Primary hyperaldosteronism in patient with Bardet–Biedl syndrome: unmasking secondary hypertension

Abstract

Summary

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by marked clinical and genetic heterogeneity, classically presenting with retinal dystrophy, obesity, polydactyly, renal dysfunction, and hypogonadism. Although arterial hypertension is frequently observed in affected individuals, it is not currently included in diagnostic criteria and remains insufficiently studied. We report the case of a 35-year-old man with clinically diagnosed BBS who developed severe, treatment-resistant hypertension and hypokalaemia. A comprehensive endocrine evaluation revealed primary hyperaldosteronism, confirmed by an elevated aldosterone-to-renin ratio, saline suppression testing, and imaging evidence of a unilateral adrenal adenoma. Laparoscopic adrenalectomy resulted in normalization of potassium levels and a significant improvement in blood pressure control. This case illustrates the complex interplay between BBS-related renal, metabolic, and neuroendocrine dysfunction and secondary endocrine causes of hypertension. Existing evidence suggests that BBSome dysfunction may be associated with alterations in metabolic and cardiovascular regulation; however, its relationship with aldosterone-producing adenomas remains uncertain. The coexistence of BBS and primary aldosteronism may be coincidental; however, shared molecular pathways cannot be excluded. To the best of our knowledge, this is the first reported case of primary aldosteronism caused by an aldosterone-producing adrenal adenoma in a patient with BBS. This report highlights the importance of a thorough evaluation for secondary hypertension in BBS patients and underscores the need for further research into the pathophysiological links between ciliopathies and endocrine hypertension.

Learning points

• Patients with Bardet–Biedl syndrome may develop hypertension at an early age; therefore, regular blood pressure monitoring is recommended.

• Multiple factors may contribute to hypertension in these patients, including obesity, renal abnormalities, endocrine disorders, and the hypothetical contribution of BBSome dysfunction.

• A targeted evaluation for secondary causes of persistent hypertension in patients with BBS is essential and should include screening for primary hyperaldosteronism.

Background

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by marked clinical and genetic heterogeneity, caused by mutations in genes encoding components of the BBSome, a protein complex essential for ciliary and neuronal signalling. More than 21 causative genes have been identified, with an estimated prevalence in Europe of 1:125,000–160,000. The syndrome classically presents with retinal dystrophy, postaxial polydactyly, obesity, renal abnormalities, cognitive impairment, and hypogonadism, with retinal degeneration affecting up to 90% of patients during childhood. Central nervous system involvement is a key feature of BBS. Experimental data indicate that BBSome dysfunction in hypothalamic neurons disrupts leptin and steroidogenic factor 1-mediated signalling, leading to altered sympathetic nervous system (SNS) activity, obesity, and abnormalities in blood pressure regulation. Although arterial hypertension is frequently observed in patients with BBS, it is not included in current diagnostic criteria and remains poorly characterized. This case is clinically important as it describes a rare and diagnostically challenging association between BBS and primary hyperaldosteronism. The coexistence of these conditions raises the possibility of shared neuroendocrine and genetic mechanisms contributing to severe hypertension in BBS, but these have not been proven and further studies are needed.

Case presentation

We present the case of a 35-year-old male diagnosed with BBS and adolescent-onset hypertension, which had previously been well managed with enalapril 5 mg once daily until the current presentation.

The patient was born via caesarean section following an uncomplicated second pregnancy, and he has a healthy older sister. Postaxial polydactyly affecting all four limbs was observed at birth and surgically corrected in early childhood.

At age 10, the patient was diagnosed with pigmentary retinitis, initially manifesting as nyctalopia, which subsequently progressed to complete blindness.

In conjunction with retinal dystrophy, the patient during childhood exhibited intellectual disability (IQ: 70; normal range: 90–109), predominantly abdominal obesity, impaired glucose tolerance, and hypogonadism associated with bilateral cryptorchidism. A clinical diagnosis of BBS was established based on the presence of five cardinal features: polydactyly, retinal dystrophy, intellectual disability, obesity, and hypogonadism, although genetic confirmation was not obtained (1).

At age 35, the patient presented with new-onset weakness in both the upper and lower right extremities, accompanied by bilateral nystagmus, which necessitated his admission to the neurology department. Electromyography revealed motor neuron involvement, while brain computed tomography returned unremarkable results. During his stay in the neurology clinic, the patient’s daytime blood pressure averaged approximately 170/90 mmHg. Antihypertensive therapy was progressively intensified, with the sequential addition of torasemide, nebivolol, olmesartan/amlodipine, and spironolactone. An SGLT2 inhibitor was also initiated to address chronic kidney disease, and the patient continued to be monitored in the outpatient clinic. Over the subsequent months, blood pressure remained uncontrolled, and hypokalaemia was subsequently detected. Consequently, the patient was referred to the Internal Medicine Clinic for further evaluation.

