First European case of Geller syndrome complicated with hypokalemic nephropathy: A case report and literature review

Abstract

Geller syndrome is caused by a gain-of-function mutation in the mineralocorticoid receptor (MR), rendering it prone to activation by elevated progesterone levels during pregnancy. It is characterized by gestational hypertension and hypokalemia. We describe the case of a 35-year-old primigravida, who presented at 22 weeks of gestation with severe hypokalemia and hypertension, complicated by hypokalemic nephropathy manifesting as diabetes insipidus and proteinuria. Initial potassium replacement, eplerenone administration and desmopressin were insufficient, whereas the administration of amiloride, a potassium-sparing diuretic that inhibits epithelial sodium channels (ENaC) in the distal nephron, led to complete resolution of the clinical syndrome. The patient had no further complications and delivered a healthy infant at 37 weeks. Genetic testing did not reveal known MR mutations, suggesting that other genetic variants or epigenetic changes in MR may warrant future investigation, particularly in isolated populations. To date, 17 cases of Geller syndrome have been reported in the literature including the herein presented, which is to the best of our knowledge the first documented in Europe. Genetic testing was performed in only one case, apart from the initially reported ones. Urgent delivery was required in four cases, while amiloride, the treatment of choice, was administered in only five, highlighting the importance of early recognition of the syndrome for effective management and prevention of adverse pregnancy outcomes.

1. Introduction

Geller syndrome is a rare genetic cause of hypertension and hypokalemia, particularly during pregnancy. In its original description, Geller et al. reported a family in which five women exhibited early-onset hypertension, which was notably worsened during pregnancy and accompanied by hypokalemia. The condition is caused by a specific mutation in the mineralocorticoid receptor (MR) gene NR3C2, which alters receptor's function such that progesterone acts as an agonist, instead of antagonist. This effect is significantly amplified during pregnancy due to elevated progesterone levels. The identified mutation, located on chromosome 4q31, results in the substitution of leucine with serine at amino acid position 810 (S810L). Geller syndrome typically follows an autosomal dominant pattern of inheritance [1].

Diabetes insipidus (DI) is characterized by large amount of undiluted urine (polyuria) and increased thirst (polydipsia). Central DI is caused due to a lack of arginine-vasopressin (AVP) while nephrogenic DI occurs due to inadequate response of the distal nephron to AVP. One of the main causes of the acquired nephrogenic DI is severe hypokalemia, which causes disruption of the tubular epithelial cells and impairs aquaporin-2 receptors where AVP acts in the distal nephron [2].

Here, we report the case of a 35-year-old woman who presented during the second trimester of her first pregnancy with severe hypokalemia and hypertension, complicated by hypokalemic nephropathy. Whole-exome sequencing did not reveal any of the known mutations associated with Geller syndrome, suggesting that alternative receptor variants or epigenetic mechanisms may contribute to its pathogenesis. Additionally, we conducted a narrative review of the literature to summarize the clinical features and complications associated with Geller syndrome.

1.1. Case presentation

A 35-year-old female of Greek Pomak origin, at 22 weeks of first gestation (G1A0), was admitted to our department from a district hospital due to severe hypokalemia (1.8mEq/L) and polyuria (7–10 L/day) not responding to aggressive potassium replacement for 48 h. She reported progressive muscle weakness and cramps over the past 3 weeks, with the onset of polyuria and excessive thirst in the last week. No gastrointestinal symptoms were reported. Her medical and family history were unremarkable, while no alcohol consumption or other drugs were reported. A normal potassium concentration had been measured in two separate occasions in the preceding three years while no hypertension was present before pregnancy.

During her initial evaluation, persistently elevated SBP values (140–150 mmHg) were recorded, while the rest of her vital signs were normal. Physical examination revealed mild muscle weakness in the lower limbs (bilateral muscle power scale 4/5) and trace peripheral edema. Laboratory report revealed severe hypokalemia (1.8mEq/L) due to renal loss (transtubular potassium gradient: 10), without any other electrolyte disturbances, mild rhabdomyolysis (CPK: 1917 mcg/L), normal thyroid-stimulating hormone (TSH: 2.43) and mildly low plasma renin (2.83 pg/mL), aldosterone (37.98 pg/mL) and albumin (3.2 g/dL) levels (Table 1). ECG did not reveal arrhythmias or other abnormalities. Measurement of total protein after 24-h urine collection repeatedly yielded persistent proteinuria (1680–2475 mg/24 h). Her platelet count was normal, whereas transaminase levels were elevated at presentation but returned to normal following normalization of CPK, suggesting an extrahepatic, muscular origin. An emergency gynecological consultation was held regarding the possibility of preeclampsia. Due to the early stage of pregnancy and the absence of severe preeclampsia manifestations, a management approach involving aggressive treatment of hypokalemia and hypertension under inpatient observation, with close obstetric follow-up, was chosen.

