Antenatal management of HNF4A-MODY and INSR mutations in pregnancy.

A 25-year-old Caucasian gravida 1, para 0 (G1P0) woman was referred at 6 weeks' gestation to Liverpool Hospital (New South Wales, Australia). Her birth weight was 3.14 kg. She had no history of hypoglycemia during childhood. She was diagnosed with diabetes at age 17 years with a weight at diagnosis of 50 kg. Her medical history included polycystic ovarian syndrome (PCOS) with clinical features of oligomenorrhoea, hirsutism, and acne. She had a strong family history of diabetes. Her father was diagnosed with type 2 diabetes mellitus (T2DM) at age 40 years, and both paternal grandmothers were also affected. These family members to date have not been tested for HNF4A or INSR mutations ( Fig. 1 ). Three-generation pedigree demonstrating coexisting HNF4A and INSR variants in the proband (generation III), diagnosed with diabetes at age 17 years with a polycystic ovarian syndrome (PCOS) phenotype. Her father (generation II) had type 2 diabetes mellitus (T2DM) diagnosed at age 40 years, and her paternal grandmother (generation I) was also affected. Genetic testing was not performed in other family members. Squares indicate males, circles indicate females, and filled symbols indicate affected individuals.

Maturity-onset diabetes of the young (MODY) is frequently underrecognized and misdiagnosed. It typically presents as early-onset diabetes in a nonobese individual, often with predominant postprandial hyperglycemia. Among its subtypes, hepatocyte nuclear factor 4 alpha ( HNF4A)- MODY is characterized by progressive β-cell dysfunction. During pregnancy, HNF4A mutations are associated with fetal macrosomia and persistent neonatal hypoglycemia resulting from fetal hyperinsulinism. The average increase in birthweight at term has been reported as ∼800 g, independent of maternal glucose control [ 1 ]. Mutations in the insulin receptor ( INSR) gene result in varying degrees of insulin resistance. Heterozygous mutations can present with hyperglycemia, hyperinsulinemia hypoglycemia, and clinical features such as hyperandrogenism, oligomenorrhoea, and acanthosis nigricans, even in the absence of obesity. Homozygous INSR mutations are associated with severe insulin resistance syndromes, characterized by intrauterine and postnatal growth restriction, dysmorphic features, and reduced life expectancy. In pregnancies affected by heterozygous INSR mutations, small-for-gestational-age offspring have been reported [ 2-4 ]. We present the case of a pregnant woman with coexisting HNF4A and INSR mutations, with fetal inheritance of the HNF4A variant. This case underscores the importance of early recognition of monogenic diabetes in pregnancy and the implications for both maternal and fetal management, including tight glycemic control, growth monitoring, and the need for ongoing metabolic surveillance of the neonate into adulthood.

At 33 + 5 weeks' gestation, fasting BGL ranged from 77 to 92 mg/dL (SI: 4.3-5.1 mmol/L), with postprandial levels above target ranging from 85 to 202 mg/dL (SI: 4.7-11.2 mmol/L), despite insulin therapy (total daily dose 57 units). At 34 weeks, fetal ultrasound showed an estimated weight of 2300 g (52nd percentile) and abdominal circumference of 316.6 mm (86th percentile). The patient developed premature rupture of membranes, and labor was augmented with oxytocin because of prolonged second stage of greater than 2 hours. Delivery occurred via vacuum-assisted vaginal birth. The neonate weighed 2860 g (90th-95th percentile). The infant was admitted to the neonatal intensive care unit for prematurity and required intravenous dextrose until day 5. Despite transitioning to enteral feeds, the mother continued to exhibit borderline hypoglycemia (BGL 54-63 mg/dL [SI: 3.0-3.5 mmol/L] with inappropriately elevated insulin of 1.8 µU/mL [SI: 11 mIU/L]; reference range, ≤1.4 µU/mL [SI: ≤9 mIU/L]), ACTH of 13 pg/mL (SI: 2.9 pmol/L) (reference range, 4.5-49 pg/mL [SI: 1.0-10.8 pmol/L]), and GH of 23.4 ng/mL (SI: 23.4 µg/L). A diagnosis of hyperinsulinemia hypoglycemia was made, and diazoxide therapy (2 mg/kg every 8 hours) was initiated from day 9 of birth. Diazoxide therapy was successfully weaned and ceased by day 25 of birth. The infant subsequently underwent a fasting challenge, which was normal. Maternal insulin was ceased postpartum because of an episode of inpatient hypoglycemia, and she was continued on metformin monotherapy because of safety considerations and breastfeeding compatibility of alternate oral hypoglycemic agents. At 2 years postpartum, the patient's HbA1c was 6.9% with a hemoglobin of 12.2 g/dL (SI: 122 g/L) and mean corpuscular volume of 73 fL [SI: 73 × 10 −15 L]). At 3 months of age, the infant continued to experience hypoglycemia (BGL 59-79 mg/dL [SI: 3.3-4.4 mmol/L]). Diazoxide was reintroduced at 6 mg/kg/day but was discontinued shortly afterward because of hirsutism. Blood glucose levels remained largely stable with the commencement of solid feeds at 6 months. At 28 months, the child was at the 7.9th percentile for height, 3.3rd percentile for weight. and 21st percentile for body mass index. The infant continues to have occasional low BGLs, and continuous glucose monitoring is being pursued. A repeat supervised fasting study is currently under consideration.

