Heerfordt Syndrome Complicated by Bilateral Simultaneous Facial Palsy, PTH-Independent Hypercalcemia, and Bilateral Obstructive Acute Kidney Injury in the Absence of Thoracic Disease: A Case Report and Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a well-documented and educationally valuable case report with a genuinely interesting clinical phenotype (Heerfordt syndrome with bilateral simultaneous facial palsy, severe calcitriol-mediated hypercalcemia, and bilateral obstructive AKI without thoracic disease). The narrative review component, comparative table, and schematic figures add value. However, several internal inconsistencies in the data/statistics, a contradictory table entry, an important missing differential diagnosis, and minor terminological errors need to be resolved.

Major issues

1. Inconsistent statistics for the "complete" form of Heerfordt syndrome (Introduction vs. Table 3)

The Introduction states: "the full triad is encountered in approximately 0.3% of sarcoidosis cohorts" [4,5], whereas Table 3 reports "Complete tetrad... ~10–15%" [4,10,14]. These two figures describe what appears to be the same concept (full/complete syndrome) but differ by almost two orders of magnitude, and the denominators may differ ("among sarcoidosis cohorts" vs. "among Heerfordt patients") — this should be stated explicitly. Please clarify the denominator for each statistic and reconcile or distinguish these two figures, with the correct supporting citation for each.

2. "Triad" vs. "tetrad" terminology inconsistency

The Introduction refers to the "full triad," while the Abstract and Discussion (Section 3.1, Table 3) define Heerfordt syndrome as a tetrad of four features (fever, parotid enlargement, uveitis, facial palsy). Please use consistent terminology throughout (tetrad if fever is counted as a cardinal feature; triad only if referring to the three signs originally described without fever), and clarify which convention is being used.

3. Citation accuracy for epidemiological figures

Reference 5 (Stern et al., Definition and Consensus Diagnostic Criteria for Neurosarcoidosis) is used to support the "0.3%" prevalence figure in the Introduction, but this reference is a diagnostic-criteria consensus paper, not an epidemiological source. Please verify this citation is correct, or replace it with the appropriate primary source. Similarly, please verify that reference 20 (Iannuzzi et al., NEJM 2007 — a general sarcoidosis review) is the correct source for the specific "40–60%" hypercalciuria figure cited in Section 3.3, rather than reference 13 (Sharma, 1996) alone.

4. Table 5 — internal contradiction

In Table 5, the row "Renal involvement" lists "None" for the present case, which directly contradicts the entire premise of the report (bilateral obstructive AKI with hydronephrosis). This appears to be a table formatting/column-alignment error (possibly introduced during typesetting/PDF export) rather than an intentional statement, but it must be corrected, as currently printed it actively misrepresents the case.

5. Discrepancy between text and Figure 3 (creatinine timeline)

Section 2.6 states creatinine "settled at 1.21 mg/dL by day ten," but Figure 3 places the value of 1.21 mg/dL at Day 14, not Day 10. Please correct either the text or the figure so the two are consistent. Please also clarify whether "serum calcium reached the normal range within seven days" (Section 2.6) is counted from admission or from corticosteroid initiation (day 7), since the two reference points give different — and currently ambiguous — interpretations.

6. Missing differential diagnosis: IgG4-related disease

Given the combination of bilateral parotid/salivary gland enlargement, sicca symptoms, and renal involvement, IgG4-related disease is an important mimicker of this phenotype and is not mentioned anywhere in the manuscript (Table 4's differential list is restricted to facial palsy, not the overall syndrome). Please discuss this differential explicitly and clarify whether serum IgG4 levels or IgG4 immunostaining on the parotid biopsy were assessed. This is a significant omission given the overlapping clinical picture.

Minor issues

7. Uncited references

References 24 (Papalia et al.) and 25 (Hilderson et al.) appear in the reference list but are not cited anywhere in the visible text. Please add the corresponding in-text citations or remove these entries.

8. Imaging terminology

Section 2.4 describes renal ultrasound findings as "grade II–III nephropathy." This is likely intended to read "grade II–III hydronephrosis" ("nephropathy" is not typically graded sonographically). Please correct.