Table 1.

Laboratory report.

Test	Value		Reference range
	Admission	Discharge on Amiloride
Potassium	1.8	4.5	3.5–5 mEq/L
Sodium	142	135	135-145 mEq/L
Magnesium	2.27	–	1.6–2.6 mg/dL
Calcium	8.9	9.6	8.5–10.2 mg/dL
Chloride	107	102	96-106 mEq/L
pH	7.51	7.41	7.35–7.45
Bicarbonate	29.5	24.1	22-26 mEq/L
Albumin	3.2	4.3	3.5–5.5 g/dL
Creatinine	0.4	0.5	0.4–1.1 mg/dL
eGFR	132	127	ml/min/1.73m2
AST	115	6	<40 IU/L
ALT	110	7	<36 IU/L
TSH	2.43	–	0.46–4.12 IU/L
CPK	1917	18	20–200 IU/L
Aldosterone	37.98	–	49.3–175 pg/mL
Direct renin concentration	2.83	–	5.41–34.53 pg/mL
WBC	8.35	10.03	4–11 K/uL
Hemoglobin	10.9	12.2	13.5–18 g/dL
Platelets	278	327	150–400 K/μL
Fractional Potassium Excretion	14.2 %	–	<9 %
Transtubular Potassium Gradient	10	–	<3
24-h urine total protein	2475	312	<300 mg

1.2. Differential diagnosis

Differential diagnosis of persistent hypokalemia and hypertension in pregnancy is presented in Table 2. Congenital adrenal hyperplasia and syndrome of apparent mineralocorticoid excess typically present in early childhood and were considered unlikely due to the late onset of hypokalemia [3,4]. Renal artery stenosis and primary hyperaldosteronism were ruled out due to low plasma renin and aldosterone levels, while Cushing phenotype is related with characteristic clinical phenotype, not suitable to our patient [[5], [6], [7]]. Recurrent hypokalemic paralysis was excluded due to normal TSH levels [8]. Liddle syndrome (pseudohyperaldosteronism) is a rare autosomal dominant syndrome, caused by dysregulation of the epithelial sodium channel (ENaC), due to a genetic mutation of the SCNN1A, SCNN1B and SCNN1G genes. It typically presents with early childhood onset resistant, salt-sensitive arterial hypertension, low plasma renin activity, metabolic alkalosis and hypokalemia [9]. Although, neither arterial hypertension nor hypokalemia were reported before pregnancy. Assuming that pregnancy was a determinant factor for the clinical manifestations of hypertension, hypokalemia and nephrogenic diabetes insipidus, we assumed that Geller syndrome might be the underlying cause in our patient. Geller syndrome is caused by a gain-of-function mutation in the mineralocorticoid receptor, which becomes sensitive to progesterone signaling (Fig. 1). This effect can exacerbate during pregnancy, where progesterone levels are high, causing hypertension and hypokalemia [1]. Treatment relies on the use of the diuretic amiloride which inhibits the ENaC channels in the distal nephron, reducing sodium retention and sparing potassium [10].

Table 2.

Differential diagnosis of hypertension and persistent hypokalemia in pregnancy.

Differential Diagnosis
Congenital adrenal hyperplasia
Syndrome of apparent mineralocorticoid excess
Renal artery stenosis
Primary hyperaldosteronism
Cushing syndrome
Recurrent hypokalemic paralysis due to thyrotoxicosis
Liddle syndrome (pseudohyperaldosteronism)
Geller syndrome

Fig. 1.

Geller syndrome pathophysiology. In normal gestation, progesterone acts as an antagonist of the mineralocorticoid receptor (MR). Contrary, in Geller syndrome, a gain-of-function mutation in the NR3C2 gene, specifically a serine-to-leucine substitution at position 810 (S810L), alters the receptor's ligand specificity, allowing progesterone to hyper-activate the MR. This leads to kaliuresis, hypokalemia, and arterial hypertension. Created with Biorender.com.

