Risk Factors and Long-Term Survival Outcomes of Sagliker Syndrome After Parathyroidectomy in a Chinese Cohort

Abstract

Introduction

Sagliker syndrome (SS) is a severe, disfiguring manifestation of refractory secondary hyperparathyroidism (SHPT). Although parathyroidectomy (PTX) corrects biochemical abnormalities, long-term outcomes after PTX in patients with SS remain uncertain. This study hypothesized that SS represents a high-risk phenotype associated with adverse long-term outcomes despite surgical intervention.

Methods

This single-center retrospective cohort study included 740 dialysis patients with severe refractory SHPT who underwent PTX. The patients were classified into SS (n = 70) and non-SS (n = 670) groups. Multivariable logistic regression was used to identify factors associated with SS; Cox models were used to evaluate associations of SS with all-cause and cardiovascular disease (CVD) mortality. Sensitivity and subgroup analyses were used to assess robustness.

Results

The prevalence of SS was 9.5%. Independent factors associated with SS included longer dialysis vintage (odds ratio [OR] = 1.21, P < 0.001), alkaline phosphatase (ALP) > 315 U/L (OR = 4.14, P < 0.001), hypoalbuminemia (OR = 0.92, P = 0.013), cardiac valve calcification (OR = 2.11, P = 0.014), and abdominal aortic calcification (OR = 2.14, P = 0.016). Exploratory cephalometry in a small subset was consistent with previous SS reports. Exploratory post-PTX analyses suggested improved quality of life (QOL; n = 25), reduced bone pain (n = 45), and stabilization of height loss (n = 15) in patients with SS (all P < 0.05). Over a median follow-up of 81 months, SS was independently associated with higher all-cause mortality (hazard ratio [HR] = 1.71, 95% confidence interval [CI]: 1.01–2.89; P = 0.045) and CVD mortality (HR = 2.44, 95% CI: 1.17–5.06; P = 0.018) after PTX.

Conclusion

In this PTX-treated cohort, SS was associated with longer dialysis vintage, high bone turnover, and vascular calcification. Although PTX may provide symptomatic benefit, SS remained associated with higher long-term mortality after PTX and may reflect irreversible systemic damage.

Graphical abstract

SHPT is a common complication of chronic kidney disease–mineral and bone disorder.^1,2 Refractory SHPT independently increases the risk of cardiovascular events and mortality, imposing substantial clinical and socioeconomic burdens.^1,3 SS, first systematically described by Sagliker et al.⁴ in 2004, represents a severe and debilitating form of renal osteodystrophy resulting from prolonged, inadequately managed SHPT. Clinically, SS is characterized by marked craniofacial and skeletal deformities, including “lion-like” facies, short stature, maxillary and mandibular destruction, and dental malocclusion, often accompanied by hearing loss and neuropsychiatric impairment.^4,5 This condition is frequently associated with socioeconomic disadvantage and delayed access to care, creating significant management challenges. Although biochemical control or kidney transplantation may halt musculoskeletal progression, established skeletal deformities are largely irreversible, resulting in substantial reductions in QOL.⁶

PTX is the definitive treatment for patients with refractory SHPT who do not respond to pharmacological therapy.^7,8 Although PTX effectively alleviates symptoms, the long-term prognosis of patients with SS after surgery remains unclear. Current evidence is limited to case reports and small-scale observational studies. In this large-scale study of a Chinese SS cohort, we evaluated clinical characteristics, risk factors, and survival outcomes after PTX, with the aim of improving recognition of this underrecognized syndrome and promoting earlier multidisciplinary intervention to prevent irreversible progression.

Methods

Study Design and Population

This single-center retrospective cohort study was conducted at the Second Affiliated Hospital of Anhui Medical University, a tertiary referral center for refractory SHPT in Anhui Province and surrounding regions. A total of 1069 patients with maintenance dialysis and refractory SHPT who underwent PTX successfully between April 2011 and April 2019 were screened. After applying inclusion and exclusion criteria, 329 patients were excluded because of incomplete baseline data, predefined exclusion conditions, or insufficient follow-up or outcome data for survival analysis. The final analytic cohort included 740 patients (Supplementary Figure S1). The sample size reflected all eligible patients in the institutional database, thereby maximizing statistical power for this rare phenotype.