MODY1 ( HNF4A ) should be considered in young, lean individuals with early-onset diabetes and a strong family history. Mutations in the INSR gene may manifest with clinical features such as hyperandrogenism, oligomenorrhoea, and acanthosis nigricans, even in the absence of obesity. Serial ultrasound monitoring and early delivery planning remain crucial in pregnancies affected by monogenic diabetes. NIPT may offer valuable early insight into fetal genotype and risk stratification when one parent is a known mutation carrier.

Prepregnancy, the patient's HbA1c was 7.3% and initially treated as T2DM with metformin 500 mg extended release twice daily. During pregnancy, her blood glucose levels (BGLs) were monitored via finger-prick capillary testing including fasting and 2-hour postprandial measurements. At 6 weeks' gestation, insulin therapy was commenced with human isophane insulin 4 units at night and insulin aspart 4 units 3 times daily. During the first trimester, fasting blood glucose levels ranged from 85 to 95 mg/dL (SI: 4.7-5.3 mmol/L); however, postprandial excursions were observed, reaching up to 205 mg/dL (SI: 11.4 mmol/L). By the end of the first trimester, her total daily insulin dose had increased to 41 units. Glycemic control was complicated by intermittent hypoglycemia (as low as 52 mg/dL [SI: 2.9 mmol/L]), necessitating frequent dose reductions to stabilize BGLs throughout the second trimester. This degree of early gestational insulin sensitivity in a lean patient was considered atypical and prompted further investigation for monogenic diabetes. A pathogenic splice-site mutation in HNF4A (c.320-1G > A) and a likely pathogenic INSR missense mutation (c.3531C > G; p.Asp1177Glu) was detected. Subsequent noninvasive prenatal testing (NIPT) predicted >95% probability of the fetus inheriting the HNF4A variant. The fetus was not predicted to have inherited the maternal INSR variant. Given fetal risk of macrosomia, the patient was recommended to undergo fortnightly fetal ultrasounds to monitor growth parameters.

Prepregnancy, her body mass index was 22.2 kg/m 2 . Laboratory tests revealed mildly elevated serum testosterone concentration of 54.7 ng/dL (SI: 1.9 nmol/L) (reference range, 5.8-52 ng/dL [SI: 0.2-1.8 nmol/L]), sex hormone binding globulin (SHBG) concentration of 2047 ng/mL (SI: 71 nmol/L) (reference range, 864-3167 ng/mL [SI: 30-110 nmol/L]), and a free androgen index of 2.7% (reference range, 0.3-4.0). She also had endometriosis and was a carrier of α and β thalassemia traits. She exhibited microcytic anemia (hemoglobin concentration of 10.4 g/dL [SI: 104 g/L] (reference range, 11.5-16.0 g/dL [SI: 115-160 g/L]) and a mean corpuscular volume of 75 fL (SI: 75 × 10 −15 L) (reference range, 80-100 fL [SI: 80-100 × 10 −15 L]). At time of diagnosis, her hemoglobin A1c (HbA1c) was 6.7% (reference range, ≥6.5%), fasting plasma glucose 85 mg/dL (SI: 4.7 mmol/L) (reference range, ≥126 mg/dL [SI: ≥7.0 mmol/L]). This was likely an underestimation given her preexisting anemia and reduced red blood cell lifespan and increased cell turnover. Diabetes-related autoantibodies (glutamic acid decarboxylase, Zinc Transporter 8, islet antigen-2) were negative, and C-peptide was within normal limits (2.4 ng/mL [SI: 0.80 nmol/L]; reference range, 1.2-4.5 ng/mL [SI: 0.4-1.5 nmol/L]).