1.3. Case management

The patient was initially treated with excessive intravenous replacement of potassium chloride (up to 300 mEq/day) and magnesium sulfate (4 g/day) from a central venous catheter and methyldopa 250 mg bid due to hypertension with target SBP 120–130 mmHg. Despite aggressive electrolyte replacement, hypokalemia persisted. Eplerenone 50 mg qd was administered but failed to maintain potassium levels more than 3 mEq/L. In parallel, a desmopressin trial showed mild initial response (urine osmolarity 2 h after desmopressin trial: 330 mOsm) and as a result desmopressin was administered in a titrated dose. Despite desmopressin administration, polyuria (4–5 L/day) persisted, suggesting a nephrogenic cause of diabetes insipidus, most likely secondary to persistent hypokalemia [11]. After titrating the dose to a maximum 16 mcg, there was a transient mitigating effect on polyuria, which however relapsed over the following days (Fig. 2).

Fig. 2.

Urine output and potassium values during hospitalization.

The combination of kaliuresis, hypokalemia and hypertension manifesting in the second trimester of gestation, and the suppressed renin-angiotensin axis raised the suspicion of Geller syndrome. Eplerenone was discontinued, and oral amiloride 10 mg once daily was initiated following the drug's importation, as amiloride is not available as a standalone formulation in Greece. This led to a rapid normalization of potassium levels within 48 h and a decrease of daily urine output to normal (2–3 L/daily) (Fig. 2). Subsequently, intravenous electrolyte replacement, desmopressin and methyldopa were tapered off without relapse of hypokalemia, polyuria and hypertension, respectively. The patient was discharged on oral amiloride 10 mg qd after 28 days of hospitalization at 26 weeks of gestation. Throughout her hospitalization, routine obstetric evaluations, including fetal ultrasound, revealed no fetal abnormalities. In the course of outpatient follow up, amiloride dose was reduced to 5 mg daily without relapse of hypokalemia.

At 37 weeks and 6 days of gestation, the patient underwent a cesarean section and delivered a healthy male infant. Amiloride was discontinued two days postpartum. Potassium levels remained normal on oral supplementation (20 mEq daily) which was eventually discontinued. One year later, there has been no evidence of recurrence, supporting Geller syndrome as the likely underlying cause of the clinical presentation. Close surveillance by a medical specialist was recommended in the event of future pregnancies.

Genetic testing using whole exome sequencing was performed but did not reveal any known pathogenic mutations in the mineralocorticoid receptor gene (NR3C2). The absence of a personal or family history of hypertension may suggest a variant form of Geller syndrome. Given that the original description of the syndrome involved a U.S. family, it is possible that, in other populations, variants distinct from the classic S810L mutation, potentially classified as variants of unknown significance, could underlie similar clinical manifestations [12].

2. Discussion

In this manuscript, we report a case of Geller syndrome, in a primigravida, presenting as hypertension and severe hypokalemia and complicated with hypokalemic nephropathy manifesting as nephrogenic DI and proteinuria. Excessive potassium replacement and eplerenone administration were ineffective to maintain potassium levels, while the administration of amiloride rapidly normalized serum potassium and blood pressure. The patient was discharged after 28 days of hospitalization and delivered a healthy infant. Amiloride was discontinued postpartum without any relapse, confirming gestation as the trigger of the clinical syndrome and excluding other pseudoaldosteronism causes such as Liddle syndrome [9].

Genetic testing was performed but did not identify any known pathogenic variants in the NR3C2 gene. Geller syndrome, first described in 2000 in a U.S. family, was linked to a specific missense mutation (S810L) in NR3C2, inherited in an autosomal dominant manner [1]. All affected individuals exhibited early-onset hypertension. In contrast, our patient had no history of arterial hypertension prior to pregnancy, nor in the post-partum period. Additionally, there was no family history of hypertension or gestational complications on the maternal side. This lack of a hereditary pattern along with the absence of the S810L mutation suggests that alternative, yet unidentified mechanisms, such as novel genetic variants outside the NR3C2 gene or post-translational modifications of the mineralocorticoid receptor, may be responsible for receptor's overactivation during pregnancy. In a cohort of 720 Caucasian and 145 African participants, the single-nucleotide risk allele rs4835490 was examined for its effects on aldosterone regulation and vasculature. The investigators found that this relatively common polymorphism significantly influenced plasma aldosterone levels and blood pressure, with its impact modified by age, sex, and origin. The association was particularly pronounced in homozygous premenopausal Caucasian women with a liberal-salt diet, whereas no similar effect was observed in men or in the African cohort. These findings demonstrate that even common NR3C2 polymorphisms, especially when present in the homozygous state, can meaningfully alter aldosterone secretion and blood pressure regulation [13]. Notably, our patient originates from the Pomak Greek minority, a closed population in which distinct genetic mutations have been reported. This raises the possibility that population-specific or founder variants, potentially including polymorphisms similar to rs4835490 that follow the autosomal recessive inheritance pattern may contribute to the observed clinical phenotype [14,15].