PTX Eligibility and SS Phenotype Ascertainment

Severe SHPT was defined according to established clinical guidelines^3,8 and required the following criteria: (i) age range of 18 to 75 years; (ii) stable hemodialysis or peritoneal dialysis for ≥3 months; (iii) serum intact parathyroid hormone (iPTH) > 800 pg/ml with hypercalcemia and/or hyperphosphatemia; (iv) inadequate response to conventional medical therapy (phosphate binders, calcitriol, or cinacalcet) and/or intensified dialysis; (v) SHPT-related symptoms, including bone pain, pruritus, muscle weakness, or pathological fractures; (vi) ultrasonographic evidence of ≥1 enlarged parathyroid gland (diameter > 1 cm) with hypervascularity; (vii) radiographic or biochemical evidence of high bone turnover.

In this retrospective cohort, SS was defined as a structured clinical phenotype based on prior literature.^4,5,9 Preoperative SS-related manifestations were recorded using a standardized assessment form. Each suspected case was independently reviewed by 2 physicians, with classification determined by consensus. SS was diagnosed when severe refractory SHPT was accompanied by progressive craniofacial deformity consistent with published descriptions, along with predefined craniofacial and skeletal features. Craniofacial features included mandibular protrusion, widened interdental spacing, zygomatic overgrowth, and malocclusion. Supportive skeletal features included documented height loss (≥ 3 cm), spinal deformity, lower-limb deformity, and pathological fracture. Archived photographs and craniofacial imaging were reviewed when available. Patients not meeting these criteria were classified as non-SS.

Exclusion Criteria

The exclusion criteria were as follows: (i) missing key baseline information required for eligibility assessment, phenotypic ascertainment, or covariate evaluation; (ii) malignancy, end-stage nonrenal organ failure, active infection, or acute metabolic complications; (iii) use of glucocorticoids or other medications affecting bone and mineral metabolism; and (iv) inability or refusal to provide informed consent. Patients without analyzable follow-up or unavailable outcome data for time-to-event analysis were also excluded.

Data Collection

Demographic, biochemical, medication, and radiological data were extracted from the institution’s electronic health records. Baseline variables included sex, age, height, dry weight, primary renal etiology, dialysis vintage, dialysis modality, and surgical approach. Biochemical parameters were obtained from a single preoperative fasting predialysis blood sample, and the measurement closest to PTX was used for analysis. Serum iPTH was quantified using chemiluminescent immunoassay (Siemens Immulite 2000; Siemens Healthineers, Erlangen, Germany), with an upper detection limit of 2500 pg/ml and a reference range of 0 to 69 pg/ml. Radiological evaluation included echocardiographic ejection fraction and assessment of cardiac valve and abdominal aortic calcification. Serum calcium was corrected for albumin concentration using the standard K/DOQI formula. For patients undergoing hemodialysis, the standard regimen was 3 sessions/wk, 4 hours per session (12 h/wk).

Surgical Methods and Perioperative Management

Preoperative evaluations ensured the absence of contraindications. Surgical treatment included total PTX or total PTX with autotransplantation, performed by experienced surgeons. The surgical approach was determined by surgeon expertise and patient clinical status.¹⁰

Follow-up and Clinical Outcomes

Participants were followed-up until December 2023. The primary outcome was all-cause mortality, and the secondary outcome was CVD mortality. All-cause mortality was defined as death from any cause after PTX. Causes of death were determined retrospectively using all available data, including medical records, dialysis documentation, emergency reports, and death certificates. For out-of-hospital deaths, additional information was obtained from previous medical records and family interviews. CVD mortality was defined according to International Classification of Diseases, 10th Revision criteria as death associated with myocardial infarction or other ischemic heart disease, heart failure, or hemorrhagic or thromboembolic stroke.¹¹ Time-to-event was calculated from PTX to death, kidney transplantation, withdrawal, or the end of the study period, whichever occurred first.