This case presents a rare antenatal scenario, not previously described ( Table 1 ), involving dual monogenic variants: a pathogenic HNF4A splice-site mutation (c.320-1G > A) and a likely pathogenic INSR missense variant (c.3531C > G; p.Asp1177Glu), identified in a young woman with longstanding diabetes, a lean phenotype, and clinical features of insulin resistance. This case highlights the complex and potentially opposing effects these mutations can have on fetal growth and neonatal glucose regulation. Published case reports of INSR mutations in pregnancy Abbreviations: BD, twice daily; BW, birth weight; dx, diagnosis; GAD, glutamic acid decarboxylase; HH, hyperinsulinemia hypoglycemia; IA2, islet antigen 2; INSR, insulin sensing receptor; IU, international units; IUGR, intrauterine growth restriction; MODY, maturity onset of diabetes in the young; PCOS, polycystic ovarian syndrome; SDS, standard deviation score; TDD, total daily dose; TDS, ; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; VSD, ventricular septal defect; XR, extended release; ZnTr8, zinc transporter 8 MODY1 resulting from HNF4A mutations is associated with fetal hyperinsulinism, resulting in macrosomia even in the setting of well-controlled maternal glucose levels. Pearson et al (2007) reported an average 790-g increase in birthweight in mutation-positive infants, independent of maternal glycemic control. Additional risk factors of maternal hyperglycemia and insulin therapy can result in an additional increase in birth weight in addition to the direct effect of the HNF4A variant in the fetus. Consistent with this, our patient's fetus had an abdominal circumference in the 86th percentile at 34 weeks, with a birthweight of 2860 g at 34 + 4 weeks (90th-95th percentile), despite antenatal insulin therapy. Furthermore, this case highlights the potential role of NIPT using circulating cell-free fetal deoxyribonucleic acid in guiding antenatal care in monogenic diabetes. In this instance, NIPT confirmed likely inheritance of the maternal HNF4A mutation, enabling early risk stratification, serial growth monitoring, and anticipatory neonatal planning. Although promising, NIPT for monogenic conditions is not yet widely available and remains limited by cost and lack of large-scale validation [ 8 ]. Until such tools are routine, serial growth assessments every 2 weeks from 28 weeks is critical in monitoring for macrosomia and early delivery, induction of labor and/or elective cesarean section may need to be considered based on fetal size on ultrasound even with excellent maternal glucose control. This case report also describes a novel INSR p.Asp1177Glu variant in the context of pregnancy [ 6 ]. Mutations associated with the INSR gene has been associated with type A insulin resistance in adults with prior reports describing insulin requirements ranging from very low (2-6 units before lunch) to extremely high (up to 900 units/day), reflecting variable insulin sensitivity [ 2-5 , 7 ]. However, the antenatal implications of INSR mutations, particularly when co-inherited with HNF4A variants, have not previously been described. Features of hyperandrogenism, which are commonly associated with INSR mutations, may be modified by the presence of an HNF4A mutation. In HNF4A -related hyperinsulinemia, increased portal insulin delivery to the liver may suppress hepatic SHBG production, resulting in elevated circulating free testosterone levels and a clinical phenotype that may mimic PCOS [ 9 ]. Furthermore, our patient had unexpectedly low insulin requirements during pregnancy. HNF4A -MODY is primarily characterized by impaired glucose-stimulated insulin secretion rather than intrinsic insulin resistance, which may partly explain this finding [ 10 ]. Additionally, the patient's history of endometriosis and its associated chronic inflammation could contribute to mild background insulin resistance, suggesting that overall, the INSR variant may have had limited clinical impact during this pregnancy. Metformin has been used to improve insulin sensitivity in patients; however, given the risk of small-for-gestational-age babies associated with INSR mutations, its use in pregnancy remains debated because of concerns regarding placental transfer and associations with reduced gestational size. Management of INSR -related diabetes outside pregnancy has also included glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter 2 inhibitors, with reported glycemic benefits [ 11 ]. However, these agents are not currently recommended for use in pregnancy because of limited safety data. HNF4A -driven neonatal hyperinsulinism may also drive persistent hypoglycemia. Postnatally, the infant in this case exhibited transient borderline hypoglycemia, which required dextrose infusion followed by diazoxide therapy. Although HNF4A -positive neonates may experience transient hypoglycemia requiring short-term intravenous glucose and diazoxide therapy, most resolve within weeks to months postpartum [ 12 , 13 ]. However, this duration may be highly variable, with some case reports describing the ongoing use of diazoxide therapy persisting into adolescence [ 14 ]. In addition, given the progressive β-cell dysfunction associated with HNF4A , carriers are also at long-term risk of developing impaired glucose tolerance and diabetes, necessitating ongoing metabolic surveillance through childhood and adolescence. Continuous glucose monitoring may be a helpful tool in these patients to identify asymptomatic hypoglycemia and hyperglycemia.

K.W. conceived and designed the case report, identified the key clinical focus, interpreted the clinical findings, contributed to the diagnostic reasoning, and drafted the manuscript. H.R. and N.R. were responsible for the diagnosis and management of the patient and critically reviewed the manuscript. All authors reviewed and approved the final draft.