Hyperparathyroidism—Jaw Tumor Syndrome: A Rare Case Report and Literature Review

ABSTRACT

Prompt identification of Hyperparathyroidism‐Jaw Tumor Syndrome (HPT‐JT) is vital, particularly for those with a family history or unusual symptoms like progressive facial changes. By employing a thorough diagnostic strategy that includes biochemical tests, imaging, and genetic analysis, we can achieve early diagnosis and effective intervention. In this case, the patient displayed maxillofacial tumors, hypercalcemia, and increased parathyroid hormone levels. Imaging confirmed a parathyroid adenoma, while histopathology showed characteristics of brown tumors. Subtotal parathyroidectomy is the recommended treatment. Additionally, regular follow‐ups every 6 months involving biochemical tests and imaging are crucial for ensuring the best patient outcomes.

1. Introduction

Hyperparathyroidism‐jaw tumor syndrome (HPT‐JT) is a rare autosomal dominant disorder caused by germline mutations in the CDC73 gene, which encodes the tumor‐suppressing protein parafibromin [1]. It primarily manifests as primary hyperparathyroidism (pHPT), often the first clinical sign, typically due to single‐gland involvement, with an approximately 20% risk of parathyroid carcinoma—higher than in other hereditary hyperparathyroidism variants [2, 3]. The syndrome is frequently complicated by the development of ossifying fibromas of the jaw, leading to facial swelling and disfigurement, as well as renal lesions, including cysts and tumors, which can impair renal function [4, 5, 6]. Women with HPT‐JT may experience uterine pathologies, such as endometrial polyps, contributing to infertility. Since its identification in the 1950s, over 200 cases have been reported [7]. Severe hypercalcemia is managed surgically, with more extensive procedures required in cases of parathyroid carcinoma [3]. Given its significant morbidity and malignancy risks, early diagnosis and comprehensive management are crucial. Here, we describe a patient who presented with multiple jaw swellings and was subsequently diagnosed with HPT‐JT.

2. Case Presentation

A 42‐year‐old female of African descent presented to the outpatient department of general surgery with a 10‐year history of progressive facial disfigurement. This was attributed to the development of multiple maxillary and mandibular swellings, which had manifested insidiously over time. Her medical history included prior treatment for uterine fibroids via myomectomy and internal fixation for a femoral fracture. Additionally, there was a family history of similar health issues; her late mother also suffered from uterine fibroids and an undiagnosed early‐onset muscle weakness.

Upon examination of the oral cavity, a maxillary swelling measuring 3 × 2 cm² was noted on the left side, extending from the maxillary body to the alveolar process, disrupting normal dentition. On the right side, a more extensive mandibular swelling measuring 4 × 4 cm² was observed at the angle of the mandible, extending both superiorly and laterally to involve both the ramus and body of the mandible, as shown in Figure 1. Neither swelling elicited pain, restricted movements, nor exhibited tenderness upon touch. The patient's weight was recorded at 68 kg, with a height of 167 cm, and the remainder of the physical examination was unremarkable.

FIGURE 1.

Left Hemi‐mandibular swelling. Right: Maxillary swelling.

3. Methods

Biochemical analysis revealed increased serum parathyroid hormone (PTH), calcium, and decreased vitamin D3 (Table 1). CT scan of the face displayed a heterogeneous enhancing soft tissue density lesion involving the ramus and alveolus of the right hemi‐mandible, with another lesion visible at the body of the maxilla, as shown in Figure 2. Parathyroid scintigraphy with technetium (Tc‐99 m‐MIBI) revealed a parathyroid adenoma involving the right lower parathyroid gland.

TABLE 1.

Blood investigations.