QOL was assessed using the Kidney Disease Quality of Life 36-Item Short-Form (KDQOL-36) scale.¹² Participants completed the survey through structured interviews before surgery and at the final postoperative follow-up. The KDQOL-36 includes the following 5 domains: symptom/problem list (12 items), effects of kidney disease (8 items), burden of kidney disease (4 items), SF-12 physical component summary, and mental component summary. Scores were calculated using the standard KDQOL-36 algorithm and linearly transformed to a range of 0 to 100 scale, with higher scores indicating better perceived QOL. Bone pain intensity was evaluated using the visual analogue scale, with scores ranging from 0 (no pain) to 10 (most severe pain). Clinical improvement was defined as a longitudinal reduction in visual analogue scale scores following surgery.

Statistical Analysis

Analyses were conducted using IBM SPSS Statistics (v23.0; IBM Corp., Armonk, NY), R software (v4.5.1; R Foundation for Statistical Computing, Vienna, Austria), and GraphPad Prism (v10.2.1; San Diego, CA). Normality was assessed using the Shapiro–Wilk test. Continuous variables were presented as mean ± SD or median (interquartile range) and compared using t test or Mann–Whitney U test. Categorical variables were presented as n (%) and compared using the chi-square test. Missing baseline C-reactive protein (CRP) values (175/740, 23.65%) were imputed using multiple imputation by chained equations under a missing-at-random working assumption; 30 imputed datasets were pooled using Rubin’s rules. Because the iPTH assay had an upper reportable limit of 2500 pg/ml, baseline iPTH was analyzed as a 3-level categorical variable: < 1500 pg/ml, 1,500–2499 pg/ml, and ≥ 2500 pg/ml. The ≥ 2500 pg/ml category reflects assay-ceiling values rather than precisely quantified concentrations. Factors associated with SS were evaluated using multivariable logistic regression. Postoperative analyses of KDQOL-36, bone pain, and height were exploratory and limited to participants with paired data; changes were assessed using the Wilcoxon signed-rank test. Survival probabilities for all-cause and CVD mortality were estimated using Kaplan–Meier analysis and compared using log-rank tests. Multivariable Cox proportional hazards models were used to examine associations between SS and mortality outcomes. In supplementary sensitivity analyses, an expanded multivariable model additionally included history of diabetes and other clinically relevant covariates. Sensitivity and subgroup analyses with interaction testing evaluated robustness. All analytical tests were 2-tailed, with P < 0.05 considered statistically significant. The authors take the responsibility for the integrity of the data. The STROBE statement was used to report these observational data.¹³

Ethics

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (PJ-YX2020-006), and written informed consent was obtained from all enrolled participants.

Results

Baseline Characteristics

Of the 1069 screened patients, 740 were included in the final analytic cohort after stepwise exclusion (Supplementary Figure S1). The cohort comprised 459 males (62.0%) and 281 females (38.0%), with a mean age of 47.68 ± 10.06 years. The median dialysis vintage was 7 (interquartile range: 5–10) years. According to the predefined phenotypic ascertainment procedure, 70 patients were classified as having SS, corresponding to a prevalence of 9.5%.

Baseline patient characteristics are presented in Table 1. Compared with the non-SS group, the SS group had a significantly longer median dialysis vintage (9 vs. 7 years; P < 0.001). Patients in the SS group exhibited significantly lower body mass index, serum albumin, serum phosphorus, and hemoglobin levels (all P < 0.05). In contrast, CRP and ALP levels were markedly higher in the SS group (all P < 0.05). A higher proportion of patients with SS had baseline iPTH values in the ≥ 2500 pg/ml category than those without SS (52.86% vs. 24.33%, P < 0.001). Prevalence of cardiac valve (72.86% vs. 47.61%) and abdominal aortic calcification (28.57% vs. 16.42%) was significantly higher in SS (all P < 0.05). Baseline use of erythropoiesis-stimulating agents, phosphate binders, calcitriol, and calcimimetics did not differ significantly between the 2 groups (all P > 0.05).

