Type 1 diabetes mellitus (T1DM) is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations.1 Genetic studies of T1DM have focused on the detection of loci associated with increased susceptibility to this multifactorial phenotype.1 Many patients eventually develop diabetic ketoacidosis, which can be a major risk of mortality.

Polycystic kidney disease (PKD) is one of the most common hereditary kidney diseases affecting the renal tubules. The affected individuals may carry autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD). ADPKD has an estimated prevalence of 1:400 to 1:1000 live births.2,3

Genetically, ADPKD is a heterogeneous disease mainly caused by mutations in PKD1 and PKD2 genes, although 5–10% of ADPKD pedigrees remain either genetically unsolved or harbor rare mutations in other genes causing ADPKD-like phenotypes such as α-glucosidase neutral AB, DNAJB11, or hepatocyte nuclear factor 1β (HNF1B) gene.4

Case report

A 35-year-old man, with a known case of metabolic syndrome and a body mass index of 30 Kg/m2, had hypertension since early adolescence and T1DM since the age of four years. His diabetes was being maintained on insulin, dyslipidemia on statin, and hyperuricemia on medications. He also had chronic kidney disease – secondary to his ADPKD. He developed end-stage kidney disease (ESKD) by the age of 32 years for which he underwent preemptive simultaneous pancreatic and kidney transplant from a deceased donor. He was discharged with a serum creatinine of 78 umol/L, estimated glomerular filtration rate > 90 mL/min/1.73 m2, and suboptimal blood sugar of 10 mmol/L.

Two days later, the patient was readmitted with 38.8 °C fever, chills, generalized weakness, fatigue, and mild abdominal pain mainly around the umbilicus. He had no gastrointestinal symptoms, urinary tract symptoms, or other systemic symptoms. On examination, he was dehydrated, with blood pressure of 90/50 mmHg, pulse rate of 120/min, and respiratory rate of 22/min. Abdominal examination revealed mild distension and a well-healed scar was visible extending from the umbilicus to the suprapubic region. There was mild tenderness below the umbilicus. On palpation, the kidney graft was non-tender. Laboratory investigation results at admission are shown in Table 1.

While the patient’s blood cultures revealed no growth, his urine culture showed Enterococcus faecium, which was sensitive to vancomycin. The pus discharge from his surgical wound grew carbapenem-resistant Klebsiella pneumoniae ssp. (sensitive to tigecycline) and Citrobacter freundii (sensitive to cotrimoxazole). His chest X-ray revealed normal lung fields with prominent heart size. Abdominal X-ray revealed no abnormally, dilated bowel loops, or signs of free gas. Echocardiography showed mild pericardial effusion measuring 7 mm behind the right atrium and grade 1 diastolic dysfunction with an ejection fraction of 55%.

Figure 1 shows the patient’s abdominal magnetic resonance imaging, with descriptions underneath.

Our multidisciplinary team decided on interventional drainage of the collection with a pigtail catheter which yielded 30 mL of frank thick pus, whose culture yielded K. pneumoniae with sensitivity to cotrimoxazole and tigecycline. Ultrasound image post drainage showed the transplanted kidney (12 cm) with normal echotexture, no hydronephrosis, resistivity index of 0.54–0.58, and with 6 mL peri-graft collection. Abdominal computed tomography showed a significant reduction in the pre-drainage pelvic collection.

The pigtail catheter was removed after a week of no further drainage and a repeat ultrasound showed peri-graft collection of only 6 mL. The patient was managed with a full course of intravenous antibiotics for three weeks. A month later, with his laboratory investigation results showing progressive improvement [Table 1], he was discharged on a small dose of insulin of 8 U/day, steroids tapered down to 2.5 mg once daily (OD). He was kept on tacrolimus 3 mg twice daily (BID), mycophenolate mofetil (CellCept) 1 g BID, and valganciclovir 900 mg OD. He continued to receive intervention tigecycline daily at our daycare facility.

