In the present case, a heterozygous frameshift mutation variant in the hnf1b gene was reported: c.1149delinsTGGCC, p.Arg351Leufs*10; this had not been previously described, but was detected in both the female patient and her mother with a phenotype typical of MODY5. In silico analysis indicated that this mutation is likely to be pathogenic. However, different phenotypes in the family were observed. In the case of the patient, renal and urinary tract malformations were detected, and she also has hypoplasia of the pancreas body associated with early diabetes without beta cell autoantibodies, hypertriglyceridemia and variable hyperglycaemia, with no gastrointestinal symptoms, as well as faecal elastase deficiency. Her mother has a history of pregnancy loss, anatomic and functional urinary tract abnormalities and recurrent urinary tract infections. She was also treated because of early hypertension, which was suspected to be from renal causes. Chronic gastrointestinal symptoms were present, and a probable exocrine pancreas secretion deficit was suspected. No hyperglycaemia was reported, however.
Epidemiology
Approximately 1–5% of all diabetes cases in the United States and other developed countries are thought to be monogenic [3, 5]. In the United Kingdom, 80% of MODY patients are misdiagnosed as T1D or T2D [6]. Amed et al. [7] reported the incidence rate of MODY in a Canadian population to be 0.4 cases per 100,000 children and youths < 18 years of age. There are 14 MODY subtypes identified, which involve extrapancreatic organs in a small percentage. However, MODY5 frequently compromises renal and other extrapancreatic organs, also known as renal cysts and diabetes syndrome (RCAD syndrome) [8], and accounts for 2–5% of all MODY types [9].
Genetics
In 1997, Horikawa et al. reported the first case of MODY5 in a Japanese family [10], which was related to a mutation in the hnf1b gene. Hnf1b contains 9 exons that encode a transcription factor, also known as TCF2, of 557 amino acids; this is a member of the homeodomain-containing superfamily of transcription factors functioning either as homodimers or heterodimers with HNF1A [11]. Hnf1b is located on chromosome 17q12, with three functional domains: the transactivation domain, the DNA-binding domain and the dimerisation domain [8, 12]. Heterozygous genetic variations comprise base substitutions leading to missense, nonsense, small deletions or insertions, frameshift and splicing mutations; in some cases, complete gene deletions have been described. Most are grouped in the first four exons of the gene, with exons 2, 4, and the intron 2 splice site being mutation hotspots [8, 13] (refer to supplement Table 1). HNF1B-associated disease results not only from an abnormal DNA binding site but also from the abnormal ability to co-activate proteins, or dimerisation leading to transactivation or transcription disruption [8].
The HNF1B protein plays an important role in the growth of collecting ducts, the renal pelvis and the ureter, and differentiation of the metanephric mesenchyme, which are all key elements for the development of the nephron and collecting system [14]. Also, it regulates the expression of genes such as fibrocystin-1 (pkhd1), kinesin-like 12 (kif12), suppressor of cytokine signalling 3 (socs3) and polycystic kidney disease 2 (pkd2), as well as others related to the pathogenesis of the renal cystic disease [14, 15].
Embryogenesis of the pancreas is a dynamic process of gene expression. The pancreas is derived from the foregut of the primitive gut tube [12], which emerges from the endoderm germ layer. Murine models have shown a high expression of hnf1b throughout the foregut-midgut region, liver and pancreas buds during the second embryonic week [12]. The consecutive activation of hnf1b, hepatocyte nuclear factor 6 (hnf6) and pancreatic and duodenal homeobox 1 (pdx1) orchestrate the differentiation of endodermal cells into pancreatic progenitors [12]. HNF1B is a key member of the transcriptional factors network (Pdx1, Sox9, Nkx6.1, and Ptf1a) that manage the process of differentiation of pancreatic multipotent cells (PMCs) to endocrine, ductal and acinar cells [16]. HNF1B is required for the proliferation and survival of multipotent cells through modulation of the Fibroblast Growth Factor (FGF) and Notch pathways [12]. Additionally, it regulates expression of the pancreatic islet lineage-defining transcription factor Ngn3 [12] and controls the key cystic disease genes GLIS family zinc finger 3 (glis3), pkhd1, mitotic kinesin like2 (kifl2), cystin 1 (cys1), BicC family RNA binding 1 (bicc1) and hnf6 [12, 17].