9. Parotid biopsy technique and facial nerve safety

Given that the patient had a documented antecedent (albeit resolved) bilateral facial palsy, additional detail on the surgical approach to the open parotid biopsy (e.g., facial nerve identification/monitoring, superficial lobe sampling) would strengthen the methodological transparency of the report and address an obvious safety concern for readers.

10. Adrenal incidentaloma characterization

The left adrenal nodule (1.3 cm, 4 HU) is classified as "non-functioning" based on imaging alone. Please clarify whether any biochemical screening (e.g., overnight dexamethasone suppression test, plasma metanephrines) was performed, or state explicitly that the "non-functioning" designation is based solely on imaging characteristics.

11. Keyword accuracy

"Granulomatous interstitial nephritis" is listed as a keyword, but renal biopsy was not performed and GIN was not histologically confirmed in this patient (Section 3.4/3.8 explicitly state it "cannot be excluded with certainty"). Consider removing this keyword or qualifying it, since its inclusion implies a confirmed diagnosis that was not established.

12. Minor laboratory interpretation wording

Table 1: Chloride 108 mmol/L (reference 98–106) is labeled "borderline elevated" — it is, in fact, mildly above the reference range rather than borderline; consider rewording.

Table 1: HDL 29 mg/dL is labeled "mildly dyslipidemic" — an HDL this low is more accurately described as "low HDL" rather than "mild" dyslipidemia.

Suggested optional additions

A brief comment on the diagnostic value of the low-normal 25-hydroxyvitamin D (22 ng/mL) despite hypercalcemia would strengthen the pathophysiological argument, since substrate consumption by unregulated extrarenal 1α-hydroxylase activity (rather than vitamin D intoxication) is supported by this finding.

Noting that serum phosphate was normal/high-normal (4.40 mg/dL) rather than low (as would be expected in primary hyperparathyroidism) could be added as a supportive biochemical point distinguishing PTH-independent calcitriol-mediated hypercalcemia from PTH-driven hypercalcemia, complementing the already-noted suppressed PTH.

Author Response

We thank Reviewer 1 for the exceptionally careful and constructive appraisal. We have addressed every point; the revised text is highlighted in the resubmitted manuscript, and the specific changes are described below.

Comment 1: Inconsistent statistics for the “complete” form of Heerfordt syndrome (Introduction vs. Table 3) — “0.3% of sarcoidosis cohorts” vs. “~10–15%”; the denominators may differ and should be stated explicitly.

Response 1: Agree. We have removed the “~0.3%” figure and reconciled the two statistics so that each denominator is now explicit. The Introduction now states that the complete tetrad is “encountered in only about 10–15% of patients presenting with Heerfordt syndrome, corresponding to well under 1% of all sarcoidosis cohorts.” Table 3 uses the same ~10–15% figure, whose denominator is patients with Heerfordt syndrome. The two figures therefore describe the same concept across two different denominators (Heerfordt patients vs. all sarcoidosis patients) and are now internally consistent, supported by reference [4]. (Introduction, paragraph 2; Table 3, final row.)

Comment 2: “Triad” vs. “tetrad” terminology inconsistency.

Response 2: Agree. The manuscript now uses “tetrad” consistently, counting fever as a cardinal feature. The word “triad” has been removed. The Introduction now reads “the complete tetrad—fever, parotid enlargement, uveitis, and facial-nerve palsy,” matching the Abstract, Section 3.1, and Table 3. (Introduction, paragraph 2.)

Comment 3: Citation accuracy for epidemiological figures — Stern et al. [5] is a diagnostic-criteria paper, not an epidemiological source; and please verify the source for the “40–60%” hypercalciuria figure.

Response 3: Agree. The “0.3%” epidemiological claim previously attributed to Stern et al. has been removed. Stern et al. [5] is now cited only for the statement that facial-nerve palsy is the most common cranial neuropathy in neurosarcoidosis, which is within the scope of that consensus paper. The “40–60%” hypercalciuria figure in Section 3.3 is now supported by Sharma (1996) and Iannuzzi et al. (NEJM 2007) [14,15] rather than a single general review. (Introduction, paragraph 2; Section 3.3.)

Comment 4: Table 5 — “Renal involvement” lists “None” for the present case, contradicting the report.

Response 4: Agree; this was a column-alignment error introduced during formatting. The “Renal involvement” cell for the present case now reads “Obstructive AKI,” consistent with the case throughout. (Table 5.)

