Identification of a novel large deletion mutation in the AVPR2 gene responsible for hereditary nephrogenic diabetes insipidus in an infant: a case report

Abstract

Background

Hereditary nephrogenic diabetes insipidus (HNDI) type1 is a rare genetic disorder that results from mutations in the AVPR2 gene, which encodes the arginine vasopressin receptor 2. The primary clinical manifestations of this disorder encompass polydipsia, polyuria and urine with low specific gravity. At present, there is no curative treatment, and the principal treatment goal is to manage symptoms in order to prevent complications such as dehydration, brain injury, and hydroureteronephrosis.

Case Description

This case report presents a 7-month-old boy who presented with persistent low-grade fever that could not be explained by common infections, rheumatological and immunological diseases and other etiologies, resulting in difficulties in diagnosis and poor treatment outcomes. However, through a comprehensive review of the medical history and meticulous screening of laboratory tests, it was discovered that the child exhibited polyuria and low-specific-gravity urine, accompanied by a family history indicating polydipsia and polyuria. Following fluid replacement and oral administration of hydrochlorothiazide, the fever abated. Whole-exome sequencing disclosed a copy-number deletion of approximately 2.046 kb at Xq28, which entailed the deletion mutation of exons 3–4 of the haploinsufficient gene AVPR2. This was expected to lead to nonsense-mediated decay, and finally, the diagnosis of HNDI type1 was confirmed.

Conclusions

The primary clinical manifestation of this case is fever, which underscores the atypical symptoms of nephrogenic diabetes insipidus during infancy. It also emphasizes the necessity of considering the potential for dehydration fever caused by diabetes insipidus when diagnosing fever of unknown origin. Furthermore, in this case, the copy number variation of the AVPR2 gene was successfully identified via whole-exome sequencing technology. A novel large-fragment deletion mutation was discovered, which broadens the mutation spectrum of the AVPR2 gene and substantially enhances the diagnostic accuracy.

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Key findings

• This case report describes a 7-month-old male infant diagnosed with hereditary nephrogenic diabetes insipidus resulting from a large-fragment deletion mutation in the AVPR2 gene. The most notable clinical manifestation was fever.

What is known and what is new?

• Hereditary nephrogenic diabetes insipidus Type I is a rare genetic disease caused by mutations in the AVPR2 gene. Its primary clinical manifestations include polydipsia, polyuria, and urine with low specific gravity. Currently, there is no curative treatment available. In the event of dehydration, patients may experience dehydration fever. The primary objective of clinical therapy is to manage symptoms and prevent and treat complications such as dehydration, brain injury, and hydronephrosis.

• This case reports a novel deletion mutation in the AVPR2 gene, which is expected to cause nonsense-mediated mRNA decay, thereby expanding the spectrum of genetic alterations.

What is the implication, and what should change now?

• In infants and young children, the clinical manifestations of hereditary nephrogenic diabetes insipidus can be non-specific or insidious, making it easy to confuse with other common diseases. This case highlights the importance of considering diabetes insipidus in the differential diagnosis when encountering a fever of unknown origin, so that appropriate treatment measures can be taken in a timely manner. If necessary, genome sequencing should be employed to determine the possibility of a hereditary cause.

Introduction

The kidneys maintain fluid and electrolyte homeostasis by precisely regulating the volume and composition of urine. The collecting duct modulates its water permeability in response to arginine vasopressin (AVP). Upon binding to the AVPR2 on collecting duct principal cells, AVP triggers an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. This activates cAMP-dependent protein kinase, leading to the phosphorylation and subsequent translocation of aquaporin-2 (AQP2). AQP2 molecules are then inserted into the apical membrane of the collecting duct, facilitating water reabsorption and urine concentration (1). Nephrogenic diabetes insipidus (NDI) results from the kidney’s impaired responsiveness to AVP, leading to diminished water reabsorption and the production of large volumes of dilute urine. The disorder is categorized into hereditary and acquired forms. Hereditary NDI (HNDI) is primarily caused by mutations in the AVPR2 or AQP2 genes.