Beyond coding mutations, epigenetic modifications of NR3C2 have also been reported, particularly in the context of neuropsychiatric disorders. NR3C2 plays a key role in regulating the hypothalamic–pituitary–adrenal axis, a central component of the stress response and an important modulator of human behavior. Qing et al. demonstrated that hypermethylation of NR3C2 in peripheral blood was associated with increased aggressive behavior in adult males [16]. Similarly, another study showed that maternal depressive symptoms in early pregnancy were linked to reduced DNA methylation at the CpG24 site of the NR3C2 in placental tissue, suggesting altered MR expression during fetal development [17]. These findings highlight that epigenetic variation in NR3C2 can influence the receptor's function and may contribute to phenotypic variability in conditions that involve MR dysregulation.

We next conducted a narrative review of the literature to identify all the previously published cases of Geller syndrome (Table 3). To date, a total of 17 cases have been reported in the literature, including our own. This comprises the 2 cases originally described by Geller et al. (from a family with 11 carriers of the S810L mutation) [1], 6 additional cases reported in original research articles [[18], [19], [20], [21], [22], [23]], and 8 cases presented in 7 conference abstracts [[24], [25], [26], [27], [28], [29], [30]].

Table 3.

Geller syndrome cases described in the literature.

Study (Date)	Article type/Origin	Number of cases	Detected mutation/gene	Clinical featuresa	Treatment during pregnancy
Geller D.S. et al. (2000)	Original Article - Case series/USA (first description)	2b	S810 L/NR3C2	-Early onset hypertension before pregnancy -No other specific features described during pregnancy	-Not described
Mulkanoor V. et al. (2017)	Conference Paper – Case series/USA	2	Genetic testing not performed	-Muscle weakness -Bilateral lower extremity edema	-IV & PO K+ replacement -Methyldopa and labetalol -Amiloride
Garg A. K. et al. (2020)	Original article - Case report/USA	1	Genetic testing not performed	-Bilateral lower extremity edema	-IV & PO K+ replacement
Pintavorn P. et al. (2021)	Original article - Case report/USA	1	Genetic testing not performed	-Muscle weakness -Rhabdomyolysis -Nephrogenic DI	-IV K+ replacement -Amiloride
Hindosh N. et al. (2022)	Original article - Case report and literature review/USA	1	Genetic testing not performed	-Headaches and visual disturbances -Bilateral lower extremity edema -Preeclampsia	-IV K+ replacement -Urgent C-section due to preeclampsia
Maturostrakul-Boonyanuth N. et al. (2022)	Conference paper – Case report/USA	1	Pending results	-Early-onset hypertension before pregnancy -Bilateral lower extremity edema	-K+ replacement
Bin Rhashbudin Shah et al. (2023)	Conference paper – Case report/New Zealand	1	Genetic testing not performed	-Asymptomatic	-K+/Mg+2 replacement -Amiloride
Suria M. et al. (2023)	Conference paper – Case report/Malaysia	1	Genetic testing not performed	-Bilateral lower limp weakness -Vomiting -Persistent Tachycardia -In-utero fetal death	-IV K+ replacement
Sarwal A. & Abraham J. (2023)	Conference paper – Case report/USA	1	Genetic testing not performed	-Asymptomatic	-IV & PO K+ replacement
Gonuguntla S. et al. (2024)	Conference paper – Case report/USA	1	Genetic testing not performed	-Preeclampsia	-Conservative management (no further description) -C-section at 34 weeks
Valiveti D. et al. (2025)	Original article - Case report/USA	1	Genetic testing not performed	-Paresthesia/lethargy -Generalized weakness -Pedal edema	-IV & PO K+/Mg+2 replacement
Cecchini A. et al. (2025)	Conference paper - Case report/USA	1	Genetic testing not performed	-Preeclampsia	-IV K+ replacement -IV Magnesium sulfate -Labetalol -Amiloride -Urgent labor at 34 weeks
Chothia M. & Ndinya F. (2025)	Original article – Case report/South Africa	1	Genetic testing not performed	-Visual disturbancies -Lower abdominal pain -Bilateral lower limb burning sensation -Nephrotic syndrome (1m before) -Preeclampsia	-IV & PO K+ replacement -Doxazocin, labetalol and amlodipine -IV Magnesium sulfate -Urgent labor at 37 weeks
J.D. Tse et al. (2025)	Original article – Case report/USA	1	Genetic testing did not reveal known mutations	-Nausea/Vomiting	-Nifedipine -PO K+/Mg+2 replacement
Current paper (2025)	Original article - Case report and literature review/Greece	1	Genetic testing did not reveal known mutations	-Muscle weakness -Rhabdomyolysis -Nephrogenic DI -Bilateral lower extremity edema	-IV K+/Mg+2 replacement -Methyldopa -Amiloride

^aAll the patients presented hypertension and hypokalemia during pregnancy.

