Prader-Willi syndrome complicated with nephrotic syndrome and acute kidney injury: a case report

Abstract

Background: Prader-Willi syndrome (PWS) is a multisystem disorder caused by aberrant genomics which silences genes in the 15q11-q13 region. It is characterized by multiple cognitive, behavioral, and endocrine abnormalities.

Case presentation: We present a case of a 28-year-old male patient diagnosed with PWS with diabetes mellitus, nephrotic syndrome (proteinuria > 3.5 g/24 h) and acute kidney injury who eventually entered end-stage renal disease and started dialysis. Through genetic diagnosis, we found that the patient had heterozygous deficiency in the chr15 deletion segment. The patient’s mother was heterozygous and the father was wild-type, suggesting that the 4.86 Mb deletion in the 15q11.2-q13.1 segment of the patient was a paternal chromosomal deletion.

Conclusion:PWS has various clinical manifestations and a poor prognosis. Early diagnosis, long-term follow-up, and in-time treatment could improve the quality of life and prognosis of PWS patients.

Background

Prader-Willi syndrome (PWS; OMIM: 176270), was first named by Prader, Labhart and Willi in 1956[1, 2]. Ledbetter et al. 1981 revealed that deletion of the 15q11–q13 region of chromosome is the cause of PWS[3]. Nicholls et al. 1989 reported the further development of nondeletion PWS, clarifying for the first time that PWS is a genetic disorder due to defects in imprinted genes[4]. The disease involves multiple systems and is a typical case of aberrant imprinted genetics[5]. The estimated incidence rate of PWS in the population is 1/10000-1/30000, with no significant racial or gender differences[6]. At present, complete epidemiological data on this disease are still lacking in China. Because of its low incidence rate and atypical early clinical features, clinicians could easily underdiagnosis or misdiagnosis.

To date, PWS is rare in nephrology and few PWS patients were reported with nephrotic syndrome, acute renal injury, or eventually end-stage renal disease (ESRD) who start renal replacement treatment. Here, we report a PWS patient with juvenile-onset diabetes mellitus, nephrotic syndrome (proteinuria > 3.5 g/24 h), and acute renal injury who finally entered dialysis. The aim of this case is to raise awareness of PWS among clinicians, to avoid misdiagnosis and to provide support for early diagnosis and comprehensive treatment.

Case Presentation

Clinical data of the initial patient (proband)

A 28-year-old male patient was admitted to the Department of Nephrology, West China Hospital, due to edema, proteinuria and skin ulceration of the right lower limb for 1 month. In the previous visits, he was diagnosed with nephrotic syndrome, diabetic kidney disease and diabetic foot infection, and the highest blood pressure level was 170/80 mmHg. His symptoms did not improve after treatment of controlling blood glucose and blood pressure, anti-infection, albumin infusion and diuretic, which leads to his second admission to our department.

The patient was born with cryptorchidism and underwent surgeries at the ages of 3 and 4. He appeared obese at the age of 5 and was diagnosed with type 2 diabetes at the age of 11. Since then, his intelligence has been worse than that of other children of the same age, and his height has not increased. His karyotype was 46, XY.

Physical examination on admission showed a temperature of 36.5°C, heart rate of 88 beats per minute, respiratory rate of 20 breaths per minute, and blood pressure of 158/109 mmHg. He weighed 98 kg with a height of 154 cm, and his body mass index was 41.32 kg/m². The patient presented with a full moon face and buffalo back. The breath sounds of both lungs were thick, and wet rales could be heard. His male genitalia was immature. Severe edema of both lower limbs and skin ulceration of the right lower limb could be observed. The muscle strength and muscle tone of the four limbs were normal. No other abnormalities were identified in the physical examination of the heart or abdomen.

Clinical data of other family members

Our study was approved by the Ethics Committee of West China Hospital, Sichuan University, and all family members signed informed consent before the study. We chose the patient as the proband and investigated the clinical symptoms and laboratory tests of his pedigree (3 individuals). The proband’s father and mother did not have clinical symptoms.

Laboratory test results

All laboratory examinations of the patient were completed, and the results were issued by the Laboratory Department of West China Hospital, Sichuan University. The Cobas 8000 automatic biochemical analyzer was used to measure oral glucose tolerance test, albumin, creatinine, and blood lipids in serum. The serum levels of hormones were determined by a Roche Cobas e801. Urine was analyzed with the automatic urinalysis SYSMEX pipeline. The Yhlo iFlash3000c and TOSOH HLC-723G8 autoreading systems were used to test insulin autoantibody and HbA1c, respectively.