In pediatric patients, the predominant form of NDI is HNDI, a rare genetic disorder. Approximately 90% of HNDI cases are classified as type I (MIM #304800) and are caused by mutations in the AVPR2 gene located in the Xq28 region of the X chromosome (2). The condition follows an X‑linked recessive inheritance pattern, primarily affecting males. However, due to skewed Xchromosome inactivation, some female carriers may also exhibit symptoms (3). To date, the ClinVar database has reported more than 600 distinct mutations of the AVPR2 gene, including 46 likely pathogenic mutations and 325 pathogenic mutations. The common types of variation are deletion and duplication, and the common molecular consequences are missense mutations and frameshift mutations (Table 1). The AVPR2 protein belongs to the G‑protein‑coupled receptor (GPCR) superfamily. Based on functional studies of over 30 variants, mutations in the AVPR2 gene lead to protein defects that are primarily categorized into the following five types:

Table 1. Pathogenic and likely pathogenic mutations of AVPR2 gene mutations reported in the ClinVar database and the mutation reported in this report.

Characteristic	ClinVar database		This report
	Classification	Number of mutations
Germline classification	Likely pathogenic	46	√
	Pathogenic	325
Variation type	Deletion	150	√
	Duplication	145
	Indel	1
	Insertion	25
	Single nucleotide	63
Molecular consequence	Frameshift	37
	Missense mutations	45
	Nonsense	16	√
	Splice site	4
	ncRNA	58
	UTR	13

ncRNA, non-coding RNA; UTR, untranslated regions.

• ❖ Class I variants result in reduced, truncated, or absent protein expression due to aberrant transcription or translation.

• ❖ Class II variants are misfolded, leading to defective intracellular trafficking and subsequent accumulation in the endoplasmic reticulum, preventing their reach to the cell surface.

• ❖ Class III variants impair downstream signal transduction.

• ❖ Class IV variants reach the cell surface but exhibit impaired ligand-binding capacity, failing to induce normal cAMP production.

• ❖ Class V variants, which do not fall into the above categories, are characterized by abnormal translocation to other organelles.

The majority of AVPR2 mutations lead to Class II mutant receptors (4).

The impairment in urinary concentrating ability among patients with HNDI exists from birth. Clinical symptoms typically manifest within the first week of life, and most affected individuals are diagnosed before the age of 3 years. Common manifestations include irritability, feeding difficulties, and failure to thrive. There is a significant risk of severe dehydration under conditions of inadequate water intake or in hot environments (5). For neonates and infants, clinical vigilance and genetic testing are essential. A diagnosis of HNDI should be strongly suspected in the presence of low-grade fever, feeding intolerance, irritability, polydipsia, polyuria, along with laboratory abnormalities such as persistent hypernatremia, elevated plasma osmolality, and low urine osmolality, especially when a positive family history is noted (6). Genetic analysis is recommended in such cases.

This report describes a 7-month-old boy who presented with persistent fever. Polyuria presented insidiously, leading to a challenging diagnostic process. This case highlights the importance of considering diabetes insipidus (DI) even when fever is the predominant symptom. A detailed family history revealed suspected hereditary patterns of the disease (Figure 1). Whole-exome sequencing identified a 2.046 kb copy number deletion at Xq28, affecting exons 3–4 of the haploinsufficient AVPR2 gene, which is predicted to cause nonsense-mediated decay. Ultimately, the patient was diagnosed with HNDI. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-924/rc).

Figure 1.

Pedigree of the family with congenital nephrogenic diabetes insipidus. Squares represent males; circles represent females. Black and white symbols represent clinically affected and unaffected individuals, respectively. The arrow represents the proband.