Blood tests	Results	Units	Reference ranges
Hemoglobin	8.7	g/dl	11–16
WBCs	9300	u/L	4000–11,000
Platelets	330,000	u/L	150,000–400,000
Prothrombin time	12	s	12
Partial thromboplastin time	32	s	32
Calcium	14.5	mg/dL	8.6–10
Phosphate	2.43	mg/dL	2.5–4.5
Vitamin D	20	nmol/dL	70–250
Parathyroid level	1351	pg/mL	15–65
Thyroid‐stimulating hormone	4.99	uIU/mL	0.35–4.94
Free T3	1.35	ng/mL	0.8–2
Free T4	7.82	ug/dL	5.1–14.1
Alkaline phosphatase level	1786	u/L	35–105

FIGURE 2.

Red arrow: Heterogenous enhancing soft tissue density lesion involving the ramus and alveolus of the right hemi‐mandible measuring 3.4 x 3.1 cm. Yellow arrow: A similar lesion is visible at the body of the left maxilla measuring 2.4 x 1.9 cm.

An incisional biopsy of the maxillary swelling revealed a lesion comprising elongated cells with round to oval nuclei and moderate cytoplasm. Numerous multinucleated giant cells on a background of dense fibro‐collagenous tissue were also observed, as shown in Figure 3. These findings suggested two similar histologic entities: brown tumors and central giant cell granuloma (CGCG). Due to financial constraints, genetic testing for multiple endocrine neoplasia, RET, and CDC73 mutations was not pursued. Considering the underlying hyperparathyroidism, a presumptive diagnosis of HPT‐JT was made, and the patient was scheduled for surgery.

FIGURE 3.

Fibro‐collagenous tissue and trabeculae with sheets of cells with round to oval nuclei. Red arrow: Multinucleated giant cells.

Bilateral neck exploration revealed a single inferior right parathyroid adenoma measuring 3.5 × 2 cm², as shown in Figure 4. Subtotal parathyroidectomy was performed. Post‐operative laboratory tests consistently demonstrated normal serum calcium and serum parathyroid hormone levels. The remainder of her post‐operative recovery was uneventful, and she was discharged. She was referred to maxillofacial surgery for further management of her jaw tumors but was subsequently lost to follow‐up.

FIGURE 4.

Post‐surgical resection of parathyroid adenoma.

4. Discussion

This case was diagnosed as HPT‐JT based on the presence of pHPT accompanied by jaw tumors affecting both the maxilla and mandible, a history of uterine tumors, and a strong familial predisposition. This case is unique due to the rare presentation of brown tumors associated with HPT‐JT.

In HPT‐JT, jaw tumors typically manifest as benign ossifying fibromas, primarily occurring in the mandible or maxilla and frequently appearing in adulthood. Benign ossifying fibromas, the predominant form of jaw tumors, are characterized by a sizable rounded mass visible without magnification [8]. Brown tumors, on the other hand, are observed in less than 3% of patients with pHPT [9]. Both brown tumors and CGCG share similarities, particularly in histopathology, characterized by giant cells. However, the presence of underlying hyperparathyroidism notably favors the diagnosis of brown tumors [10, 11]. These jaw tumors can lead to functional symptoms such as difficulty breathing or may be cosmetically undesirable, with surgical removal remaining the preferred treatment option [12]. Additionally, uterine tumors are frequently observed in conjunction with HPT‐JT [13]. Renal involvement is also noted, albeit less frequently, and commonly presents as cystic kidney disease [14]. Furthermore, some patients may develop rare renal tumors such as Wilms' tumor and mixed‐epithelial stromal tumors [14].

Parafibromin, a protein widely distributed throughout the body, is frequently implicated in HPT‐JT cases. Three‐fourths of individuals exhibit mutations within the gene's coding region, primarily frameshift or nonsense mutations [1, 15]. The penetrance of HPT‐JT syndrome is incomplete, with the severity of clinical manifestations varying based on the type of mutation [16]. Mutations that significantly disrupt protein function are more likely to produce the classic phenotype, whereas missense mutations may lead to atypical presentations [16]. The overall disease penetrance of CDC73 mutations remains poorly understood. However, a study in a Dutch population reported that the risk of developing pHPT increases with age [17].