Clinical manifestations
Dubois-Laforgue et al. [18] referred patients with likely MODY characteristics and renal functional and/or morphological anomalies for hnf1b gene screening. The prevalence of diabetes was 83% and that of renal malformations was 91%. They found chronic kidney disease (CKD) stages 3 and 4 in 44% of the sample, hypomagnesaemia in 75% and liver test abnormalities in 71%. Diabetes was the first clinical manifestation in 37% of the subjects and renal disease in 39%, while they presented concomitantly both disease in 24%. At diagnosis, 47% of the patients presented symptomatic hyperglycaemia (polyuria, weight loss) but only 5% had ketoacidosis; values of A1C < 7% and ≥ 13% were reported in 32 and 34%, respectively.
HNF1B-associated disease exhibits autosomal dominant inheritance, but de novo mutations account for 50–60% of cases. Additionally, there is no phenotype-genotype correlation; the clinical presentation of the same inherited mutation can even vary significantly within families [11]. The reason for this is not completely understood, but it has been suggested that microenvironment modifiers, stochastic variation in temporal hnf1b gene expression and other genes may influence this phenotypic diversity [8, 12].
MODY5 typically develops in adolescence or early adulthood, with a mean age of diagnosis of 24 years, but this can vary widely [8]. Hyperglycaemia is caused by different mechanisms: decreased insulin production due to pancreatic hypoplasia, hepatic insulin resistance and altered glucose-sensing mechanisms [8, 12].
In many cases, pancreatic exocrine deficit has been described with atrophy or a lack of the head and body of the pancreas, with a prevalence of 20–50% [19]. It is usually asymptomatic and documented by reduced faecal elastase [12], as evidenced in our patient. We suspect that symptoms reported as irritable bowel syndrome in the mother and grandfather probably correspond to a deficit in the exocrine pancreas.
Mutations in the hnf1b gene are the most frequent cause of monogenic congenital anomalies of the kidney and urinary tract (CAKUT) and remain one of the major causes of CKD in the prenatal and childhood period: 20–31% [20, 21]. However, in a Belgian cohort of 205 CAKUT patients (paediatric and adult), the prevalence of hnf1b mutations was 10% [22]. Nagano et al. [9] performed hnf1b screening in cases with CAKUT, cystic kidneys, renal dysfunction of unknown cause or Bartter-like syndrome, finding a prevalence of 5.5%. Cystic kidneys were found in 73%, followed by renal hypoplasia (27%). In patients with extra-renal anomalies, 38% developed diabetes, 22% pancreatic malformations, 32% liver abnormalities and 11% female genital malformations [23].
Raaijmakers et al. [22], in a prospective cohort, found that some renal characteristics increased the probability of identifying patients with a mutation in the hnf1b gene. The combination of two bilateral renal abnormalities, such as multicystic renal dysplasia, renal agenesis, ectopic kidney, hypoplasia or renal dysplasia, had a relative risk (RR) of 2.9 (95% CI; 1.29–6.67; P = 0.010), while cysts of unknown origin had an RR of 6.1 (95% CI; 2.50–15.01; P < 0.001) and hypomagnesaemia an RR of 4.2 (95% CI; 1.78, 10.03; P = 0.001). They proposed these findings as clinical criteria to restrict genetic analysis and reduce screening costs without missing affected patients.
Additionally, functional kidney anomalies have been reported, such as proteinuria less than 1 g a day, while renal function ranges from normal kidney function in 31.7% to CKD in 55.5% and end stage renal disease (ESRD) in 12.8%. They present as Gitelman-like syndrome (hypomagnesaemia and hypocalciuria) related to the HNF1B transcription function over the FXYD Domain Containing Ion Transport Regulator 2 (fxyd2) gene that encodes sodium-potassium ATPase in the distal convoluted tubule, which plays an important role in magnesium reabsorption [14]. Our patient had asymptomatic but slightly low serum magnesium; however, it was believed that she would benefit to continue with a small oral magnesium supplement [24, 25]. Many patients have hyperuricaemia and some present early gout flare, based on regulation of transcription of the uromodulin (umod) gene by HNF1B, which is involved in urate transport [14]. Primary hyperparathyroidism has been identified because HNF1B inhibits the transcription of parathormone (pth) [26, 27].
Hepatic dysfunction affects 65% of patients with hnf1b deletions [19], characterised by elevated serum transaminases, alkaline phosphatase and sometimes mild hyperbilirubinaemia. Histological studies show bile ductopenia, steatosis, and periportal fibrosis, which could lead to cases of neonatal or adult cholestasic hepatopahy. Therefore, some experts have proposed regular laboratory monitoring, annual or biannual abdominal ultrasonography and avoiding hepatotoxic substances [8, 19].