The laboratory findings of the patients are shown in Table 1, which suggested hyperglycemia, hypoproteinemia, hypertriglyceridemia, abnormal renal function, nephrotic range proteinuria (proteinuria > 3.5 g/24 h), decreased serum testosterone and increased estradiol. CT examination of the chest showed bilateral pleural effusion. No obvious abnormalities were observed in the insulin autoantibody. The echocardiogram of the heart structure and left ventricular systolic function were normal. Ultrasound examinations of the kidneys did not reveal any abnormalities. Based on clinical manifestations and laboratory results, the diagnosis of PWS was suspected.

Gene diagnosis

To confirm the diagnosis of the proband and to screen for Prader-Willi syndrome in this pedigree, we performed whole-exome sequencing in the 3 family members. Gene amplification and sequence analysis were completed at Beijing Chigene Translational Medicine Research Center. The process includes the following steps: high-throughput sequencing technology to screen for mutations, bioinformatics, and clinical information analysis technology to analyze genetic data, and Sanger sequencing technology to verify suspected pathogenic mutations.

In this patient’s whole-exome sequencing data, a probable pathogenic chromosomal number variation of approximately 4.86 Mb was detected at position chr15seq[GRCH37]del(15)(q11.2q13.1) (chr15:23687596–28544662). Further in-depth data analysis found that the patient had a deletion section of chr15. Considering his mother was heterozygous, and his father was wild-type, the 4.86 Mb deletion in the 15q11.2-q13.1 region could be a paternal chromosomal deletion (Fig. 1). The clinical symptoms of this patient also highly matched the clinical phenotypes of the disease described above. Thus, the diagnosis of PWS was made.

Treatment and follow-up of the proband

The patient was given insulin for blood glucose control, anti-infection and nutritional support, but during the treatment process, creatinine gradually increased, urine volume decreased, edema was obvious, and the treatment effect of protein infusion and diuresis was poor. After internal jugular vein catheterization, his renal function did not recover during maintenance hemodialysis. Then, this patient returned to the local hospital. After a year of follow-up, the patient died of an infection caused by a falling and fracture.

Discussion And Conclusion

PWS is the first clarified genetic disease affecting multisystem[4]. In most cases, this disease is sporadic and the etiology is the gene defect in the imprinted gene region of chromosome 15 (15q11-q13), which contains key genes such as SNRPN, NDN, MAGEL2, MKRN3, UBE3A, etc[7]. If the gene defect comes from the paternal strand, it will lead to PWS, and if the gene defect comes from the maternal strand, it will cause Angelman syndrome (AS; OMIM: 105830). The current clinical diagnosis mainly refers to the standards of Holm et al. in 1993[8] and the revised criteria of Cassidy et al. in 2012[6]. The major clinical manifestations of PWS during infancy include growth retardation and delayed language and motor development, short stature and cognitive deficiency in childhood, and obesity, prominent growth retardation, gonadal dysplasia, juvenile-onset diabetes mellitus, abnormal behavior and learning difficulties in adolescence. Obesity and its complications are the major causes of morbidity and mortality in PWS[9]. From the early stage, patients with PWS present severe obesity, and it often causes T2DM and the prevalence of T2DM in PWS is approximately 25% [10]. Despite the high prevalence of DM, few data were reported regarding diabetic kidney disease (DKD) in PWS[11, 12]. According to a Japanese cohort, 5.9% showed proteinuria (> 300 mg/g), and 23.5% showed microalbuminuria (30–300 mg/g) of DKD in PWS[12].This has been the only available data regarding diabetes kidney disease (DKD) in PWS. Hardly even any report of PWS combined with diabetes mellitus and massive proteinuria (proteinuria > 3.5 g/24 h).

This patient presented with cryptorchidism in infancy, obesity in childhood, prominent growth retardation, and juvenile-onset diabetes mellitus in adolescence, and he experienced the typical progression of PWS. However, the patient was not adequately recognized in infancy, childhood and adolescence, and the best time for treatment was missed because of the failure to make a definite diagnosis during his previous visits. Due to the lack of early diagnosis and treatment, the patient was admitted to our hospital on this occasion with signs of nephrotic syndrome and acute kidney injury in addition to poor glycemic control. Despite active treatment, the renal function could not be recovered, and the patient finally entered ESRD to start renal replacement therapy. During the later follow-up of the patient, he maintained dialysis at a hospital in his hometown and eventually died following a traumatic fracture and infection. In a survey conducted in the United States, the mean age of death in patients with PWS was 29.5 ± 16 years (range 2 months to 67 years) [13]. Another study also mentioned that the average age at death was 31.6 years (SD = 14.5), with the oldest individual with PWS dying at 59 years of age and the youngest dying at 1 year of age. Although not statistically significant, the diagnosis time of the deceased individuals was later than that of the living individuals (7.4 vs. 3.8 years)[14]. Therefore, early diagnosis, long-term treatment and follow-up have an important impact on improving the prognosis of PWS.

