Pregnancy outcome with maternal HNF1B gene mutations and 17q12 deletions

Abstract

There is an increasing body of literature regarding monogenic diabetes, particularly the more common forms of glucokinase and HNF1-alpha mutations (MODY2 and MODY3). There is relatively little published literature regarding rarer mutations. HNF1-beta mutations and 17q12 deletions may be associated with a broad range of organ dysfunction, renal disease and diabetes in particular resulting in high-risk pregnancies. This manuscript describes pregnancy outcomes in a woman with an HNF1-beta mutation and 2 women with an HNF1B/17q12 deletion and reviews the previously published literature. It highlights the significant rate of adverse maternal and fetal outcomes, and the maternal features suggestive of the diagnosis which should be considered in preconception counselling.

Introduction

Hepatic nuclear factor homeobox B (HNF1B) is a gene which plays an important role in the normal development of multiple organs. HNF1B is located on chromosome 17q12 and comprises nine coding exons. ¹ One hundred and six different HNF1B mutations have been described including missense, nonsense and splice-shift mutations, gross deletions, and frameshift deletions or insertions. ² Heterozygous mutations in HNF1B result in a highly variable multisystem phenotype (Table 1) including renal abnormalities, progressive renal dysfunction and maturity-onset diabetes type 5 (MODY5). Maternal and fetal mutation status contribute to birth weight and potential complications in MODY pregnancies. ³ In HNF1B-MODY and 17q12 deletion the maternal and fetal phenotype impact pregnancy outcome depending predominantly on the systems involved, especially maternal and fetal renal disease, complications of maternal diabetes, and maternal Mullerian duct malformations as well as the effects of maternal glycaemia. 17q12 deletions and duplications may also involve LHX1 and ACACA genes and may additionally be associated with learning disability, behavioural abnormalities and neurological disorders (Table 1). ⁴ The estimated prevalence of 17q12 deletion in Denmark is 1.6 per 1,000,000 citizens. ⁴ HNF1B mutation is inherited in an autosomal dominant pattern, however, approximately 50–60% of cases represent new mutations. ⁵ There is a paucity of information regarding pregnancy outcomes with maternal HNF1B mutation and 17q12 deletion. The course of pregnancy in one woman with an HNF1B mutation and two women with HNF1B/17q12 deletion are described, and the literature reviewed.

Table 1.

Prevalence of clinical features in HNF1B mutation and 17q12 deletion.

Phenotypic feature	Prevalence
Renal abnormalities 6	61–91%
Diabetes mellitus 7	39–45%
Hyperparathyroidism 7	53%
Elevated liver enzymes4,8,9	48–71%
Liver abnormalities 10	20–32%
Pancreatic malformations11,12	23%
Hypokalaemia13,14	46%
Hypomagnesaemia 7	42%
Hyperuricaemia 9	37%
Genital tract abnormalities 6	18–80%
Neurodevelopmental delay6,8,15	30–89% (17q12 deletions) 0–11% (HNF1B mutations)
Eye abnormalities6,7	41%
Neonatal cholestasis	-
Cardiac anomalies167	20%
Transient neonatal hypercalcaemia 17	-

Case 1

A 31-year-old White Australian woman presented at 12 weeks’ gestation for antenatal care in her second pregnancy. Her past medical history was significant for assumed type 1 diabetes mellitus diagnosed at age 11 years, polycystic ovarian syndrome, essential hypertension, non-alcoholic fatty liver disease, and moderate splenomegaly. There was no evidence of portal hypertension on doppler ultrasound, and splenomegaly has been reported as a clinical feature in individuals with HNF1B mutation. ¹⁸ At age 30 years, negative GAD and IA2 antibodies were noted, and C-peptide was 0.7 nmol/L (0.3–0.7) consistent with residual endogenous insulin production. Hypomagnesaemia was present, renal ultrasound disclosed small bilateral renal cysts and small cortical echogenic foci. The woman's maternal and paternal grandmother had type 2 diabetes mellitus of an uncertain age of onset. Genetic testing revealed a heterozygous whole gene deletion (c.1-?_1674 + ?del).

The woman's first pregnancy at another hospital resulted in an emergency caesarean section (CS) at 37 weeks' gestation for preeclampsia with a non-reassuring cardiotocograph, delivering a live male with a birth weight of 3400 g (97th percentile).