Upon examination in the Internal Medicine Clinic, the patient presented in poor condition, exhibiting complete blindness, bilateral brachial plexopathy, and right-sided flaccid upper-limb paresis. The examination findings included macrocephaly, narrow palpebral fissures, nystagmus, large auricles, and a high-arched palate. Additionally, he displayed brachydactyly and clinodactyly in the upper limbs, as well as brachydactyly and syndactyly of the second and third toes on the left foot. Cardiopulmonary examination findings were unremarkable.

Investigation

Laboratory tests revealed a normal blood count and liver function. Renal function was impaired, consistent with chronic kidney disease stage G3bA1. Antihypertensive therapy was adjusted to include an α-blocker and a non-dihydropyridine calcium channel blocker. Plasma aldosterone–renin ratio (ARR) testing was performed following recommended protocols, and biochemical confirmation was obtained with a saline suppression test (2 L of 0.9% sodium chloride infused over four hours; see Table 1). Due to the patient’s deteriorating condition, adrenal venous sampling (AVS) was not performed. Imaging examinations included an abdominal CT scan (Fig. 1). Electrocardiogram and chest radiograph were unremarkable. Transthoracic echocardiography demonstrated normal left ventricular dimensions and preserved systolic function without valvular pathology (Fig. 2A). Renal ultrasound showed fetal lobulation, a feature consistent with BBS, and multiple small peripelvic and parenchymal cysts up to 1–1.5 cm in diameter, with no evidence of calculi or obstructive drainage abnormalities (Fig. 2B).

Table 1.

Laboratory tests.

Laboratory tests	Measured value	Reference range
Urea (mmol/L)	10.2	3.2–7.3
Creatinine (µmol/L)	164	20–110
eGFR (mL/min/1.73 m2)	41.4	>60
Ca (mmol/L)	2.29	2.12–2.62
Mg (mmol/L)	0.81	0.70–0.95
Na (mmol/L)	141	135–145
K (mmol/L)	3.11	3.5–5.6
Cholesterol (mmol/L)	3.44	≤5
LDL (mmol/L)	2.03	<2.6
TG (mmol/L)	0.76	<1.7
HDL (mmol/L)	1.06	>1.55
Cortisol 08:00 am (nmol/L)	603	145.4–619.4
Cortisol 10:00 pm (nmol/L)	184.3	94.9–462
TSH (IU/mL)	2.99	0.27–4.2
FT4 (pmol/L)	17.4	10.3–24
Anti-TPO (U/mL)	30.5	0–24
LH (mU/mL)	13.2	0.8–7.6
FSH (mU/mL)	45.2	0.7–11.1
Testosterone (nmol/L)	5.03	9.9–52.4
DHEAS (µmol/L)	0.75	2.17–15.2
HOMA-IR	1.1
IGF-1 (ng/mL)	107	63–223
ACTH (pg/mL)	19.2	0–46
PTH (pg/mL)	37.6	11–87
OGGT 0 min glucose (mmol/L)	6.6
OGGT 120 min glucose (mmol/L)	8.4
Aldosterone (pmol/L), 08:00 am	2,270
Upright		600–980
Supine		30–650
Renin (IU/mL), 08:00 am	1.57
Upright		4.4–46.1
Supine		2.8–39.9
Aldosterone–renin ratio	1 443	0–80
Aldosterone (pmol/L), level post-saline	1 540	<171 (post-saline cut-off)

Figure 1.

An abdominal CT scan revealed a left adrenal adenoma measuring 23 × 18 mm, with a native density of 7 Hounsfield units.

Figure 2.

(A) Transthoracic echocardiography. (B) Abdominal ultrasound.

Treatment

The patient underwent laparoscopic adrenalectomy, and histological examination confirmed a benign aldosteronoma.

Outcome and follow-up

Blood pressure decreased after the intervention, causing a gradual reduction in the number of medications. His regimen comprised nebivolol 5 mg and amlodipine 10 mg daily at the sixth month. Hypokalaemia was resolved within days, and the postoperative course was uneventful, indicating successful treatment of hyperaldosteronism. Over the following year, his neurological symptoms worsened owing to progression of BBS rather than the surgical intervention. Although he had received optimal treatment for secondary hypertension, he died two years later from progressive neurological impairment.