Comment 5: Discrepancy between text and Figure 3 (creatinine timeline); and clarify the reference point for calcium normalization.

Response 5: Agree. Section 2.6 now states that creatinine “settled at 1.21 mg/dL by day fourteen,” matching Figure 3. We have also clarified that serum calcium “reached the normal range within seven days of starting corticosteroids” — i.e., counted from corticosteroid initiation, not from admission — removing the previous ambiguity. (Section 2.6.)

Comment 6: Missing differential diagnosis: IgG4-related disease; and clarify whether serum IgG4 or IgG4 immunostaining was assessed.

Response 6: Agree; this is an important addition. Section 3.1 now discusses IgG4-related disease explicitly as a key mimic of the overall phenotype (bilateral salivary-gland enlargement, sicca symptoms, tubulointerstitial renal disease) and contrasts its storiform fibrosis and IgG4-rich plasma-cell infiltrate with our patient’s well-formed non-caseating granulomas, markedly elevated ACE, and PTH-independent calcitriol-mediated hypercalcemia. We have also clarified the IgG4 workup: dedicated serum IgG4 measurement and IgG4 immunostaining were not performed during the admission; however, total serum IgG was within the reference range (12.20 g/L), and the biopsy showed well-formed non-caseating granulomas without the storiform fibrosis or obliterative phlebitis that typify IgG4-related disease, together arguing against that diagnosis. (Section 3.1.)

Comment 7: Uncited references 24 (Papalia et al.) and 25 (Hilderson et al.).

Response 7: Agree. Both are now cited in the text and the reference list was renumbered accordingly. Papalia et al. (now reference 18) is cited in Section 3.4 in support of the statement that acute kidney injury can arise from any of the recognized renal mechanisms or their combination. Hilderson et al. (now reference 24) is cited in Section 3.6 regarding the limited structured guidance for renal sarcoidosis. (Sections 3.4 and 3.6.)

Comment 8: Imaging terminology — “grade II–III nephropathy” should read “grade II–III hydronephrosis.”

Response 8: Agree. Corrected to “grade II–III hydronephrosis.” (Section 2.4.)

Comment 9: Parotid biopsy technique and facial-nerve safety.

Response 9: Agree. Section 2.5 now specifies the surgical approach and the facial-nerve precautions taken in light of the antecedent (resolved) bilateral facial weakness: “Because of the antecedent (albeit resolved) bilateral facial weakness, the specimen was taken from the superficial lobe only through a standard modified Blair approach, with intraoperative identification and preservation of the facial-nerve trunk and its peripheral branches; no new facial weakness followed the procedure.” (Section 2.5.)

Comment 10: Adrenal incidentaloma characterization — clarify whether biochemical screening was performed or that “non-functioning” is imaging-based only.

Response 10: Agree. Section 2.4 now states that dedicated biochemical screening for hormonal excess (an overnight 1 mg dexamethasone-suppression test and plasma metanephrines) was not pursued, as there were no clinical or biochemical features to suggest a functioning lesion, and that the “non-functioning” designation therefore rests on imaging characteristics alone (1.3 cm, 4 HU). (Section 2.4.)

Comment 11: Keyword accuracy — “Granulomatous interstitial nephritis” implies a confirmed diagnosis not established here.

Response 11: Agree. The keyword “granulomatous interstitial nephritis” has been removed from the keyword list, consistent with the fact that renal biopsy was not performed and GIN was not histologically confirmed. (Keywords.)

Comment 12: Minor laboratory interpretation wording — chloride “borderline elevated”; HDL “mildly dyslipidemic.”

Response 12: Agree. Table 1 now labels chloride 108 mmol/L as “Mildly elevated” and HDL 29 mg/dL as “Low HDL,” rather than the previous wording. (Table 1.)

Suggested optional additions (25-hydroxyvitamin D; serum phosphate):

Response: We thank the reviewer and have incorporated both points in Section 3.3. The low-normal 25-hydroxyvitamin D (22 ng/mL) despite hypercalcemia is now framed as consistent with substrate consumption by unregulated extrarenal 1α-hydroxylase rather than vitamin D excess; and the normal-to-high-normal serum phosphate (4.40 mg/dL), rather than the low phosphate expected with PTH-driven disease, is noted as a supportive biochemical point distinguishing this PTH-independent, calcitriol-mediated pattern from primary hyperparathyroidism, complementing the already-noted suppressed PTH. (Section 3.3.)