In her second pregnancy, the woman had well-controlled diabetes mellitus using metformin and a basal-bolus regimen of insulin with HbA1c 34 mmol/mol (5.3%) at 12 weeks' gestation. Renal function and urine albumin: creatinine ratio was normal. Serum magnesium ranged between 0.4 and 0.5 mmol/L throughout the pregnancy, with no improvement with oral magnesium supplements. Serum calcium, potassium and phosphate were normal. No renal abnormality was noted on fetal ultrasound. The pregnancy course was uneventful other than fetal macrosomia. The woman proceeded to elective repeat CS at 37 weeks' gestation, delivering a live male with a birth weight of 4413 g (100th percentile). The woman declined predictive gene testing for her infant.

Case 2

A 28-year-old White Australian woman presented at 22 weeks' gestation for antenatal care. Two years previously 17q12 microdeletion was diagnosed after the woman was noted to have benign intrahepatic cholestasis with significant hypomagnesaemia. Serum magnesium was 0.4 mmol/L despite oral supplementation. Maternal ultrasound revealed bilateral renal cysts. Renal function and urine protein were normal. Hepatic transaminases were mildly elevated and hypocalciuria was present. The woman declined amniocentesis. The pregnancy was complicated by gestational diabetes mellitus which was managed with insulin with good control, and progressive pruritus with elevated bile acids managed with ursodeoxycholic acid. Fetal ultrasound demonstrated kidneys that were morphologically normal but relatively enlarged. Vaginal delivery was induced at 37 weeks' gestation, resulting in a live female with a birth weight of 3206 g. (90th percentile) The neonatal course was complicated by hyperinsulinaemic hypoglycaemia requiring intravenous glucose. Microarray sequencing of the baby confirmed a 17q12 deletion of approximately 1.57 Mb including HNF1B.

Case 3

The care of a 28-year-old woman from the Republic of Congo was transferred from another hospital at 10 weeks' gestation. Diabetes mellitus was diagnosed 4 years earlier and assumed to be type 1 diabetes. The woman's history was also significant for chronic kidney disease (CKD) stage 4/5, hypertension and anaemia. Her medications included a basal-bolus regimen of insulin, darbepoetin, iron and nifedipine. Six weeks earlier the woman's HbA1c had been 130 mmol/mol (14%). She admitted omitting insulin for days at a time without diabetic ketoacidosis. GAD, IA2 and zinc transporter antibodies were negative, and C-peptide was 1.0 nmol/L consistent with residual endogenous insulin production. Her renal function had rapidly declined from an estimated glomerular filtration rate of 62 to 15 mL/min/1.73 m² over the preceding 18-month period. MODY gene panel testing revealed a heterozygous missense variant NM_000458.3(HNF1B)c.1484T>A (p.(Met495Lys)), a variant that has been reported in at least three patients with MODY 5 genotype. Liver function tests and serum magnesium were normal. Urine protein: creatinine ratio was 3105 mg/mmol (0–30). HbA1c was 68 mmol/mol (8.4%) at 10 weeks' gestation. Ophthalmoscopy revealed mild non-proliferative retinopathy. Maternal kidneys were structurally normal on ultrasound.

The woman commenced dialysis 3 days per week. A fetal morphology scan at 20 weeks revealed fetal growth restriction (FGR) with an abdominal circumference on the 9th centile and estimated fetal weight on the 11th centile; no organ malformations were seen. At 23 weeks’ gestation, the frequency of dialysis was increased to 4 days per week. Fetal ultrasound at 24 weeks' gestation revealed progressive FGR. At 25⁺⁴ weeks’ gestation the woman presented to another hospital with abdominal pain, and fetal bradycardia was noted. The woman proceeded to urgent CS for presumed placental abruption, delivering a live male with a birth weight of 602 g. (5th centile) The newborn course was complicated by persistent pulmonary hypertension of the newborn, grade 2 intraventricular haemorrhage, retinopathy of prematurity, apnoea of prematurity, chronic neonatal lung disease and probable cytomegalovirus hepatitis, and was discharged from the hospital at a corrected gestational age of 46⁺⁶ weeks with a weight of 3465 g. Renal ultrasound was unremarkable and serum magnesium was normal. The result of genetic testing is pending.