Case presentation

This case involves a 7-month-old boy who presented with a 1-month history of fever. He was born full-term via spontaneous vaginal delivery and has a history of thalassemia. There was no history of animal exposure or tuberculosis. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the parents of the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

The patient presented with a 1-month history of fever, with a peak temperature of 40 ℃. It was not accompanied by any respiratory symptoms or gastrointestinal symptoms. Nasopharyngeal swab tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After 3 days of symptomatic treatment, his fever decreased to low-grade and persisted for over 10 days without any other discomfort. He was then hospitalized at a tertiary care hospital. Routine blood tests and acute-phase proteins showed no significant elevation. Viral polymerase chain reaction (PCR) tests for adenovirus, respiratory syncytial virus, influenza A/B, parainfluenza virus, and mycoplasma pneumoniae were negative. Blood cultures showed no growth of bacteria. Thyroid function tests revealed normal results. Immunoglobulin levels were mildly decreased. Chest X-ray, electrocardiogram, echocardiography, abdominal ultrasound and head MRI revealed no significant abnormalities. He received sequential intravenous antibiotic therapy with vancomycin for 4 days followed by cefoperazone for 2 days, along with intravenous immunoglobulin (IVIG) therapy. The symptom of fever continued to persist, leading to his transfer to our institution.

Upon repeat assessment, the acute phase inflammatory markers remained within normal limits, including white blood cell and neutrophil counts, C-reactive protein (CRP), procalcitonin (PCT), and erythrocyte sedimentation rate (ESR). Most liver and renal function parameters were within the normal range. Bicarbonate level was decreased at 14.5 mmol/L, while mild elevations were noted in sodium (145.2 mmol/L; reference range, 136–145 mmol/L), chloride (110.3 mmol/L; reference range, 99–110 mmol/L), and magnesium (1.03 mmol/L; reference range, 0.70–0.95 mmol/L). Potassium, calcium, and phosphorus levels were normal. No detection of SARS-CoV-2 RNA was observed. Fungal markers including (1,3)-β-D-glucan and galactomannan were negative, and the T cell enzyme-linked immunospot assay for tuberculosis (T-SPOT.TB) assay showed no reactivity. Targeted next-generation sequencing (NGS) pathogen detection in blood returned negative results. Urinalysis indicated hyposthenuria with a specific gravity of 1.005. Urine bacterial culture was negative. Stool routine examination and culture were unremarkable.

The patient continued to experience low-grade fever after admission but was well-feeding and remained in good spirits, without respiratory, gastrointestinal, or other systemic symptoms or signs. Based on clinical data from both external hospitals and our own hospital, the initial high fever was likely associated with SARS-CoV-2 infection. However, the subsequent persistent fever lacked evidence of ongoing infection: complete blood count and acute-phase inflammatory markers were repeatedly within normal limits, and extensive pathogen testing, including blood NGS, returned negative. Empirical treatment with antibiotics and antifungals (including voriconazole, cefoxitin, and azithromycin) showed no improvement. No clinical or laboratory findings suggested rheumatic disease or malignancy, such as bone or joint pain, limited mobility, elevated ESR, or hyperglobulinemia. Notably, urinalysis showed hyposthenuria (specific gravity 1.005), and simultaneous electrolyte analysis revealed mild hypernatremia. Upon further inquiry, the family reported polyuria, which had led to intentional fluid restriction. The patient’s mother and maternal grandfather also had histories of polydipsia and polyuria without diabetes, though they had never been evaluated for DI. These findings raised suspicion for dehydration fever secondary to DI. Further workup revealed that the serum osmolality was 286 mOsm/kg and the urine osmolality was 73 mOsm/kg, indicating hypotonic urine (osmolality <300 mOsm/kg). Urine electrolyte analysis showed that sodium, potassium, chloride, calcium, and magnesium were within normal ranges; phosphorus and creatinine levels were low. Based on the patient’s presentation with polydipsia and polyuria, a positive family history, hypotonic urine, and paradoxically mild hypernatremia, a clinical diagnosis of hereditary diabetes insipidus was established. The fever resolved after fluid replacement and oral hydrochlorothiazide administration. Whole-exome sequencing was performed and revealed a ~2.046 kb copy-number deletion in the Xq28 region, involving exons 3–4 of the AVPR2 gene. Predictions of the pathogenicity of the variant by using REVEL, SIFT, PolyPhen-2, MutationTaster, and GERP++ indicated that it was likely pathogenic. The deletion was heterozygous in the patient’s mother and absent in the patient’s father (Table 2, Figure 2). A definitive diagnosis of HNDI was made. The family was advised to attend regular outpatient follow-ups.