Table 1.

Baseline clinical, laboratory, and treatment characteristics of the SS and non-SS groups

Characteristics	Overall N = 740	SS group, n = 70	Non-SS group, n = 670	P-value
Demographic characteristics
Sex (male/female)	459/281	39/31	420/250	0.253
Age (yrs)	47.68 ± 10.06	46.51 ± 9.25	47.8 ± 10.14	0.309
BMI (kg/m2)	21.63 (19.73–24.38)	20.43 (18.98–22.26)	21.80 (19.83–24.57)	< 0.001
Primary renal disease, n (%)				0.549
Chronic glomerulonephritis	586 (79.19)	58 (82.86)	528 (78.81)
Diabetic nephropathy	19 (2.57)	1 (1.43)	18 (2.69)
Hypertensive nephropathy	74 (10.00)	8 (11.43)	66 (9.85)
Polycystic kidney disease	21 (2.84)	0 (0.00)	21 (3.13)
Others	40 (5.41)	3 (4.29)	37 (5.52)
Medical history, n (%)
History of smoking	173 (23.38)	11 (15.71)	162 (24.18)	0.111
History of hypertension	531 (71.76)	49 (70.00)	482 (71.94)	0.732
History of diabetes	30 (4.05)	2 (2.86)	28 (4.18)	0.594
History of cardiovascular disease	92 (12.43)	6 (8.57)	86 (12.84)	0.304
Dialysis- and surgery-related characteristics
Dialysis vintage (yrs)	7 (5–10)	9 (8–12)	7 (5–9)	< 0.001
Dialysis modality, n (%)				0.206
Hemodialysis	679 (91.76)	67 (95.71)	612 (91.34)
Peritoneal dialysis	61 (8.24)	3 (4.29)	58 (8.66)
Surgical approach, n (%)				0.676
tPTX + AT	646 (87.30)	60 (85.71)	586 (87.46)
tPTX	94 (12.70)	10 (14.29)	84 (12.54)
Laboratory parameters
Hemoglobin (g/l)	107.58 ± 21.78	102.00 ± 24.75	108.16 ± 21.38	0.024
ALB (g/l)	37.04 ± 4.57	34.79 ± 4.23	37.28 ± 4.55	< 0.001
CRP (mg/l)	3.90 (1.36–8.20)	5.00 (2.81–10.70)	3.70 (1.25–8.05)	0.013
Corrected calcium (mmol/l)	2.42 (2.27–2.58)	2.44 (2.29–2.56)	2.42 (2.26–2.58)	0.796
Serum phosphorus (mmol/l)	2.08 ± 0.51	1.95 ± 0.48	2.10 ± 0.51	0.022
Alkaline Phosphatase (U/L)	315.00 (177.50–687.00)	807.00 (510.25–1324.50)	299.50 (170.25–630.25)	< 0.001
iPTH category, n (%)				< 0.001
< 1500 pg/ml	272 (36.76)	11 (15.71)	261 (38.96)
1500–2499 pg/ml	268 (36.22)	22 (31.43)	246 (36.72)
≥ 2500 pg/ml	200 (27.03)	37 (52.86)	163 (24.33)
Cardiovascular assessments
Cardiac ejection fraction (%)	61 (60–64)	60 (59–63)	61 (60–64)	0.057
Cardiac valve calcification, n (%)	370 (50.00)	51 (72.86)	319 (47.61)	< 0.001
Abdominal aortic calcification, n (%)	130 (17.57)	20 (28.57)	110 (16.42)	0.011
Medication history, n (%)
ESAs, n (%)	592 (80.00)	59 (84.29)	533 (79.55)	0.346
Phosphate binders, n (%)	63 (8.51)	5 (7.14)	58 (8.66)	0.666
Calcitriol treatment, n (%)	133 (17.97)	18 (25.71)	115 (17.16)	0.076
Calcimimetics, n (%)	26 (3.51)	3 (4.29)	23 (3.43)	0.712