^bThe typical manifestations of Geller syndrome during pregnancy were described in two women S810L carriers that underwent 5 gestations. In total 11 family members carried the mutated NR3C2 gene.

Nephrogenic DI and rhabdomyolysis which were profound in our case, have been previously described once as a complication of severe hypokalemia [19]. Early-onset hypertension despite originally described as a typical feature of the syndrome was only present in one case in the literature [1,25]. Lower limb weakness and mild bilateral edema were the most common clinical features described in the literature, presenting in 29.4 % (5/17) [19,21,24,27]and 41.2 % (7/17) of the cases respectively [18,[20], [21], [22],24,25]. Preeclampsia was diagnosed in four patients (23.5 %) and was a determinant factor for urgent delivery [20,22,29,30]. Of note, this was also considered in the case of our patient, particularly on the grounds of severe proteinuria, for whom a watch-and-wait approach with close obstetric follow-up was opted for. Given that gestational hypertension is a hallmark of Geller syndrome and may resolve with effective treatment using amiloride, clinicians should carefully reassess the diagnosis of preeclampsia in suspected cases to avoid unnecessary interventions, potentially leading to adverse fetal outcomes [31]. Central nervous system-related complications, namely visual disturbances, headaches and lethargy, were described in 3 patients (17.6 %) [[20], [21], [22]]. Nausea and vomiting were present in two cases (11.8 %) [23,27]. One patient experienced in-utero fetal death, possibly related to the decompensated state caused by persistent hypokalemia and hypertension [27]. Two patients (11.8 %) were completely asymptomatic and the typical features of the syndrome were found during their routine follow-up of gestation [26,28].

Most patients received symptomatic treatment during pregnancy, including potassium supplementation and antihypertensive medications. Urgent delivery was reported in 4 patients (23.5 %) as a complication of the syndrome [20,22,29,30]. Notably amiloride was administered in only 5/17 patients (29.4 %) [19,24,26,30], and among them, only one required urgent delivery [30].

Of the 17 reported cases, 13 (76.4 %) originated from the United States, with one case each reported from South Africa [22], New Zealand [26] and Malaysia [27]. To our knowledge this is the first report of Geller syndrome in Europe. Genetic testing confirmed the diagnosis only in the original cases described by Geller et al. Most subsequent reports indicated that genetic testing was unavailable, while in one case, the results were still pending [25] and in another the genetic testing was negative, despite the typical clinical presentation of the syndrome [23]. Of note, a study investigating genetic variability in patients clinically diagnosed with Bartter syndrome type 3, but lacking typical pathogenic variants in the CLCNKB gene, identified a likely pathogenic variant in the NR3C2 gene (A951V) in a male patient from Spain, who was born prematurely due to his mother's preeclampsia with severe, uncontrolled hypertension, indicating a possible Geller syndrome [32].

Despite genetic testing is valuable in confirming the diagnosis, it may not always be accessible or positive for the S810L mutation. Since genetic testing has been reported in only a few cases, mostly from the United States, there is a lack of comprehensive characterization of the genetic background of the syndrome. Consequently, it can be speculated that alternative genetic variants or epigenetic mechanisms as mentioned above, may contribute to the syndrome's manifestations in different populations. Broader recognition of the clinical syndrome and expanded genetic analysis are of value to uncover such factors.

In conclusion, this case highlights the importance of considering Geller syndrome in pregnant women presenting with hypertension and hypokalemia, even in the absence of confirmatory genetic testing. The early recognition of the syndrome is essential, as prompt administration of Amiloride, a diuretic that inhibits the ENaC channel and is considered the treatment of choice, can prevent unnecessary interventions and reduce the risk of pregnancy-related complications.

CRediT authorship contribution statement

Efstratios Gavriilidis: Writing – original draft. Christina Antoniadou: Writing – original draft. Georgia Dimopoulou: Investigation, Data curation. Evangelos Papadimitriou: Writing – review & editing. Stefania-Aspasia Bakola: Writing – review & editing, Data curation. Charalampos Papagoras: Writing – review & editing, Supervision. Panagiotis Skendros: Writing – review & editing, Supervision. Dimitrios Tsilingiris: Writing – review & editing, Conceptualization.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

Our manuscript has no associated data.