Table 2. Mutation information of the AVPR2 gene in the patient.

Gene	Chromosome locus	Nucleotide and amino acid change	Pathogenicity analysis	The mode of inheritance	Parent of origin
AVPR2	Xq28	g.153171370_153173416del	Likely pathogenic	X-linked	Patient’s mother

Figure 2.

The whole-exome sequencing followed by Sanger validation. There is a large deletion of approximately 2.046 Kb at Xq28 (chrX: 153171370-153173416), which has been confirmed that this mutation is inherited from the patient’s mother.

Discussion

HNDI is predominantly caused by mutations in the AVPR2 gene, which encodes the AVP receptor. It has an estimated prevalence of 1 in 150,000–250,000 (2,7,8). Despite being a rare genetic disorder, HNDI can exert a significant impact on the growth and neurodevelopment of children. Early recognition and intervention can notably improve the long-term prognosis (9). The most prominent clinical manifestations of NDI are polydipsia, polyuria, and urine with low specific gravity. Polyuria is defined as a urine output exceeding 150 mL/kg/24 h in neonates, 110 mL/kg/24 h in infants under 2 years, and 50 mL/kg/24 h in children older than 2 years (6). However, the symptoms of polydipsia and polyuria are often subtle and may remain unrecognized or be underestimated by caregivers. As illustrated in the present case, the family noticed an increase in urine output but did not recognize it as a sign of disease. As a result, they failed to proactively inform the medical staff and made the dangerous decision to restrict fluid intake. Furthermore, children affected may exhibit non-specific clinical manifestations, such as feeding difficulties, dehydration-induced fever, vomiting, nausea, irritability, and lethargy (10-12). A delayed diagnosis may lead to persistent polyuria or inadequate fluid intake, which can result in chronic dehydration and hypernatremia. Acute severe hypernatremia, due to rapid osmotic shifts, can cause acute cerebral shrinkage, which elevates the risk of intracranial hemorrhage, seizures, or coma. The long-term consequences include risks of brain injury and developmental delay. Another significant complication that needs to be considered is the development of urinary tract dilation and hydronephrosis, which is associated with high-volume diuresis and potential bladder dysfunction (13).

In the current case, the most prominent clinical manifestation was fever, which presented a significant diagnostic challenge, as initial diagnostic considerations usually prioritize more common entities such as infectious, autoimmune, or neoplastic diseases. During the screening process for these etiologies, it is essential to conduct a careful and astute interpretation of laboratory findings. When neither the clinical presentation, laboratory results, nor response to empirical antimicrobial therapy supported the presence of an infectious or inflammatory process, we re-evaluated the data and identified the paradoxical combination of hyposthenuria and hypernatremia, which redirected our focus to DI as the underlying cause.

Key laboratory investigations for DI include serum electrolytes, glucose, creatinine, blood urea nitrogen, serum and urine osmolality, urinalysis, and AVP levels. A urine osmolality below 200 mOsm/kg in the setting of serum osmolality exceeding 300 mOsm/kg is indicative of nephrogenic DI. Elevated serum sodium levels (>143 mmol/L), in the absence of excessive sodium intake and accompanied by low urine specific gravity, strongly suggest the presence of DI. Plasma AVP is a diagnostically meaningful biomarker for differentiating central DI from nephrogenic DI. However, its clinical applicability is restricted owing to a short half-life. Copeptin, the C-terminal segment of the AVP precursor, has emerged as a more stable surrogate marker (14). The water deprivation test remains to serve as the gold standard method for diagnosis and classification of DI (15,16). Nevertheless, it is contraindicated in cases with hypernatremia (serum sodium >146 mmol/L). The simultaneous presence of hypernatremia and hypotonic urine obviates the need for this test, as it itself is diagnostic of a defect in water homeostasis (17). When DI is suspected, it is essential to obtain a detailed family history, since both central and nephrogenic forms of DI can result from hereditary as well as acquired causes (18). In the present case, a positive family history was documented. In this patient, whole-exome sequencing identified a copy-number variation in the AVPR2 gene, significantly enhancing diagnostic accuracy. Specifically, a large deletion, which is a novel mutation that has not been reported previously, was detected. This deletion is expected to lead to nonsense-mediated decay and may be associated with a more severe disease phenotype (19).

