Blog

– Borderline resectable oral cavity cancer is a surgical dilemma
Can chemo-immunotherapy increase operability?

A new Phase II trial suggests yes

🧪 NeoLOCUS trial (Lancet Regional Health SE Asia)

Regimen:
Carboplatin + nab-paclitaxel + low-dose nivolumab
•oral metronomic therapy (methotrexate + celecoxib + erlotinib)

🎯 Population
Borderline resectable OSCC
n = 34

📊 Key results

• ORR: 66.6%
• R0 resection after 2 cycles: 75.7%
• Overall surgical conversion: 90.3%
• Major pathological response: 41%
• pCR: 13.8%

🧬 Interesting biology
Good responders showed reduction in FOXP3+ Tregs, suggesting immune-microenvironment modulation.

⚠️ Safety
Grade ≥3 toxicity: 14.7%
No treatment-related deaths.

💡 Why this matters

Borderline OSCC often fails surgery after standard NACT.
This low-dose IO + metronomic + chemo strategy may offer an affordable outpatient approach in LMIC settings.

But this is single-arm Phase II → randomized validation needed.

Abstract

Context: Patients with elevated parathyroid hormone (PTH) and consistently normal serum calcium levels, in whom secondary causes of hyperparathyroidism have been excluded, may represent the earliest presentation of primary hyperparathyroidism (PHPT).

Objective: The objective of the study was to characterize patients with normocalcemic PHPT referred to a bone disease unit.

Design: This was a longitudinal cohort study.

Setting: Ambulatory patients were referred to the metabolic bone disease unit.

Patients: The study population included 37 patients [aged 58 yr, range 32–78; 95% female; serum calcium, 9.4 ± 0.1 (SEM) mg/dl (2.3 ± 0.02 mmol/liter), reference range, 8.5–10.4 (2.1–2.6 mmol/liter); PTH, 93 ± 5 pg/ml].

Interventions: Interventions included yearly (median 3 yr; range 1–8 yr) physical examination, biochemical indices, and bone mineral density (BMD).

Main Outcome Measures: We measured the development of features of PHPT.

Results: Evaluation for classical features of PHPT revealed a history of kidney stones in five (14%), fragility fractures in four (11%), and osteoporosis in 57% [spine (34%), hip (38%), and/or distal one third radius (28%)]. BMD did not show preferential bone loss at the distal one third radius (T scores: spine, −2.00 ± 0.25; hip, −1.84 ± 0.18; one third radius, −1.74 ± 0.22). Further signs of PHPT developed in 40% (seven hypercalcemia; one kidney stone; one fracture; two marked hypercalciuria; six had >10% BMD loss at one or more site(s) including four patients developing World Health Organization criteria for osteoporosis). Seven patients (three hypercalcemic, four persistently normocalcemic) underwent successful parathyroidectomy.

Conclusions: Patients seen in a referral center with normocalcemic hyperparathyroidism have more substantial skeletal involvement than is typical in PHPT and develop more features and complications over time. These patients may represent the earliest form of symptomatic, rather than asymptomatic, PHPT.

Lowe, Hyesoo et al. “Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype.” The Journal of clinical endocrinology and metabolism 92 8 (2007): 3001-5 .

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Hyperparathyroidism #PrimaryHyperparathyroidism #CancerSurgeon #EndocrineSurgery #Teacher #Surgeon #HeadandNeckSurgeon #SurgicalOncologist #ParathyroidAdenoma #Hypercalcemia #ElevatedCalciumLevels #Miami #MountSinaiMedicalCenter #MSMC #Mexico #Hialeah

👉Hyperparathyroidism is associated with a wide array of symptoms related to neurocognitive and psychiatric function

👉Patients often report difficulties with memory and concentration, “brain fog”, mood related problems including depression, anxiety and irritability

👉They may also report weakness, general fatigue, sleep disturbance, joint and muscle pain

👉While the specific etiology of these symptoms is not clearly defined, they have been noted with increased frequency in this population