Reviewer 2 Report

Comments and Suggestions for Authors

The authors describe a rare phenotype of sarcoidosis and review the existing literature. In my opinion, the case is well documented and presented, and the literature review is unbiased and well presented, too. I suggest accepting the manuscript after revision.

Minor comment:

1. Figure 2: Provide a figure or two that shows calculi in both ureters.
2. Of the 14 cases reported in the literature, only 8 are analyzed in Table 5.
3. Please clarify whether serum or urinary calcium and UACR were measured after treatment, and whether 24-hour urinary calcium was measured.

Author Response

We thank Reviewer 2 for the positive assessment and the helpful suggestions, which we have addressed as follows.

Comment 1: Figure 2 — provide a figure or two that shows calculi in both ureters.

Response 1: Agree. Figure 2 has been reorganized into three labelled panels: (A) a coronal reconstruction showing both kidneys with bilateral intrarenal calcifications and pelvicalyceal fullness, and (B,C) representative axial images demonstrating the bilateral upper-ureteric calculi (8 mm on the right and 6 mm on the left) together with small non-obstructing renal calculi. The caption has been updated to describe panels A, B, and C. (Figure 2 and its caption, Section 2.4.)

Comment 2: Of the 14 cases reported in the literature, only 8 are analyzed in Table 5.

Response 2: Agree, and we have clarified this in the text. Section 3.5 now states that the focused literature search returned 14 directly relevant English-language reports, of which eight contained sufficient clinical, biochemical, and outcome detail for structured comparison; the remaining six lacked adequate detail and were therefore not included in Table 5. (Section 3.5.)

Comment 3: Clarify whether serum or urinary calcium and UACR were measured after treatment, and whether 24-hour urinary calcium was measured.

Response 3: Thank you for raising this. Serum calcium was measured serially and was used to monitor the metabolic response; it normalized within seven days of starting corticosteroids and remained normal at the three-month review (Table 1). We have now stated explicitly in the Limitations (Section 3.8) that a 24-hour urinary calcium measurement and a spot urine albumin-to-creatinine ratio were not obtained (24-hour urinary protein was quantified instead, at 595.9 mg), so the magnitude of hypercalciuria could not be documented directly. (Table 1; Section 3.8.)

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript has reported a special case of Heerfordt syndrome presenting dominantly metabolic and renal complications other pulmonary invovlement. It is very rare for the case with extrathoracic sarcoidosis, which has teaching meaningful for clinician. The full clinical manifeations, laboratory and radiology results were well presented, as well as the thearpoy and follow-up.  

Minor: The dignosis of sarcodosis is characterized by biopsy-proved non-caseating granulomatous inflamation histologiccally, it is suggested to add the pathological images of parotid gland biopsy in the main text.

Author Response

We thank Reviewer 3 for the supportive evaluation and for highlighting the importance of histological documentation.

Comment 1 (Minor): The diagnosis of sarcoidosis is characterized histologically by biopsy-proven non-caseating granulomatous inflammation; it is suggested to add the pathological images of the parotid gland biopsy in the main text.

Response 1: We fully agree that histological images would strengthen the report, and we made every effort to include them. Regrettably, we were unable to retrieve diagnostic-quality photomicrographs of the parotid biopsy for inclusion, as the original slides were not available to us for re-imaging at adequate resolution. To compensate, we have retained and expanded the detailed morphological description of the biopsy in Section 2.5: well-formed, compact, non-caseating epithelioid granulomas with scattered multinucleated giant cells distributed in the interlobular stroma; no necrosis, fibrinoid degeneration, or vasculitic change; negative special stains for acid-fast bacilli (Ziehl–Neelsen) and fungi (Grocott methenamine silver and periodic acid–Schiff); and negative tissue cultures for mycobacteria and fungi. Should the editorial office consider photomicrographs essential, we would be glad to work with our pathology department to obtain re-cut and re-photographed sections. (Section 2.5.)

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Ok

Reviewer 2 Report

Comments and Suggestions for Authors

The authors addressed my comments adequately.