ALB, albumin; AT, autotransplantation; BMI, body mass index; CRP, C-reactive protein; iPTH, intact parathyroid hormone; SS, Sagliker syndrome; tPTX, total parathyroidectomy; ESAs, erythropoiesis-stimulating agents.

Data are expressed as mean ± SD, median (interquartile range), or n (%), as appropriate.

CRP data were available for 565 patients.

The ≥ 2500 pg/ml iPTH category represents values reported at the assay upper limit.

Risk Factors for SS

In Table 2, we show the logistic regression analyses of factors associated with SS. In univariable analysis, longer dialysis vintage, lower body mass index, lower serum phosphorus, elevated ALP, higher iPTH categories, lower albumin, lower hemoglobin, and the presence of vascular calcifications were associated with an increased risk of SS development (all P < 0.05).

Table 2.

Univariate and multivariable logistic regression analysis of risk factors for Sagliker syndrome

Variables	Univariate logistic regression	P-value	Multivariable logistic regression	P-value
	OR (95% CI)		OR (95% CI)
Dialysis vintage (yrs)	1.22 (1.14–1.31)	< 0.001	1.21 (1.12–1.31)	< 0.001
BMI (kg/m2)	0.86 (0.79–0.94)	< 0.001	0.95 (0.87–1.04)	0.244
Serum phosphorus (mmol/l)
≤2.08 vs. > 2.08	1.88 (1.12–3.16)	0.017	1.48 (0.84–2.63)	0.179
Alkaline phosphatase (U/L)
> 315 vs. ≤315	6.23 (3.21–12.08)	< 0.001	4.14 (1.90–9.74)	< 0.001
iPTH (pg/ml)
1500–2499 vs. < 1500	2.12 (1.01–4.47)	0.048	1.15 (0.50–2.79)	0.742
≥ 2500 vs. < 1500	5.39 (2.67–10.87)	< 0.001	1.42 (0.60–3.55)	0.436
ALB (g/l)	0.89 (0.84–0.94)	< 0.001	0.92 (0.86–0.98)	0.013
Hemoglobin (g/l)	0.99 (0.98–1.00)	0.025	0.99 (0.98–1.01)	0.270
Cardiac valve calcification	2.95 (1.71–5.11)	< 0.001	2.11 (1.18–3.92)	0.014
Abdominal aortic calcification	2.04 (1.17–3.56)	0.013	2.14 (1.14–3.95)	0.016

ALB, albumin; ALP, alkaline phosphatase; BMI, body mass index; CI, confidence interval; iPTH, intact parathyroid hormone; OR, odds ratio; SS, Sagliker syndrome.

iPTH was analyzed in 3 categories, with < 1500 pg/ml as the reference group. The ≥ 2500 pg/ml category represents values reported at the assay upper limit. Serum phosphorus and ALP were dichotomized as ≤2.08 vs. > 2.08 mmol/l and > 315 vs. ≤315 U/L, respectively.

In multivariable analysis, longer dialysis vintage (OR = 1.21, 95% CI: 1.12–1.31, P < 0.001) and ALP levels > 315 U/L (OR = 4.14, 95% CI: 1.90–9.74, P < 0.001) remained independently associated with SS. Furthermore, lower albumin (OR = 0.92, 95% CI: 0.86–0.98, P = 0.013), cardiac valve calcification (OR = 2.11, 95% CI: 1.18–3.92, P = 0.014), and abdominal aortic calcification (OR = 2.14, 95% CI: 1.14–3.95, P = 0.016) were independently associated with SS.