👉Read more at:

👉https://www.jscimedcentral.com/jounal-article-pdf/JSM-Head-and-Neck-Cancer-Cases-and-Reviews/headneck-1-1002.pdf

• Intraoperative rapid PTH does not itself define cure:
  • It is an intraoperative predictor of adequacy of resection
• Formal cure after parathyroidectomy:
  • Is still biochemical eucalcemia lasting at least 6 months
• Rapid PTH works:
  • Because intact PTH has a short half-life:
    • Roughly 3 to 5 minutes:
      • So levels should fall quickly after all hyperfunctioning tissue is removed
• The AAES guidelines:
  • Recommend intraoperative PTH monitoring with a reliable protocol for minimally invasive parathyroidectomy:
    • They note cure rates of about 97% to 99% in selected patients when adjunctive IPM is used
• Core concept:
  • The practical question in the OR is:
    • “Has all hypersecreting parathyroid tissue been removed?”
      • Rapid PTH helps answer that in real time
• Most protocols use a baseline sample before incision and / or immediately before excision:
  • Then a post-excision level at 10 minutes, with an additional 20-minute sample when the decline is borderline or delayed
• The most common reason the curve is misleading:
  • Is a PTH spike from gland manipulation:
    • Which is why many surgeons rely on the highest pre-incision or pre-excision value rather than only the pre-incision sample 
• Main intraoperative PTH protocols
  • The classic comparative study of 260 patients with concordant imaging:
    • Found overall accuracy of:
      • 97.3% for Miami, 92.3% for Vienna, 83.8% for Rome, and 65% for Halle criteria
    • In that same study:
      • Miami criteria was the best-balanced criterion for predicting cure:
        • Whereas Rome and Halle were somewhat better for detecting multigland disease but at the cost of more negative conversions to bilateral exploration
• The Miami criterion:
  • Is the most widely used:
    • A > 50% fall from the highest pre-incision or pre-excision PTH level, measured 10 minutes after excision of the abnormal gland
  • In the major Miami experience and subsequent reviews:
    • This approach achieved about 97% to 98% sensitivity, 97% specificity, ~99% PPV, and ~97% to 98% overall accuracy for postoperative eucalcemia
  • Long-term follow-up from the Miami group also showed durable outcomes with very low recurrence after focused surgery guided by intraoperative rapid PTH
  • This is why, in everyday endocrine surgery practice, the Miami criterion is usually the most useful protocol:
    • It is easy to remember, fast, reproducible, and has the best overall balance between avoiding persistent disease and avoiding unnecessary wider exploration
  • A 2024 network meta-analysis including 72 studies and 19,072 patients found that among conventional criteria:
    • The Miami criterion had the best diagnostic properties overall
• Vienna criterion:
  • The Vienna criterion also uses a > 50% drop at 10 minutes:
    • But the reference is the defined pre-incision baseline rather than the highest pre-excision value
  • It was designed to standardize interpretation and improve identification of multigland disease
  • In the comparative dataset above:
    • Vienna performed well, with 92.3% overall accuracy:
      • But still not as well as Miami for routine prediction of cure
    • In practical terms, Vienna is reasonable if your team insists on a strict, fixed baseline, but it is less forgiving when pre-excision manipulation creates a spike:
      • That is one reason many high-volume groups prefer Miami’s use of the highest available baseline
• Halle criterion:
  • Is much stricter:
    • Success is called only when PTH drops into the low-normal range:
      • Classically around 35 pg/mL:
        • Shortly after excision
  • This gives excellent specificity, but it performs poorly as a routine stopping rule because many successfully treated patients still have PTH levels above that threshold intraoperatively:
    • Especially if starting levels are high or clearance is delayed
  • In the Barczyński comparison, Halle had 100% specificity but only 65% overall accuracy:
    • Meaning it would trigger many unnecessary further explorations
  • For that reason, Halle is usually not the best default criterion for standard sporadic PHPT with concordant imaging:
    • It is too strict for routine use
• Rome criterion:
  • Is a more complex, stricter protocol