Discussion

HNF1B mutations are associated with a wide phenotypic spectrum. No strong genotype–phenotype correlation has been reported although missense and frameshift mutations may be associated with greater penetrance of diabetes and renal disease, respectively. There may be significant intrafamilial variability of renal phenotype in adults with HNF1B nephropathy. Renal manifestations include renal dysfunction, hypoplastic glomerulocystic kidney disease, cystic renal dysplasia, solitary functioning kidney, horseshoe kidney, and oligomeganephronia. Renal disease is often diagnosed before diabetes mellitus, mean age of onset being 21 and 24 years respectively. Renal dysfunction may occur in individuals with HNF1B mutations in the absence of structural anomalies on imaging, although diabetic nephropathy and hypertension may have been significant factors in the renal dysfunction and proteinuria seen in the woman in case 3. ¹³

The decline in renal function is typically gradual in children and adults (annual mean decline in eGFR −2.1 mL/min/1.73 m2 in children, −2.45 mL/min/year in adults), although abrupt decline to end-stage renal failure (ESRF) may occur at any age including infancy.^10,13 ESRF has been reported in 13–15% of adults. ¹³ In one study, 6/14 (43%) paediatric patients progressed to ESRF at a median age of 10.7 years. ¹⁰ HNF1B intragenic variants result in more severe renal function impairment and poor renal prognosis in neonates than 17q12 deletions. ⁶

Unlike some other forms of MODY, HNF1B carriers are not sensitive to sulphonylureas and usually require early insulin therapy.

Pregnancy outcomes have previously been described in 6 pregnancies with maternal HNF1B mutations (Table 2). Overall three pregnancies were complicated by polyhydramnios, two by a decline in maternal renal function, two by delivery prior to 37 weeks' gestation, and there was one intrauterine fetal death.

Table 2.

Outcomes of pregnancies with maternal HNF1B mutations.

Author	Maternal features	Fetal features	Pregnancy complications	Pregnancy outcome
Alvelos et al. 2	CKD2, solitary cystic kidney Bicornuate uterus Pancreatic atrophy	Hyperechoic kidneys	Decline in maternal renal function Polyhydramnios GDM	CS at 35 weeks’ gestation Infant required dialysis at 16 months of age
Deng et al. 19	Diabetes mellitus CKD2, multiple renal cysts	Renal echogenicity	Decline in maternal renal function	SVD at 39 weeks’ gestation
Haider et al. 20	Dysplastic kidney GDM, Hypoplastic pancreas Hypomagnesaemia	Not affected	Nil	SVD at 39 weeks’ gestation
Mikusheva et al. 21	Renal abnormality Diabetes mellitus Hypomagnesaemia Bicornuate uterus	Not stated – subsequently found to have a gene mutation	Polyhydramnios Macrosomia Preterm labour	CS at 30 weeks’ gestation because of pre-term labour
Gondra et al. (1) 22	Not stated	Not stated	Polyhydramnios	IUFD at 22 weeks’ gestation
Gondra et al. (2) 22	Not stated	Not stated	Polyhydramnios	Livebirth at 39 weeks' gestation

In 10 pregnancies where the fetus was found to have a de novo HNF1B mutation, two resulted in preterm delivery, two in term delivery, and six pregnancies were terminated.^22,23

Details of the course of pregnancy which were not terminated have been reported in 13 pregnancies with maternal 17q12 deletion. Seven infants were born prior to 37 weeks' gestation, there were six term deliveries and there was one neonatal death (Table 3).^4,16,24–27

Table 3.

Proposed framework for pregnancy management with maternal HNF1B mutation or 17q12 deletion.

Preconception Ultrasound examination to exclude disorders of Mullerian development Folic acid, other pregnancy vitamins as indicated Monitor renal function, proteinuria, and blood pressure every 3 months; test for underlying diabetes mellitus annually with HbA1c and/or oral glucose tolerance test (OGTT) Preconception diabetes mellitus – optimise control; assess for microvascular and macrovascular complications Optimise blood pressure control using agents known to be safe in pregnancy – consider home blood pressure monitoring Measure ionised calcium and parathyroid hormone annually Discuss the possibility of pre-implantation genetic diagnosis Consider discussion surrogacy if CKD stage 4/5 or recurrent adverse pregnancy outcomes due to disorders of Mullerian development

Pregnancy Early testing for impaired glucose tolerance – OGTT and/or HbA1c Early dating scan 8–10 weeks' gestation Minimum fortnightly reviews re glycaemic control if pregestational diabetes Monthly clinic visits monitoring renal function, proteinuria and blood pressure Offer prenatal diagnostic gene testing Consider aspirin from 12 weeks' gestation for the prevention of preeclampsia Early fetal morphology scan +/− MRI at 17–18 weeks Monthly fetal scan for growth, dopplers, amniotic fluid volume from 20 weeks' gestation

Postpartum Predictive diagnostic gene testing Discuss appropriate contraception

In 26 pregnancies where the infant was affected by 17q12 deletion where the mutation was de novo or where inheritance was uncertain, there were 14 live births, 10 pregnancies were terminated, and outcome was not stated in two pregnancies.^{4,16,24,26,28,29} Delivery occurred prior to 37 weeks in three of the eight pregnancies where the gestation of delivery was provided. Polyhydramnios was reported in four pregnancies.