The management of DI focuses on ensuring adequate fluid intake and a low-sodium diet. Dehydration caused by a deficit of free water, which can be attributed to either inadequate intake or excessive losses via urine, feces, or perspiration, should be corrected using 2.5% dextrose in water or quarter-normal saline. In instances of significant hypernatremia, the serum sodium concentration must be closely monitored, and the rehydration regimen should be adjusted to prevent a decrease exceeding 0.5 mmol/L per hour, as rapid correction in plasma sodium can lead to irreversible cerebral injury (20). For infants, breastfeeding (approximately 93 mOsm/L) is preferred over standard formula (135–177 mOsm/L) or specialized medical formulas. Among children who consume solid foods, dietary sodium should be restricted (6). For instance, in a patient with a urine osmolality of 100 mOsm/kg, the consumption of each gram of table salt (34 mOsm) leads to an approximate increase of 340 mL in urine output. The recommended daily dietary osmotic load is 15 mOsm/kg, requiring about 150 mL/kg of water for solute excretion. Notably, the recommended protein intake of 3 g/kg/day alone provides approximately 12 mOsm/kg/day, which emphasizes the necessity for stringent sodium restriction (7,21). In addition to dietary measures, pharmacologic therapy may be employed for NDI. Thiazide diuretics have been proven to reduce urine output and increase urine osmolarity in patients with DI. The proposed mechanism is that thiazides initially diminish sodium reabsorption in the distal convoluted tubule, which leads to an increase in sodium excretion. This induces a contraction in extracellular fluid volume, thereby causing a decrease in the glomerular filtration rate (GFR) and an increase in proximal tubular sodium and water reabsorption. Consequently, less water and sodium are delivered to the collecting ducts, and water excretion is reduced. The effect of thiazide diuretics may be attributed to the upregulation of AQP2, the sodium-chloride cotransporter (NCC), and the epithelial sodium channel (ENaC) (22). The recommended starting doses are 1 mg/kg/day of hydrochlorothiazide or 10 mg/kg/day of chlorothiazide. Concomitant sodium restriction (e.g., to 300 mg daily) maximizes the drug’s effect in reducing polyuria. Common side effects include hypokalemia and hypercalcemia. Hypokalemia may be managed with potassium supplementation or the addition of amiloride (23). Indomethacin, a non-selective cyclooxygenase inhibitor, reduces urine output by inhibiting prostaglandin synthesis and enhancing proximal tubular water reabsorption. Its gastrointestinal side effects can be alleviated with proton pump inhibitors. Initiating therapy with a thiazide diuretic and a low-sodium diet (e.g., 0.5 g of NaCl per day) can reduce urine output by up to 70%. Additive effects are observed when this treatment regimen is combined with indomethacin (24). Long-term follow-up should include monitoring of growth and development, periodic measurements of serum sodium to detect latent hypernatremia, and annual renal ultrasonography to identify complications such as urinary tract dilatation.

Conclusions

The diagnostic and therapeutic process of this case emphasizes several critical considerations. Firstly, clinicians encounter a substantial risk of misdiagnosing congenital NDI, especially in pediatric patients. The presenting symptoms are often non-specific, subtle, or readily ascribable to more common childhood illnesses. This situation is also reflected in this case. Second, a detailed family history was proven to be instrumental. The identification of polydipsia and polyuria among family members provided a crucial clue suggesting a possible diagnosis of HNDI. Furthermore, definitive diagnosis was established through comprehensive genetic testing. Whole-exome sequencing revealed a previously unreported large deletion in the AVPR2 gene on the X chromosome, which confirmed the diagnosis of X-linked congenital NDI. The incorporation of genetic testing provided decisive diagnostic support, illustrating the efficacy of precision medicine in modern clinical practice.

Supplementary

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the parents of the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.