  • In one description, it requires a > 50% fall from the highest pre-excision level and / or a value within the normal range and / or an additional fall by 20 minutes
  • The point of Rome is to improve detection of persistence and multigland disease:
    • Especially when the early curve is ambiguous
  • A 2022 study evaluating the Rome approach found that the 20-minute / baseline ratio:
    • Had the highest diagnostic significance and suggested the 20-minute sample is particularly informative
  • Rome can be useful when the 10-minute value is borderline, when preoperative localization is less reliable, or when multigland disease is a real concern:
    • But as a standard protocol for all focused cases, it adds complexity and tends to increase exploration without clearly outperforming Miami for overall cure prediction
• What do meta-analyses say about using ioPTH at all?
  • Beyond comparing criteria, the broader question is whether using ioPTH improves outcomes
  • A 2021 systematic review / meta-analysis of 28 studies and 13,323 patients found operative failure rates of 3.2% with ioPTH versus 5.8% without ioPTH:
    • With a significant reduction in persistent / recurrent PHPT when ioPTH was used
  • Another 2021 systematic review / meta-analysis focused on minimally invasive parathyroidectomy included 12 studies and 2,290 patients and found that ioPTH use was associated with higher cure rates (OR 3.88, 95% CI 2.12–7.10) and a lower need for reoperation:
    • It did increase conversion to bilateral exploration, but without higher morbidity
  • So the evidence supports the value of ioPTH, especially when doing focused or minimally invasive surgery and when multigland disease is a concern
• Are stricter cutoffs better?
  • Usually, not enough to justify routine adoption
  • Newer work continues to test stricter thresholds:
    • A 2025 ROC analysis found that a 60% drop gave the best balance of sensitivity and specificity in that cohort, outperforming 50% and 70% on AUC, but the authors also cautioned that stricter thresholds may cause overtreatment and unnecessary exploration
    • Similarly, a 2025 two-center study suggested that combining the Miami rule with normalization to the reference range may help in selected cases, but the overall literature still favors the Miami criterion as the best general-purpose rule, which is consistent with the large network meta-analysis
• Practical interpretation in the OR
  • A resident-friendly approach is:
    • Draw pre-incision and pre-excision PTH
    • Remove the suspected gland
    • Check 10-minute PTH
    • If > 50% drop from the highest baseline → likely cure, stop if anatomy and clinical context fit
    • If borderline or not adequate → wait for 20-minute level and continue exploration if still not satisfactory
    • That approach handles the common real-life issues:
      • Manipulation spikes, delayed clearance, and occult multigland disease
• When rapid PTH is especially helpful:
  • Rapid PTH is most helpful in:
    • Focused / minimally invasive parathyroidectomy
    • Discordant or equivocal localization
    • Suspicion for multigland disease
    • Reoperative surgery
    • Cases where confirmation of adequacy of excision will determine whether you stop or proceed to wider exploration
• Bottom line: which protocol is most useful?
  • For most sporadic PHPT cases, especially with focused surgery:
    • The Miami criterion is the most useful protocol:
      • It has the best combination of simplicity, speed, evidence base, and diagnostic performance, and it remains the most widely adopted and best-supported criterion in comparative studies and network meta-analysis
• Key references:
  • Wilhelm SM, et al. AAES Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016. 
  • Barczyński M, et al. Evaluation of Halle, Miami, Rome, and Vienna intraoperative iPTH assay criteria. Langenbecks Arch Surg. 2009. 
  • Khan ZF, et al. Intraoperative Parathyroid Hormone Monitoring in the Surgical Management of Sporadic PHPT. Endocrinol Metab. 2019. 
  • Quinn AJ, et al. Systematic review/meta-analysis of ioPTH in MIP. JAMA Otolaryngol Head Neck Surg. 2021. 
  • Medas F, et al. Systematic review/meta-analysis of rapid ioPTH. Int J Surg. 2021. 
  • Staibano P, et al. Network meta-analysis of diagnostic test accuracy. JAMA Otolaryngol Head Neck Surg. 2024/2025 indexing. 