Urogenital tract malformations are seen in up to 50% of patients and it is often seen in female patients associated with fertility problems [19]. Various malformations have been documented, such as a rudimentary or absent uterus, a bicornuate or didelphys uterus, a double vagina or vaginal aplasia. In males, epididymal or seminal vesicle cysts, deferent ducts atresia, hypospadias, varicocele, cryptorchidism, agenesis of the vas deferens, and asthenospermia have been reported in a few cases [4, 26, 28].
Neurologic abnormalities, including developmental delay and neuropsychiatric disorders, are characteristic in patients with 17q12 deletion (58 and 27%, respectively) [19]. The hnf1b deletion typically also includes the LIM homobox (lhx1) and Acetyl-CoA carboxylase alpha (acaca) genes. In early brain development, lhx1 is expressed and plays a role in the differentiation of neural cells and the transcriptional control of axonal guidance. Acaca encodes acetyl-CoA carboxylase alpha, a key enzyme in fatty acid metabolism. These two genes have been associated with neurodegenerative diseases, epilepsy, autism, mental retardation and neurodegenerative diseases [29,30,31]; however, the responsible mechanisms are under investigation (Fig. 3).
Complications associated with MODY5
Chronic complications associated with MODY5 are not frequently reported in the literature. In a cohort of 27 adult carriers of a hnf1b mutation with a median age of 35 years, none developed diabetic retinopathy or neuropathy in the follow-up [32]. On the other hand, Dubois-Laforgue et al. [18] observed retinopathy in 27% of the cohort and peripheral neuropathy in 26% during follow-up; these were associated with older age and a longer duration of diabetes, higher A1C, CKD3–4/ESRD and more frequent insulin therapy. Microalbuminuria was present in 32% of the patients and proteinuria in 26%. Overt coronary artery disease was present in 10% of the subjects and 66 and 31% of patients evolved to CKD 3–4 and ESRD, respectively. In a Japanese cohort [9], the kidney disease progressed to CKD 4 or 5 in 13.7%, with 3% requiring renal transplantation.
Diabetes might present as new-onset diabetes after transplantation (NODAT); prior analysis of the hnf1b gene should be considered in all individuals with unexplained congenital anomalies of the kidneys and urinary tract undergoing renal transplantation to improve post-transplant management [8, 12].
Faguer et al. [33] developed a 17-item hnf1b risk score as a screening tool. A score of more than 8 points is suggestive of MODY5 disease (sensitivity 98%, specificity 41.1%, PPV 19.8%, NPV 99.4%). However, this score lacks external validation and is reported to lead to false negatives [9, 26].
Treatment
The current treatments have not been completely standardised because of the small number of cases and lack of large cohorts or randomised clinical trials. The hyperglycaemic management of MODY5 should begin with a stringent diet created by a nutritionist. Although some cases can be managed (or initially) with dietary recommendations solely [18, 34], as is the case reported in this paper, metformin has been tested in all MODY patients. Its efficacy in MODY5 is significantly lower than that of sulphonylureas; therefore, metformin is not routinely recommended [35]. There are some interesting data for MODY3 treatment with incretins, but this is usually added to insulin or sulphonylureas management. We did not find experience with incretin therapy in MODY5. Glinides or sulphonylureas have been an option for treatment with variable glycaemic control and a response period [4, 18, 28, 35]; however, it has been reported that some MODY5 patients do not respond adequately to sulfonylureas [4] as a consequence of hypoplasia and pancreatic dysfunction. The majority of patients require insulin treatment during the follow-up [36]. In a cohort of patients initially treated with diet or oral anti-diabetic agents, insulin was initiated in 67% of cases. The median insulin dosage was 0.55 IU/kg/day (IQR 0.39–0.70). Surprisingly, the same cohort exhibited residual insulin secretion in 80% of cases [18]. Although our patient has not required insulin in recent years, we have shown a slow increase in blood glucose recently, but with no anti-diabetic drug indication at present. She will probably require anti-hyperglycaemic treatment in the next few years, as reported for other patients. Our group suspects that some patients secrete insulin with adequate biological activity based on affected organogenesis pathways and pancreatic insulin synthesis, and that their hepatic insulin sensitivity is sufficient to avoid metabolic disorders.
Proteinuria has to be treated with anti-proteinuric agents as a recommended treatment [37]. Pancreatic exocrine insufficiency is treated with pancreatic enzyme supplements. Gout can be prevented and treated by usual medical care and nutritional support.