The clinical differential diagnosis of
HNF1B nephropathy includes other genetic forms of congenital anomalies of the kidneys and urinary tract (CAKUT), ADTKD-
UMOD, -
MUC1, or -
REN but also autosomal dominant polycystic kidney disease (ADPKD), depending on the ultrasound picture and extrarenal symptoms. In exceptional cases, ADPKD can manifest itself in very young patients (very early onset [VEO]-ADPKD) [
24]. In most adult cases, the prognosis of ADPKD is unfavorable, with consistent growth of cysts and deterioration of renal function. The progression of cyst growth and renal insufficiency in
HNF1B nephropathy has not been as thoroughly studied so far and was central focus of the here presented study.
Genotype-phenotype correlation
The present work shows a lack of genotype-phenotype correlations among the various types of
HNF1B gene mutations, as has been reported previously [
11,
14]. One could have expected gene deletions and loss-of-function mutations with higher frequency in patients with more severe disease as has been reported for other kidney disorders [
25,
26]. However, this issue is controversially discussed, and other authors even describe a more favorable renal outcome in patients with gene deletions compared to other mutations in
HNF1B [
27‐
29]. Possible explanations include a dominant negative effect of
HNF1B non-deletion mutations or the involvement of other genes located in the deletion interval on chromosome 17q12.3. This interval spans additional 14 genes to
HNF1B and affected patients are also at risk to develop neuropsychological symptoms. These comprise intellectual disabilities, learning difficulties, externalization disorders as attention-deficit hyperactivity disorder and autistic traits with variable severity [
30‐
32]. Few patients with intellectual disability and intragenic
HNF1B mutations have also been described [
32]. To date, however, no studies have systematically called for expert neuropsychological testing in
HNF1B patients, such as those included in the present study. Follow-up studies will have to address this important issue strongly impacting the quality of life of affected individuals.
Like in previous studies,
HNF1B mutations were equally distributed among boys and girls. De novo mutations were observed in 40% of patients with a preponderance of deletion mutations (83%). A similar observation was made in [
14]. Paired segmental duplications along with breakpoints are most likely involved in the pathogenesis of this recurrent chromosomal microdeletion [
33]. One striking observation of the present study is the high degree (81%) to which
HNF1B mutations are inherited through the maternal lineage in familial cases. Ulinski et al. reported dominant inheritance in 8/17 families; however, no parental data were presented [
11]. In a study involving 42 patients with complete gene deletions, Heidet et al. identified de novo mutations in 14 of these patients; for seven patients, there was proven dominant inheritance, with maternal transmission in 6/7 (86%) [
14]. A similar parent-of-origin effect was recently described for non-renal autosomal disease, e.g., familial early puberty [
34] and hereditary paraganglioma [
35]. Alterations of genomic imprinting or maternal imprinting of modifying genes were believed to be involved in these cases. No cascade testing after routine scans in pregnant women has been performed in our study ruling out a selection bias. Alternatively, the fertility of adult men with
HNF1B mutations may be reduced. In-depth genetic studies will be necessary to elucidate these parent-of-origin mechanisms.
Renal function
Among a subset of HNF1B patients, CRF and ESRD seem to develop when the patients are very young. Five patients rapidly developed ESRD with a GFR below 30 ml/min1.73m
2 already at an early age. Extrarenal symptoms did not differ from the rest of the cohort but all were affected by severe bilateral dysplasia. ESRD is a sequela of severe dysplasia of both kidneys, independent of the underlying gene mutation. Presumably, additional genetic factors or modifiers, environmental factors, or epigenetic influences aggravate the disease in this subset of patients. Similar observations have been made in the subset of young children with VEO-ADPKD [
36], for whom additional genetic variants were identified in
PKHD1 or
HNF1B and were presumed to act as disease modifiers. VEO-
HNF1B nephropathy requires special attention and medical care, including early renal replacement therapy.
Non-VEO-
HNF1B nephropathy has a more favorable course, with only a slow decline of renal function over time during childhood; normal renal function is preserved for many children. In children with cyst progression, the annual decline in GFR seems to be pronounced. In previous studies, a normal GFR (70 ml/min/1.73m
2 or higher) was documented in 56% of pediatric study patients in [
11] and in 39% of pediatric study patients in [
13]. During adulthood, loss of renal function seems to accelerate, as suggested by the results of Faguer et al. in a series of 27 adult
HNF1B patients with a median annual decrease in GFR of − 2.45 ml/min/1.73m
2 [
37]. Continuous follow-up of the pediatric registry with transition into adulthood will be important for defining this acceleration of decline in renal function as patients’ age increases. Possible causes might be related to arterial hypertension, DM, proteinuria, or dietary salt intake.