• Prevalence of PHPT during pregnancy:
  • Is reported to be between 0.15% and 1.4%
• PHPT during pregnancy may have serious consequences to the mother and to the fetus:
  • If it remains unrecognized or untreated:
    • In up to 80% of patients, it is not recognized due to physiological changes during pregnancy that mask gestational PHPT, such as:
      • Hemodilution:
        • Related to intravascular fluid expansion
      • Hypoalbuminemia
      • Increased glomerular filtration rate:
        • Resulting in hypercalciuria
      • Transplacental transfer of calcium
  • Clinical presentation of PHPT durign pregnagncy may range from:
    • Hyperemesis, lethargy, hypertension, thirst, abdominal pain, depression, constipation, bone fracture, maternal heart rhythm disorders, maternal hypertension to preeclampsia, nephrolithiasis, pancreatitis, hyperemesis gravidarum, and hypercalcemic crisis:
      • Because the understanding of this concept and standard monitoring of all pregnant patients in developed countries:
        • The presentation of PHPT during pregnancy is very mild:
          • It is diagnosed in earlier stages
  • Sestamibi scan is contraindicated during pregnancy:
    • Due to radiation exposure risk to the fetus:
      • Ultrasound is the only diagnostic option since it carries no risk of radiation exposure and is easy to perform
  • Management of PHPT during pregnancy:
    • Should be individualized based on symptoms and severity of hypercalcemia:
      • Parathyroidectomy is indicated in symptomatic patients and patients with severe hypercalcemia:
        • When calcium level is elevated above 11 mg/dL (2.74 mmol/L)
      • Parathyroidectomy should be performed only in the second trimester:
        • To prevent miscarriage and anesthetic drugs exposure in the first trimester or spontaneous delivery in the third trimester
      • Mild form of PHPT causes low risk of maternal and obstetrical complications:
        • Therefore the patients can be managed conservatively, and parathyroidectomy can be deferred until after the delivery
      • Some medications, such as bisphosphonates, are contraindicated during pregnancy
      • Calcitonin:
        • Showed limited data and poor effectiveness:
          • But it does not cross the placenta and appears to be safe
      • Cinacalcet:
        • Has shown good results in several studies:
          • Although safety data are limited
      • Recent paper published by Rigg et al. retrospectively reviewed data of 28 pregnant patients with PHPT (22 managed medically and 6 surgically by elective parathyroidectomies):
        • Showed that 30% of those who were managed medically developed preeclampsia, and 66% managed medically had preterm deliveries