Exploratory Cephalometric Findings

In this exploratory subset (Supplementary Table S1), the SS group showed higher values for the A point–nasion–B point angle and the Articulare–Gonion–Menton angle, as well as a larger total anterior facial height than the non-SS group (all P < 0.05). Skeletal class II malocclusion was present in all patients with SS and in none of the non-SS patients (P < 0.05). Representative lateral cephalometric radiographs are shown in Supplementary Figure S2.

Exploratory Post-PTX Clinical Outcomes

Exploratory analyses in SS patients with available paired follow-up data suggested postoperative improvement after PTX. Follow-up photographs suggested stabilization and partial alleviation of craniofacial deformity in representative cases (Figure 1). Among the 25 patients assessed using the KDQOL-36 questionnaire, significant post-PTX improvements were observed across all subscales, including physical component summary, mental component summary, burden of kidney disease, symptoms and problems of kidney disease, and effects of kidney disease (all P < 0.05; Table 3). Bone pain scores were significantly reduced after surgery in 45 patients with paired visual analogue scale data (P < 0.001; Figure 2a). In 15 patients with marked preoperative stature reduction and complete follow-up data, height loss appeared to stabilize after PTX (P < 0.05; Figure 2b).

Figure 1.

Longitudinal facial changes in representative patients with Sagliker syndrome. (a, d) Baseline facial appearance before initiation of dialysis. (b, e) Facial features at the time of parathyroidectomy (PTX), demonstrating characteristic “lion-like” facies with progressive craniofacial remodeling, maxillary and mandibular enlargement, dental malocclusion, and lip incompetence. (c, f) Postoperative follow-up images after PTX, showing stabilization and partial improvement of craniofacial deformities. Note: Written informed consent was obtained from the patients for the publication of these images.

Table 3.

Exploratory analysis of KDQOL-36 domain scores before and after parathyroidectomy (n = 25)

KDQOL-36 domains	Pre-PTX	Post-PTX	Z	P-value
PCS	27.03 (22.52–35.64)	32.62 (29.64–38.09)	−2.031	0.042
MCS	37.74 (33.58–52.54)	48.72 (42.35–57.10)	−2.408	0.016
BKD	6.25 (0.00–25.00)	31.25 (18.75–40.63)	−3.272	0.001
SPKD	79.17 (61.46–95.83)	91.67 (89.58–95.83)	−3.487	< 0.001
EKD	53.13 (45.32–67.19)	65.63 (56.25–71.88)	−1.987	0.047

BKD, burden of kidney disease; EKD, effects of kidney disease; MCS, mental component summary; PCS, physical component summary; PTX, parathyroidectomy; SPKD, symptoms and problems of kidney disease.

Figure 2.

Exploratory analysis of changes in bone pain and body height after PTX in patients with SS. Clinical parameters were compared between baseline (pre-PTX) and follow-up (post-PTX). (a) Significant reduction in bone pain scores after surgery (n = 45). (b) Comparison of body height in a subgroup of patients with SS (n = 15) who exhibited significant preoperative stature reduction and provided complete follow-up data. Each line represents 1 patient. ∗P < 0.05, ∗∗∗P < 0.001. PTX, parathyroidectomy; SS, Sagliker syndrome.

Survival Outcomes

During a median follow-up of 81 months, 102 deaths (13.78%) occurred. Among them, 19 occurred in the SS group and 83 in the non-SS group. Among the 49 deaths classified as cardiovascular deaths, the causes were heart failure (n = 26), stroke (n = 18), and myocardial infarction or other ischemic heart disease (n = 5). Kaplan-Meier survival analysis (Figure 3) showed significantly higher all-cause mortality (log-rank test χ² = 7.233, P = 0.007) and CVD mortality (log-rank test χ² = 10.096, P = 0.001) in the SS group than in the non-SS group.

Figure 3.

Kaplan–Meier analysis of all-cause and cardiovascular disease mortality. Survival probability for all-cause mortality (a) and cardiovascular disease mortality (b) were compared between the SS group and non-SS group. SS, Sagliker syndrome.