The recommended diagnostic approach prioritizes genetic testing for CDC73 mutations and thorough screening of all family members, particularly in familial pHPT and early‐onset pHPT and with the occurrence of ossifying jaw fibromas, renal tumors, or uterine tumors [4]. Upon diagnosis, a comprehensive assessment for associated jaw, renal, and uterine tumors is essential. Historically, management of HPT‐JT has primarily involved surgical intervention, particularly parathyroidectomy, to address pHPT. Given the elevated risk of parathyroid carcinoma associated with HPT‐JT, en bloc resection of the affected parathyroid gland along with surrounding tissues has been recommended when malignancy is suspected [18, 19]. In cases of severe or symptomatic hypercalcemia, intravenous fluids and bisphosphonate infusions have been utilized as supportive treatments [20]. Additionally, the calcimimetic agent cinacalcet hydrochloride has been employed to manage hypercalcemia in patients with inoperable parathyroid adenomas or carcinomas [21, 22]. Surgical resection has also been the primary treatment for ossifying fibromas of the jaw, with the extent of surgery tailored to the tumor's size, location, and associated symptoms [23]. Renal and uterine manifestations have been managed according to standard clinical guidelines, often involving regular monitoring and surgical intervention when necessary. Following this, we performed a subtotal parathyroidectomy, preserving approximately 40 mg of healthy parathyroid tissue in the left superior lobe.

The need for CDC73 genetic confirmation is critical for diagnosis but may be hindered by limited testing availability, incomplete penetrance, and atypical mutations that complicate clinical suspicion. Surgical decision‐making is equally complex, as the choice between various approaches depends on factors such as the extent of gland involvement, tumor pathology, and recurrence risk. Furthermore, patients with HPT‐JT appear to be at an elevated risk of parathyroid carcinoma, ranging from 10%–38% [18, 24]. Evidence from the literature shows total calcium levels and the size of the gland as potential markers of parathyroid carcinoma [25].

A comprehensive literature review was conducted to identify recent studies on HPT‐JT, revealing 24 unique cases [26, 27, 28]. The reported cases included 54 patients, comprising 32 females and 22 males. The mean age at diagnosis was 35.1 ± 6.6 years, with males presenting earlier than females. The youngest patient documented was a 19‐year‐old girl who presented with multiple jaw swellings, which were diagnosed as ossifying fibromas [29]. The oldest patient was a 57‐year‐old male who presented with recurring nephrolithiasis, brown tumors, and osteoporosis [15]. No significant differences were observed between males and females regarding age at presentation, disease progression, or treatment outcomes. The late presentation in our patient can be attributed to limited access to healthcare, cultural and social stigma, and an overall low health literacy. The most prevalent involvement of parathyroid tissue often presents as an adenoma of a single gland, as evidenced in our patient.

To conclude, it is crucial to maintain a high index of suspicion for HPT‐JT in individuals presenting with jaw tumors at younger ages, particularly those under 30 years, along with a thorough investigation into their family history. Heightened suspicion and comprehensive familial inquiries are crucial for timely diagnosis and intervention. Although firm surveillance guidelines are lacking, potential screening methods for individuals with CDC73 mutations may include biannual assessment of serum calcium and parathyroid hormone levels, routine dental imaging, and periodic monitoring for kidney lesions using ultrasound, computed tomography, or magnetic resonance imaging.

Author Contributions

Maria Memon: conceptualization, writing – review and editing. Nouman Ibrahim: resources, writing – review and editing. Muhammad Momin Khan: visualization, writing – original draft. Aakash Rai Khatri: investigation, resources. Mahesh Kumar Meghwar: validation, visualization. Farina Fatima Siddiqui: writing – review and editing. Maisam Ali Rajput: resources, validation. Alaa Jlailati: writing – review and editing.

Consent

The patient has provided written informed consent to publish this case report and the accompanying images. If requested, the editor‐in‐chief of this journal may review a copy of the written consent.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Research data are not shared.