In addition to high rates of polyhydramnios, prematurity and fetal renal abnormalities, fatal cardiopulmonary abnormalities, diaphragmatic hernia, and duodenal atresia have been described in neonates with HNF1B mutations and 17q12 deletions.

Most pregnancy complications with maternal HNF1B mutations and 17q12 deletions relate to maternal renal disease and diabetes mellitus, as well as the risks of miscarriage, fetal growth restriction, preterm delivery and breech presentation with disorders of Mullerian development (Table 3). Poor maternal diabetes control in the first trimester is associated with an increased risk of fetal malformations and miscarriage.^30,31 Poor maternal diabetes control during pregnancy is associated with an increased risk of stillbirth, fetal macrosomia, birth injury, neonatal hypoglycaemia and jaundice. ³² Polyhydramnios may occur due to maternal diabetes mellitus and/or fetal polyuria. ²² Maternal renal dysfunction may be associated with reduced fertility, and an increased risk of maternal anaemia, hypertension, decline in maternal renal function which may be irreversible, preterm delivery, preeclampsia and FGR in pregnancy. ³³

Preimplantation diagnosis is possible with maternal or paternal mutations/deletions. Prenatal diagnosis may be made using chromosome microarray analysis on chorionic villous or amniotic fluid samples. ³⁴ Fetal kidneys can be visualised from 9 to 12 weeks of pregnancy, although hyperechogenic kidneys cannot be appreciated until 17–18 weeks of pregnancy. ³⁵ Simple renal cysts may be diagnosed on ultrasound at 14 to 16 weeks of gestation however almost all resolve during pregnancy. ³⁶ Non-contrast magnetic resonance imaging (MRI), particularly bi-parametric MRI, may have a role as an adjunct to ultrasound in defining fetal renal abnormalities.^37,38

Neonatal predictive genetic testing is crucial to identify affected infants who require long-term follow-up regarding potential complications of HNF1B mutations and 17q12 deletions. Close follow-up of the infant’s renal function is important as rapidly progressive kidney disease requiring dialysis in infancy has been described with HNF1B mutations. ² High blood pressure was identified in 22% of children with HNF1B gene abnormalities. ³⁹ Knowledge of the presence of fetal/neonatal gene mutation is critical to guide the need for ongoing follow-up as fetal-onset HNF1B deletion-associated renal parenchymal abnormalities and neonatal reduced renal function may initially resolve in infancy/early childhood, with later development of renal, metabolic and neurodevelopmental abnormalities. ⁴⁰ Identification of children who may benefit from regular assessment and early assistance with respect to neurodevelopmental or behavioural disorders is important, a prospective cohort study of 223 French school-aged children (mean age 9.6 years) found that 12.7% and 3.6% of children carrying an HNF1B deletion and a disease-associated variant respectively had special educational needs, compared with 1.2% of French children in general. ⁴¹ Counselling parents with an affected child is complicated by highly variable penetrance and expression with gene mutations/deletions, the lack of genotype–phenotype correlation, and considerable variability of phenotype between and within family members carrying the same mutation.

Conclusion

1. HNF1B mutations/deletions are associated with a broad array of pathology without genotype–phenotype congruity and significant variability amongst carriers within the same family.

2. MODY5 due to HNF1B mutations may be misdiagnosed as type 1 diabetes mellitus. HNF1B mutations should be considered where renal abnormalities are present (including renal dysfunction/albuminuria disproportionate to the known duration of diabetes), where diabetes-specific antibodies are negative, and in the setting of significant hypomagnesaemia, unexplained abnormal liver function abnormalities, or anomalies of the genital tract.

3. Pregnancies in women with HNF1B mutations represent a significant risk of adverse maternal and fetal outcomes and require close surveillance. Preconception counselling is important to reduce the risk of pregnancy complications. Adverse outcomes are predominantly related to maternal renal disease, diabetes mellitus and Mullerian tract anomalies, and fetal renal disease.

4. Unexplained acute deterioration in renal function may occur.

5. Pre-implantation and prenatal diagnostic testing may be performed.

6. Predictive gene testing is important to identify children who need regular surveillance for neurodevelopmental or behavioural disorders, and who are at risk for metabolic and renal complications.