PKD1 and PKD2 genes. Approximately 50% of patients with the condition develop end-stage renal failure by the age of 60 years [1, 2].

ADPKD is considered an adult disease; however, approximately 3% of children with the mutation that causes ADPKD have very early onset or unusually rapidly progressive disease [3]. Renal prognosis is poor, with some cases requiring renal replacement therapy in childhood. Although the efficacy of tolvaptan treatment for renal cysts in ADPKD has been demonstrated in adults, it is not yet indicated for pediatric patients, and reports of its use in this population are rare.

TSC2 and PKD1 are located adjacent to each other on chromosome 16, and contiguous gene deletion syndrome is known to manifest both tuberous sclerosis (TSC) and ADPKD. It has also been noted that many patients with adjacent gene syndrome experience rapid renal cyst enlargement in ADPKD [4–6].

In this study, we report the case of an 11-year-old girl with PKD1/TSC2 contiguous gene deletion syndrome who presented with rapid renal cyst enlargement and was treated with tolvaptan.

Case report

The patient is an 11-year-old girl who was born at 38 weeks and 5 days of gestation, weighing 2060 g and measuring 44 cm in length, with no remarkable family history, including tuberous sclerosis and multiple cystic kidney disease. She had congenital vitiligo, epileptic seizures, and electroencephalography abnormalities. Consequently, she was diagnosed with West syndrome and started on antiepileptic drugs. At the age of 2 years, she was diagnosed with tuberous sclerosis based on head magnetic resonance imaging (MRI) findings and leukoplakia. At the age of 6 years, an abdominal MRI revealed multiple cysts in the right and left kidneys, which led to the diagnosis of ADPKD. Abdominal MRI scans performed between the ages of 10 years and 3 months and 11 years and 2 months showed a rapid increase in the height-adjusted total kidney volume (HtTKV (ml/m)) from 587 to 810 ml/m. Genetic testing revealed the deletion of the 3′ end of TSC2 (exon 42) and the 3′ end of PKD1 (exons 27–46) (Fig. 1). Based on the genetic test results, a definite diagnosis of PKD1/TSC2 contiguous gene deletion syndrome was made. Her parents had no mutations in the PKD1 or TSC genes.

Fig. 1.

Genetic test results [MLPA (multiplex ligation-dependent probe amplification) analysis]. MLPA analysis was performed. The results showed deletions at 3′ of TSC2 (exon 42) and PKD1 (exons 27–46). Since TSC2 and PKD1 are adjacent to each other at the 3′ of 16p13.3, the deletion in this region may have caused abnormalities in both genes. The deletion was determined to be an insertion of exon 25 and part of intron 25 of PKD1 between exon 42 of TSC2 and intron 26 of PKD1

At 11 years and 9 months of age, at the induction of treatment, she was 139.2 cm tall (− 1.41 standard deviation [SD]) and weighed 34.9 kg (− 0.75 SD). Her blood pressure was 127/74 mmHg, and physical examination revealed angiofibromas, leukoplakia, and shagrin patch scars. Her developmental index was 55 on the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) scale at 10 years of age, with a full-scale intelligence quotient of 55. She was able to complain of thirst and to drink independently. She was taking lamotrigine, everolimus, atomoxetine hydrochloridearipiprazole, valsartan, and amlodipine besilate. Blood biochemistry tests showed a serum creatinine level of 0.39 mg/dL and an estimated glomerular filtration rate (eGFR) of 129.68. Urinary findings were negative for urinary occult blood, with a protein/Cre ratio of 0.19 g/g/Cr and β2-Microglobulin 406 μg/L. MRI at age 11 years and 9 months showed HtTKV of 946 ml/m (Fig. 2). The renal prognosis of the patient was judged to be poor due to the rapid growth of the renal cyst. After an in-hospital ethics review, informed consent was obtained from the parents and tolvaptan therapy was introduced on admission. Tolvaptan was started at a low dose of 7.5 mg in the morning and 3.25 mg in the evening (0.3 mg/kg/day). The in/out balance of fluids and body weight were monitored. The patient was monitored for electrolyte abnormalities, including hypernatremia, elevated liver enzyme levels, and changes in urine osmolality, among others. Over 2 weeks, the dose was increased to the target dose of 30 mg in the morning and 15 mg in the evening (1.3 mg/kg/day). The patient had no problems during hospitalization and continued to take the drug after discharge. MRI scanning 12 months after the treatment revealed that the HtTKV was 976 ml/m (Fig. 2).

Fig. 2.

Magnetic resonance imaging (MRI) of the kidney. Multiple renal cysts were found in both kidneys and the renal volume was rapidly increasing over time. After the start of tolvaptan treatment, the increase in renal volume was suppressed

Urine output was not measured before treatment initiation. After the tolvaptan introduction, urine volume proportionally increased with an increase in fluid intake. Specifically, 2 weeks after initiation, the patient consumed approximately ~ 3 L of water/day, with a corresponding urinary output of approximately the same volume. The annual increase in HtTKV decreased from 37 to 3%.

The patient’s eGFR was 109 mL/min/1.73 m², and it remained within the normal range even after the introduction of tolvaptan.

At 12 months after treatment initiation, the serum creatinine level was 0.5 mg/dL, and the protein/Cre ratio was 0.06/g/Cr. The treatment was considered markedly effective (Fig. 3).