Consensus Recommendations – Early Breast Cancer

• ER-Positive / HER2-Negative Disease:
  • Genomic Testing:
    • Strong support for multigene assays (Oncotype DX, MammaPrint, etc.) in:
    • Node-negative disease
    • 1 to 3 positive nodes:
      • Especially postmenopausal:
        • In premenopausal patients with 1 to 3 nodes → chemotherapy often still favored even with low genomic risk
• Chemotherapy:
  • Postmenopausal:
    • N1 (1 to 3 nodes), low genomic risk:
      • Chemotherapy can be omitted
  • Premenopausal:
    • N1 disease:
      • Chemotherapy generally recommended:
        • Ovarian suppression contribution acknowledged but not universally accepted as replacement
• Ovarian Function Suppression (OFS):
  • Recommended in:
    • High-risk premenopausal patients
    • Node-positive disease AI + OFS preferred over tamoxifen alone in higher-risk settings
• CDK4/6 Inhibitors:
  • Abemaciclib recommended in:
    • High-risk node-positive (monarchE-like criteria)
  • Ribociclib:
    • Data discussed but not yet fully standard globally
• HER2-Positive Early Breast Cancer:
  • Neoadjuvant Therapy:
    • Standard for:
      • Tumors ≥ 2 cm
      • Node-positive disease
    • Preferred regimen:
      • Taxane + dual anti-HER2 (trastuzumab + pertuzumab)
  • Residual Disease After Neoadjuvant Therapy:
    • T-DM1 (KATHERINE data) remains standard
  • Duration of Trastuzumab:
    • 12 months remains consensus standard
    • 6 months acceptable only in select lower-risk or toxicity cases
  • De-escalation:
    • Small node-negative HER2+ (< 2 cm):
      • TH regimen acceptable (APT-like approach)
      • Ongoing interest in response-adapted therapy
• Triple-Negative Breast Cancer (TNBC):
  • Neoadjuvant Therapy:
    • Standard:
      • Anthracycline + taxane backbone
      • Addition of pembrolizumab:
        • Supported in stage II to III
  • Residual Disease:
    • Continue pembrolizumab:
      • KEYNOTE-522 strategy
    • Capecitabine considered if no prior immunotherapy
  • BRCA-Mutated:
    • Adjuvant olaparib recommended:
      • OlympiA criteria
• Axillary Management:
  • Clinically Node-Negative:
    • Sentinel lymph node biopsy (SLNB) standard
    • 1 to 2 Positive Sentinel Nodes (Upfront Surgery):
      • Omission of ALND supported if:
        • Undergoing breast-conserving therapy Whole-breast RT planned – ACOSOG Z0011 principles upheld
  • After Neoadjuvant Therapy:
    • If cN+:
      • ycN0:
        • SLNB acceptable if ≥ 3 nodes retrieved + dual tracer
        • Residual nodal disease → ALND still recommended in most settings
• Radiation Therapy:
  • Hypofractionation:
    • Standard for most patients
  • Ultra-hypofractionation (FAST-Forward-like) widely accepted
  • Omission of RT:
    • May be considered in:
      • Age ≥ 70
      • Small ER+ tumors
      • Planned endocrine therapy
• Regional Nodal Irradiation:
  • Recommended in:
    • Node-positive disease
    • High-risk biology
• De-escalation Themes:
  • Avoid overtreatment in:
    • Low-risk luminal A disease
    • Elderly / frail patients
    • Tailor treatment based on:
      • Biology > anatomy alone
      • Genomic profiling
      • Patient preference
• Liquid Biopsy & MRD:
  • ctDNA promising but:
    • Not yet standard for treatment decision:
      • Still investigational for escalation / de-escalation
• Germline Mutation Carriers
  • BRCA1/2:
    • Consider bilateral mastectomy (case-dependent)
    • Adjuvant olaparib in high-risk early disease
    • PALB2 increasingly treated similarly to BRCA in high-risk scenarios
• Artificial Intelligence and Imaging:
  • MRI not routine for all early-stage patients
  • PET-CT not recommended for stage I routine staging
  • AI emerging for:
    • Risk stratification
    • Imaging interpretation
    • Treatment personalization
• Key Global Themes of St. Gallen 2025:
  • Precision > escalation Biology-driven treatment
  • Safe de-escalation when supported by data
  • Increased use of CDK4/6 inhibitors and immunotherapy in early disease
  • Continued minimization of axillary surgery

• Increased Bone Turnover (Primary Mechanism)