Hypomagnesemia was diagnosed in 24% of our study patients but higher rates have been reported in cohorts composed mostly of older patients. Renal magnesium wasting in
HNF1B disease was first described in [
9] in 44% of 21 patients. Faguer et al. reported hypomagnesemia (Mg < 0.75 mmol/l) in 63% of patients with a median age of 35 years at last follow-up [
37]. In a case series of three adult male patients, pronounced hypomagnesemia was the first clinical manifestation of ADTKD-
HNF1B [
38]. Besides significant differences in defining hypomagnesemia, the development of this condition seems to be strongly age-related.
Hyperuricemia was documented in 37% of our study patients, with an early onset at a median patient age of 1 year. Only 20% of patients in the study by Bingham et al. [
39] exhibited elevated uric acid levels. Because uric acid concentrations are not routinely measured at many pediatric centers, hyperuricemia may be underdiagnosed. Among patients with kidney dysplasia, hyperuricemia disproportionate to renal function highly suggests
HNF1B nephropathy as underlying cause. However, an important differential diagnosis is ADTKD caused by variants in uromodulin (ADTKD-
UMOD), presenting as familial juvenile hyperuricemic nephropathy and MCKD [
40,
41]. The cause of hyperuricemia in both ADTKD-
UMOD and ADTKD-
HNF1B is not well understood, but hyperuricemia seems to be a consequence of tubulointerstitial dysfunction. Novel experimental studies have linked
HNF1B to mitochondrial energy metabolism in renal tubular cells [
42] providing a possible link to transcellular substrate movements. More experimental work will be necessary for better defining the role of
HNF1B in uric acid transport and metabolism.
Hyperglycemia, elevated HbA1c levels, or both were found in only 8% of our patients. Decramer et al. [
13] found DM in 17% of patients; Bingham et al. [
39] in 58% (mean age at diagnosis 25 years); Faguer et al. [
37] in 48% (median age 35 years); and Edghill et al. [
43] in 48%. These results indicate that impaired glucose tolerance and DM are rarely observed in childhood but, even more so than hypomagnesemia, develop later in the clinical course of
HNF1B disease. However, under certain circumstances, e.g., after renal transplantation with concomitant high doses of steroids, tacrolimus, or both, DM may be unmasked in
HNF1B-positive patients [
44], requiring specific treatment and often a change in the immunosuppressive regimen. New-onset diabetes after transplant (NODAT) is a serious complication compromising renal graft function [
45]. Therefore, screening for
HNF1B mutations should be considered pre-transplant for patients with ESRD caused by (cystic) kidney dysplasia. In a subgroup of patients,
HNF1B disease first manifests as a disturbance of glucose metabolism [
46]. A recent Norwegian study estimated that the overall prevalence of monogenic diabetes gene mutations (including
HNF1A,
HNF4A,
HNF1B,
GCK, and
INS) in children with autoantibody-negative DM is very rare with 6.5% [
47]. A study using high-throughput genetic analysis of 4016 patients with type 2 DM (34% with age at diagnosis of < 40 years) identified only one
HNF1B mutation (age at diagnosis 14 years), whereas mutations in
HNF1A and
GCK occurred much more frequently [
48].
HNF1B seems to play a minor role in children (and adults) with isolated autoantibody-negative DM.
Elevated liver enzyme activity was detected in 21% of our patients, in 13% in [
39], and in 40% in [
37]; thus, there is a high degree of variability among the separate studies. Results of liver ultrasound seem to be normal in most cases reported so far; however, a longitudinal follow-up of our pediatric patients into adulthood will be of interest in elucidating the long-term effects of liver dysfunction in
HNF1B disease.
Genital tract anomalies resulting from Müllerian duct aplasia and failure of fusion of the Müllerian ducts have repeatedly been described in patients with
HNF1B mutations [
49,
50]. In our cohort, only one patient was found to have hypoplastic testicles and no other urogenital abnormalities were detected. Bingham et al. [
39] described uterine malformations in 14% of female patients and genital tract malformations in 5% of male patients. Edghill et al. [
43] found genital tract anomalies in 9% of patients. Oram et al. identified mutations in
HNF1B in 18% (9/50) of women with combined uterine and renal abnormalities but in none (0/58) with isolated malformations of the uterus [
51]. Overall, genital tract malformations are an inconsistent finding. However, when they are combined with renal abnormalities,
HNF1B mutation analysis seems advised.
In summary, this report presents the results of a longitudinal dataset from one of the largest pediatric cohorts of patients with HNF1B nephropathy. With few exceptions, HNF1B nephropathy among children is a rather non-progressive disorder with respect to cyst development and a slowly progressive disease with respect to kidney damage. In contrast, VEO-HNF1B nephropathy is associated with high morbidity rates and early ESRD. Hyperuricemia is a frequent finding in very young patients, whereas the prevalence of hypomagnesemia, elevated liver enzyme activity, and hyperglycemia is higher among teenagers. A close genotype-phenotype correlation is lacking; however, we describe a significant parent-of-origin effect in HNF1B disease, with an 80% preponderance of maternal inheritance. Future studies employing the combined efforts of international registries are necessary for identifying the underlying mechanisms.