Fig. 3.

Height-adjusted total kidney volume (HtTKV) and estimated glomerular filtration rate (eGFR) before and after the introduction of tolvaptan. There was a rapid increase in HtTKV before tolvaptan initiation; however, after tolvaptan introduction, the growth rate decreased significantly. The annual increase in HtTKV decreased from 37 to 3% following the tolvaptan introduction. The level of eGFR remained consistently > 100 mL/min/1.73 m² both before and after tolvaptan initiation

Tolvaptan administration increased the urinary output. The patient was aware of thirst and could independently manage fluid intake. There were no signs of dehydration or significant changes in body weight. The patient acknowledged the increased urinary output and water intake but reported no adverse impact on daily life. Before the introduction of tolvaptan, urine osmolality averaged approximately 600 mOsm/kg in spot urine. After the introduction of tolvaptan, the mean urine osmolality dropped to approximately 200 mOsm/kg in spot urine. The patient has progressed without any other major adverse events.

Discussion

In this case, tolvaptan was introduced to an 11-year-old girl with TSC2/PKD1 adjacent gene syndrome who presented with rapidly enlarging renal cysts. Twelve months after the initiation of treatment, the progression of renal cyst growth was controlled without apparent adverse events.

Tolvaptan is the only treatment that inhibits renal cyst enlargement in ADPKD [7]. Tolvaptan inhibits the binding of vasopressin to its receptor and suppresses the increase in cAMP levels, thereby inhibiting the formation of renal cysts. Studies on tolvaptan in adults demonstrated a significant reduction in the rates of TKV augmentation and eGFR decline. Serious adverse events with tolvaptan treatment included electrolyte abnormalities and liver dysfunction [8, 9]. To the best of our knowledge, there is only one case of a pediatric patient with severe neonatal ADPKD who responded well to tolvaptan in the literature [10]. Gimpel et al. [3] reported that tolvaptan should not be routinely administered to children with ADPKD. The efficacy of tolvaptan in pediatric ADPKD is unknown, and the adverse effects of the drug and its long-term effects on development should also be noted. A clinical trial of tolvaptan in pediatric patients with ADPKD is currently underway in Europe. The participants of this trial are patients with ADPKD aged 4–17 years with at least 10 renal cysts, who can complain of thirst and are able to urinate autonomously, and the dose is specified according to the patient’s body weight [11]. The dosage in our case was determined with reference to this clinical trial.

The patient not only has ADPKD but also the PKD1/TSC2 contiguous gene deletion syndrome. TSC causes the appearance of renal cysts in approximately 20–30% of patients [12–14]. However, the rapidly worsening renal cysts in this case were judged to be due to ADPKD. In an analysis of 196 patients with TSC, all five patients who showed early severe renal cysts also had PKD1 abnormalities [15]. In addition, an analysis of patients with the PKD1/TSC2 contiguous gene deletion syndrome who presented with early severe renal cysts reported that the renal cyst exacerbations were due to PKD1 inactivation [16].

This patient belongs to the high-risk group of the most severe form of ADPKD and also has the PKD1/TSC2 contiguous gene deletion syndrome; thus, she is judged to have a poor renal prognosis. HtTKV (total kidney volume/height) is the most reliable marker of disease progression in predicting renal prognosis in ADPKD, and the Mayo Classification defines the most severe form of the disease as an annual increase in HtTKV of at least 6%. In the most severe disease group, the time to end-stage renal failure is predicted to be approximately 10 years [17]. In this case, HtTKV increased 37%/year from 10 to 11 years, which was judged to be extremely severe ADPKD.

The TSC2/PKD1 contiguous gene deletion syndrome is characterized by congenital renal cysts and early-onset renal cysts, and the renal prognosis is poor; Sampson et al. reported that multiple cystic kidneys in the TSC2/PKD1 contiguous gene deletion syndrome are often detectable in infancy and generally lead to renal failure in the late teens [13]. Matsubara et al. also reported that the TSC2/PKD1 contiguous gene deletion syndrome has a worse renal prognosis than normal TSC or ADPKD and should be differentiated in patients who present with giant renal cystic lesions at an early age [5]. In this case, genetic testing revealed TSC2/PKD1 contiguous gene deletion syndrome and hypertension, which together with the rapid rise in HtTKV predicted an extremely poor renal prognosis. Based on this prediction, we decided to introduce tolvaptan therapy, which has been proven to be effective in adults.

Twelve months after the introduction of tolvaptan, the rate of increase of HtTKV dropped from 37 to 3%. Treatment was judged to be effective. We will continue the treatment with tolvaptan and carefully monitor its long-term efficacy, adverse reactions, and effects on growth and development.

In conclusion, tolvaptan was administered to an 11-year-old girl diagnosed with the TSC2/PKD1 contiguous gene deletion syndrome due to enlarging renal cysts. The drug attenuated renal cyst enlargement without major adverse events. This implicates that tolvaptan may be effective in children with severe ADPKD with rapidly enlarging renal cysts.

Funding

This study did not receive any financial support from any funding agency.

Data availability

All datasets generated for this study are included in the article/supplementary material.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Informed consent

Informed consent was obtained from the parents of the participants included in the study.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.