Discussion

Arterial hypertension is a significant yet poorly understood aspect of BBS, currently not included in the diagnostic criteria. Clinical observations indicate that patients with BBS often develop hypertension early in the course of the disease potentially due to renal impairment, obesity, and endocrine abnormalities. Data from genome-wide association studies suggest that BBS gene variants may contribute to hypertension in affected individuals and the general population (1). Preliminary experimental data indicate that the BBSome complex participates in systems relevant to cardiovascular regulation, including baroreceptor mechanisms and the renin–angiotensin–aldosterone axis (2). A study by Mujahid et al. involving 152 subjects with BBS showed that systolic blood pressure is significantly higher in BBS patients compared with age- and sex-matched controls. Furthermore, patients with BBS were reported to be approximately eight times more likely to develop hypertension than their non-affected family members. These findings have prompted some authors to consider hypertension a prominent phenotypic feature of the syndrome (3). Our patient was diagnosed with mild hypertension in early adolescence. We should explicitly emphasize that the novelty of this case lies in the presence of BBS-associated arterial hypertension, further exacerbated by newly diagnosed primary hyperaldosteronism. Diagnosis of BBS was based on established clinical criteria referenced in current guidelines (4); however, the absence of genetic testing represents a significant limitation. Several plausible mechanisms may contribute to the increased prevalence of hypertension in BBS. Ciliary dysfunction in endothelial and vascular smooth muscle cells, secondary to BBSome defects, may impair mechanosensory signalling and vascular responsiveness, thereby perturbing vascular tone (5). Additionally, obesity, affecting over 70% of BBS patients, is another major factor in arterial hypertension. In obesity, adipose-derived adipokines and cytokines can upregulate CYP11B2 (aldosterone synthase) in adipocytes, potentially promoting local aldosterone synthesis (6). In addition to aldosterone, adipocytes secrete numerous factors, including components of the renin–angiotensin system, that may stimulate aldosterone secretion from adrenocortical cells. Excess aldosterone promotes sodium retention, haemodynamic overload, and renal structural and functional injury and may promote progression to chronic kidney disease and adverse cardiovascular outcomes. Renal involvement is common in BBS and significantly contributes to morbidity and mortality. Up to 82% of patients exhibit structural or functional kidney anomalies, often manifesting early and sometimes progressing to end-stage renal disease requiring dialysis or transplantation (7). Leptin, an adipocyte-derived hormone that signals the energy stored to the hypothalamus, plays a central role in obesity pathophysiology, and leptin receptors are highly expressed in hypothalamic neurons. Preliminary data suggest that impaired BBSome-dependent trafficking of leptin receptors could alter hypothalamic regulation of appetite, energy expenditure, and sympathetic tone, which may influence blood pressure homeostasis (8). The ventromedial hypothalamic nucleus plays a crucial role in metabolic regulation, energy homeostasis, and blood pressure control. Its neurons express steroidogenic factor 1 (SF-1) and are influenced by the BBSome.

Primary hyperaldosteronism is the most common cause of secondary hypertension in general population. Approximately 30% of cases are due to aldosterone-producing adenomas. Despite compelling clinical observations of an increased prevalence of arterial hypertension in patients with BBS, existing evidence remains largely associated and does not establish causality. Mechanistic hypotheses, including ciliary dysfunction in endothelial and vascular smooth muscle cells, impaired BBSome-mediated regulation of leptin receptors, and potential modulation of SF-1-dependent CYP11B2 expression, are biologically plausible but require independent experimental validation. The absence of genetic confirmation in this patient limits our ability to distinguish different causes of hypertension. These data suggest that the coexistence of BBS and PA is likely coincidental.

In conclusion, the clinical phenotype of BBS is multifactorial, with obesity and renal dysfunction constituting powerful confounders that can both mediate and amplify the impact of BBSome dysfunction on blood pressure. To clarify these relationships, prospective cohort studies with integrated genetic analysis are needed. It is imperative to emphasize the need for investigating secondary causes of hypertension, including primary aldosteronism, in patients with BBS who present with resistant hypertension and/or hypokalaemia.

Declaration of interest

The authors declare that they have no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

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

Patient consent

Written informed consent for publication of clinical details and clinical images was obtained from a relative of the patient.

Author contributions statement

ЕМ performed the literature search and wrote the abstract and discussion. SL performed the literature search. TsvT wrote case presentation. MD collected the data. EM was the physician in charge of the patient, and she gave permission to other authors to contribute to the case report.