The clinical scoring system for PWS is susceptible to factors such as age, disease duration and ethnicity, leading to missed diagnosis or misdiagnosis. The risk of recurrence of PWS could results from different genetic mechanisms. Therefore, genetic diagnosis and identification of the genetic mechanism are necessary. The pathogenesis of PWS is the genetic abnormality on chromosome 15q11.2-13, which can be caused by four different types of defects: (1) deletion of the 15q11.2-13 fragment of the paternal chromosome (65%-75% in the west, 80% in China and Asia); (2) maternal uniparental disomy (mUPD)(20%-30%); (3) microdeletion and mutation in the imprinting center (1%-3%); and (4) chromosome balanced translocation (< 1%)[15, 16]. Methylation-specific polymerase chain reaction (MS-PCR) is the most widely used diagnostic technique and has the advantages of high efficiency, specificity, sensitivity, rapidity, and inexpensiveness. It has a detection rate of over 99% for PWS and can detect deletions, UPD, and imprinted center defects simultaneously, making it the preferred strategy for diagnosing PWS, but the disadvantage is that it is unable to distinguish specific genotypes[17]. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a standardized kit for the simultaneous detection of gene deletions, duplication mutations and methylation status at multiple chromosomal loci with the help of designed specific probes, which has high sensitivity and specificity and has gradually replaced MS-PCR for the genetic diagnosis of PWS. Chromosomal microarray analysis (CMA) can identify deletion sizes and breakpoints in deletion-type PWS and can also detect isodisomy in PWS[18]. In addition, MS-PCR can also be used for prenatal diagnosis by amniotic fluid exfoliated cells at 16–20 weeks of pregnancy[18]. In this study, the patient had a positive genetic test result, which clarified the diagnosis of PWS.

The treatment of PWS should be based on the characteristics of patients of different ages, with integrated interventions targeting endocrine metabolic disorders and psycho-behavioral problems, improving quality of life, preventing complications, and prolonging life expectancy. Behavioral treatments such as strict diet control, three-meal planning, and physical exercise are important to prevent obesity and metabolic disorders[19]. Recombinant human growth hormone therapy (rhGH) is beneficial in infants, children, and adults, and therefore, once rhGH therapy is initiated, it is recommended that treatment be continued and long-term if the actual benefits outweigh the risks[19]. Unfortunately, due to severe obesity and uncontrolled diabetes, rhGH is contraindicated in this case and cannot be used. Mille et al[20]. found that metformin was effective in improving the sense of satiety and decreasing food-related distress and anxiety in patients with PWS as well as morbid obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists can suppress appetite, promote insulin secretion, and have both weight loss and hypoglycemic effects. GLP-1 receptor agonists have been used with good efficacy in the treatment of PWS[21]. In addition, with the widespread use of sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-2 inhibitor as an add-on drug to GLP-1 receptor agonists for glycemic and body weight control of patients with PWS is also effective[22]. However, in this patient, early inadequate cognition of the disease, unclear diagnosis and reduced renal function which led to a missed opportunity for treatment. In recent years, research on laparoscopic bariatric surgery in PWS patients with severe obesity has gradually increased, but different research results vary. The weight loss after bariatric surgery is more pronounced in the first 1–2 years after surgery, making it difficult to achieve sustained long-term weight loss[23, 24]. Finally, the prevention of osteoporosis and fractures is also particularly important for PWS patients. Therefore, the treatment of PWS should be individualized, early treatment after clear diagnosis, with long-term follow-up and observation.

In conclusion, PWS has a diverse clinical presentation that varies with age and has a poor prognosis. With the continuous development of medicine, clinicians should also focus on early genetic diagnosis, long-term follow-up, and in-time treatment to improve the quality of life and prognosis of patients.

Abbreviations

Declarations

Ethics approval and consent to participate

The ethics committee of West China Hospital approved this research(ethical approval number: 2021(506)). This study had been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent for publication

A written informed consent was obtained from the patient for publication of this case report and any accompanying images. 

Availability of data and material

The datasets used during the current study available from the corresponding author on reasonable request. Gene testing and analysis report during this study is included in its supplementary information files.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the Foundation of Sichuan Medical Association(Q17058). The funding sponsor didn’t take part in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Authors' contributions

Tingli Wang collected data and finished the article, Siwei Bi proofreaded and revised the manuscript, and Xuhua Mi reviewed the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors thank the patient for allowing us to publish this case report. The authors wish to thank all the participants of this study for their important contributions. The authors also wish to thank the Beijing Chigene Translational Medicine Research Center for their work and help.

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