• Thyroid hormones (T3 and T4):
  • Stimulate bone remodeling:
    • But they disproportionately increase:
      • Osteoclastic bone resorption
    • Mechanism:
      • Thyroid hormone increases osteoblast activity:
        • Which in turn stimulates osteoclasts:
          • Via the RANKL pathway
    • This results in:
      • ↑ osteoclast-mediated bone resorption
      • ↑ release of calcium and phosphate from bone
    • Key physiologic effects:
      • Accelerated bone turnover
      • Net bone loss
      • Calcium release into circulation
    • This explains why hyperthyroidism
    • is associated with:
      • Hypercalcemia (usually mild)
      • Hypercalciuria
      • Osteopenia / osteoporosis
  • Increased Sensitivity to Catecholamines:
    • Thyroid hormone enhances β-adrenergic activity:
      • Which further stimulates bone turnover
    • This contributes to:
      • Increased osteoclast activity
      • Further calcium mobilization from bone
  • Suppressed Parathyroid Hormone (PTH):
    • Because calcium increases, the body responds physiologically:
      • Serum calcium rises
      • PTH becomes suppressed
  • Increased Renal Calcium Excretion:
    • Because of the higher filtered calcium load:
      • Hypercalciuria develops
      • Patients may occasionally develop nephrolithiasis:
        • However, stones are much less common than in primary hyperparathyroidism.
  • Increased IL-6 and Cytokine Activity:
    • Hyperthyroidism may increase cytokine signaling such as:
      • IL-6
      • TNF-α
    • These cytokines stimulate osteoclast differentiation and further promote bone resorption
• Typical laboratory pattern:

Test	Finding
Calcium	Mildly ↑
PTH	Suppressed
Phosphate	Normal or mildly ↑
1,25-Vitamin D	Normal
Urinary calcium	↑

This helps differentiate thyrotoxicosis-related hypercalcemia from primary hyperparathyroidism.

• Clinical Characteristics:
  • Typical hypercalcemia seen in hyperthyroidism:
    • Once thyrotoxicosis is treated, calcium levels usually normalize

Characteristic	Feature
Frequency	~15–20% of patients with hyperthyroidism
Severity	Usually mild (Ca 10.5–11.5 mg/dL)
Mechanism	Increased bone resorption
PTH	Suppressed
Treatment	Correction of hyperthyroidism

• Important Surgical Teaching Point:
  • When evaluating hypercalcemia with suppressed PTH, consider:
    • Differential diagnosis
      • Malignancy
      • Hyperthyroidism
      • Vitamin D intoxication
      • Granulomatous disease (sarcoidosis)
      • Medications (thiazides)
  • Thus, thyroid function tests should be obtained in unexplained hypercalcemia
• Key References:
  • Mosekilde L. Hyperthyroidism and bone metabolism. Endocrinol Metab Clin North Am. 1990.
  • Ross DS et al. 2022 American Thyroid Association Guidelines for Thyrotoxicosis. Thyroid. 2022.
  • Mundy GR, Martin TJ. The hypercalcemia of malignancy and endocrine disorders. Metabolism. 1982.
  • Bilezikian JP et al. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. ASBMR.
• Teaching pearl for residents:
  • If you see hypercalcemia with suppressed PTH and symptoms of thyrotoxicosis, always check TSH before assuming malignancy