Our patient had a strong family history of both ADPKD and DM. His father was diabetic without kidney disease and his mother had ADPKD without diabetes and underwent kidney transplant. One brother and two sisters of the patient had ADPKD; the brother had a kidney transplant. Two other sisters had ADPKD with T1DM and were on insulin. A younger sister had neither ADPKD nor diabetes at the time of assessment [Figure 2a].

The proband’s sister III-1 underwent targeted next-generation sequencing panel that contains polycystic kidney disease-associated genes (including PKD1, PKD2, PKHD1, HNF1B, REN, UMOD, and MUC), which revealed a heterozygous 2-bp deletion (NM_001009944.2; c.5014_5015delAG) in the coding region, exon 15, of the PKD1 gene. This mutation was then verified by Sanger sequencing [Figure 2b]. It was also revealed that our proband, his mother, and three sisters (III-2, III-5, and III-6) were all carriers.

Discussion

Inherited and congenital kidney disease is an essential cause of ESKD in the Omani population which is characterized by high rate of consanguinity (56.3%).5,6 Omani patients with inherited kidney disease start renal replacement therapy at a relatively young mean age of 29 years.7,8

Our patient, who had a strong family history of both T1DM and ADPKD, developed both these conditions in early childhood (caused by a heterozygous frameshift deletion mutation in PKD1) leading to early kidney failure. Enlarged kidneys with multiple bilateral cysts along with hepatic cysts and hypertension were the typical characteristics of ADPKD in his family for multiple generations. Our patient received a preemptive simultaneous pancreatic and kidney transplant from a deceased donor but multiple complications followed.

Both clinical investigations and molecular genetic analysis proved the diagnosis of ADPKD. He was found to carry a previously reported heterozygous 2-bp deletion (NM_001009944.2; c.5014_5015delAG) in exon 15 of the PKD1 gene.5 Mutations in PKD1 (16p13.3) account for around 85% of ADPKD patients and are expected to lead to ESKD by on average age of 53.3 years, much earlier than the average age of ESKD in patients with PKD2 (4q22.1) mutations (72.7 years).9 Furthermore, truncating PKD1 mutations are linked with ESKD onset at younger ages than non-truncating mutations.10 In agreement with these studies, our patient and several members of his family developed ESKD at younger ages (proband: 32 years, III-5: 35 years, and III-6: 34 years). Our patient’s family history confirms a possible association between the mutation types and phenotypic outcome. Hence, the age of onset of renal failure can be influenced by the causal mutation, highlighting the importance of molecular genetic analysis for ADPKD patients.

Regarding T1DM, genetic susceptibility, and environmental factors interact to form the basic element in its progression.11 In the pedigree of our report, T1DM in combination with ADPKD was diagnosed in our patient and his two sisters (III-5 and III-6) who were all found positive for glutamic acid decarboxylase and anti-islet cell antibodies. It is rare for three or more siblings to develop T1DM, even though such cases have been reported in large families and in other populations.12–14 The lifetime risk of developing T1D is increased in relatives depending on which human leukocyte antigen haplotypes are shared.15,16 The lifetime risk in siblings of T1D-affected patients is unidentified, and our report of the family of our patient should inspire clinicians to evaluate their risks of diabetes.

Conclusion

We have described an Omani patient diagnosed with early-onset T1D and with a heterozygous frameshift mutation in the PKD1 gene who developed ESKD in his early thirties. His family had a long history of ADPKD and T1D. The study of familial clustering of specific diseases is an essential concept in genetic epidemiology that facilitates lifetime risk evaluation and early assessment, both in patients and their relatives. We recommend early genetic diagnosis in such cases to facilitate early treatment and thereby prevent the disease progression and the
associated morbidity.

Disclosure

The authors declared no conflicts of interest. The study was approved by the Research and Ethical Review and Approval Committee of the Ministry of Health (MOH) in Oman (MH/DGP/R&S/PROPOSAL_APPROVED/18) and conducted per the Declaration of Helsinki. Informed consent was obtained from the patient and his family members.

Acknowledgments

We thank our patient and his family for their trust in us. Each person listed as an author has participated sufficiently in the intellectual content, the analysis of data, and/or the writing of the manuscript to take public responsibility for it. Each author has reviewed the manuscript, believes it represents valid work, and approves it for submission.

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