• Familial hypocalciuric hypercalcemia (FHH):
  • Also known as benign familial hypercalcemia hypocalciuria:
    • Is an autosomal dominant disorder with nearly 100% penetrance:
      • Characterized by:
        • Lifelong asymptomatic hypercalcemia
        • Low urinary calcium excretion
        • Inappropriately normal or mildly elevated PTH levels
• Genetics and Pathophysiology
  • FHH results from heterozygous loss-of-function mutations affecting the:
    • Calcium-sensing receptor (CaSR) signaling pathway
  • Three genetic subtypes exist:
    • FHH1:
      • Most common – 65% to 70% of cases:
      • Inactivating mutations in CASR gene:
        • Encoding the calcium-sensing receptor
    • FHH2 (rarest):
      • Mutations in GNA11 gene:
        • Encoding the Gα11 protein subunit
    • FHH3:
      • Mutations in AP2S1 gene:
        • Affecting receptor endocytosis
  • These mutations cause reduced sensitivity of parathyroid cells and renal tubular cells:
    • To extracellular calcium:
      • Resulting in a rightward shift in the set point for PTH suppression and increased renal calcium reabsorption (hypocalciuria)
• Clinical Features
  • FHH is typically benign and asymptomatic:
    • With hypercalcemia often detected incidentally
  • Most patients require no intervention
  • Onset occurs in the first week of life:
    • With lifelong persistence
  • Rarely, adults may develop pancreatitis or chondrocalcinosis
  • FHH3:
    • May present with a more pronounced phenotype than FHH1 or FHH2
• Laboratory Findings
  • The characteristic biochemical profile includes:
    • Elevated serum calcium (mild to moderate)
    • Low urinary calcium excretion:
      • Fractional excretion of calcium typically < 0.01
    • Normal or low-normal serum phosphate
• Distinguishing FHH from Primary Hyperparathyroidism:
  • Differentiating FHH from primary hyperparathyroidism (PHPT):
    • Is critical because FHH does not require surgery:
      • Whereas PHPT is often treated surgically
    • However, significant biochemical overlap exists between these conditions
  • Key distinguishing features:
    • Important caveats:
      • Up to 20% of FHH patients have fractional excretion of calcium > 0.01, and there is considerable overlap in all biochemical parameters
      • The 24-hour urine calcium excretion has 96% sensitivity for PHPT but only 29% specificity for FHH:
        • While the calcium/creatinine clearance ratio has 47% sensitivity for PHPT but 93% specificity for FHH
• Genetic Testing:
  • Genetic testing for CASR, GNA11, and AP2S1 mutations is appropriate in:
    • Young patients with hypercalcemia
    • Patients with family history of hypercalcemia
    • Fractional excretion of calcium < 0.02
    • Fail parathyroidectomy
    • Multigland disease
• Management:
  • FHH is a benign condition that does not require surgery
  • Parathyroidectomy is contraindicated as hypercalcemia persists after subtotal parathyroidectomy and total parathyroidectomy causes permanent hypoparathyroidism
  • For symptomatic cases (particularly FHH3):
    • The calcimimetic cinacalcet has been used successfully to lower calcium levels and alleviate symptoms
• References
  Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism. Marx SJ. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research. 2018;33(1):27-31. doi:10.1002/jbmr.3339.
  Familial Hypocalciuric Hypercalcemia and Related Disorders. Lee JY, Shoback DM. Best Practice & Research. Clinical Endocrinology & Metabolism. 2018;32(5):609-619. doi:10.1016/j.beem.2018.05.004.
  Mutations Affecting G-Protein Subunit α11 in Hypercalcemia and Hypocalcemia. Nesbit MA, Hannan FM, Howles SA, et al. The New England Journal of Medicine. 2013;368(26):2476-2486. doi:10.1056/NEJMoa1300253.
  Familial Hypocalciuric Hypercalcemia in an Infant: Diagnosis and Management Quandaries. Goldsweig B, Turk Yilmaz RS, Ravindranath Waikar A, Brownstein C, Carpenter TO. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research. 2024;39(10):1406-1411. doi:10.1093/jbmr/zjae137.
  Hyperparathyroid and Hypoparathyroid Disorders. Marx SJ. The New England Journal of Medicine. 2000;343(25):1863-75. doi:10.1056/NEJM200012213432508.
  Hypercalcemia: A Review. Walker MD, Shane E. JAMA. 2022;328(16):1624-1636. doi:10.1001/jama.2022.18331.
  Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences. Vargas-Poussou R, Mansour-Hendili L, Baron S, et al. The Journal of Clinical Endocrinology and Metabolism. 2016;101(5):2185-95. doi:10.1210/jc.2015-3442.
  Urinary Calcium Indices in Primary Hyperparathyroidism (PHPT) and Familial Hypocalciuric Hypercalcaemia (FHH): Which Test Performs Best?. Arshad MF, McAllister J, Merchant A, et al. Postgraduate Medical Journal. 2021;97(1151):577-582. doi:10.1136/postgradmedj-2020-137718.
  Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations. Howles SA, Hannan FM, Babinsky VN, et al. The New England Journal of Medicine. 2016;374(14):1396-1398. doi:10.1056/NEJMc1511646.