In multivariable Cox regression models, SS remained associated with both all-cause and CVD mortality after sequential adjustment for covariates. In fully adjusted Cox regression models (model 3), SS was independently associated with higher risks of both all-cause mortality (HR = 1.71, 95% CI: 1.01–2.89, P = 0.045) and CVD mortality (HR = 2.44, 95% CI: 1.17–5.06, P = 0.018; Table 4).

Table 4.

Cox regression analysis of SS and non-SS groups for all-cause and CVD mortality

Characteristics	Model 1a HR (95% CI)	P-value	Model 2b HR (95% CI)	P-value	Model 3c HR (95% CI)	P-value
All-cause mortality
Non-SS group	1.00 (Reference)	–	1.00 (Reference)	–	1.00 (Reference)	–
SS group	1.96 (1.18–3.25)	0.010	2.10 (1.27–3.49)	0.004	1.71 (1.01–2.89)	0.045
CVD mortality
Non-SS group	1.00 (Reference)	–	1.00 (Reference)	–	1.00 (Reference)	–
SS group	2.76 (1.41–5.39)	0.004	3.07 (1.57–6.01)	0.002	2.44 (1.17–5.06)	0.018

ALB, albumin; CI, confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; EF, ejection fraction; HR, hazard ratio; SS, Sagliker syndrome.

^aModel 1: Unadjusted (crude) hazard ratio.

^bModel 2: Adjusted for age and sex (only in all-cause mortality group).

^cModel 3: Adjusted for age, sex, ALB, EF, and cardiac valve calcification in the all-cause mortality analysis, and for age, history of cardiovascular disease, ALB, EF, cardiac valve calcification, and CRP in the CVD mortality analysis.

Sensitivity and Subgroup Analyses

Sensitivity analyses confirmed the robustness of the prognostic findings. After excluding patients who died within the first 2 years of follow-up, SS remained associated with all-cause mortality (HR = 2.14, 95% CI: 1.19–3.85, P = 0.012) and CVD mortality (HR = 3.51, 95% CI: 1.62–7.60, P = 0.002; Supplementary Table S2). In an expanded multivariable model additionally adjusted for history of diabetes, history of CVD, dialysis modality, surgical approach, and primary disease, SS remained associated with both all-cause and cardiovascular mortality (all P < 0.05; Supplementary Table S3). Subgroup analyses likewise showed a consistent association across the prespecified clinical strata (Figure 4). The prognostic impact of SS on all-cause and CVD mortality was consistent across all examined subgroups, including age, sex, history of CVD, hypertension, abdominal aortic calcification, and surgical approach (all P for interaction > 0.05).

Figure 4.

Subgroup analysis of the association between SS and mortality outcomes. (a) All-cause mortality HRs adjusted for sex, age, ALB, EF, and cardiac valve calcification. (b) Cardiovascular disease mortality HRs adjusted for age, history of cardiovascular disease, ALB, EF, cardiac valve calcification, and CRP. ALB, albumin; CI, confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; EF, ejection fraction; HR, hazard ratio; SS, Sagliker syndrome; tPTX + AT, total parathyroidectomy with autotransplantation; tPTX, total parathyroidectomy.

Discussion

To our knowledge, this study represents the largest cohort analysis of SS to date. In this PTX-treated cohort, SS was associated with increased long-term all-cause and CVD mortality, despite exploratory postoperative improvements in symptoms and QOL. These findings suggest that SS extends beyond a skeletal abnormality and may reflect an advanced phenotype of refractory SHPT characterized by substantial preexisting systemic injury.

SS represents the terminal stage of renal osteodystrophy, historically termed “uremic leontiasis ossea.”¹⁴ Sagliker et al.⁴ first defined this condition as a distinct clinical entity in 2004, reporting a prevalence of 0.5% in a Turkish hemodialysis population.¹⁵ In our cohort of patients with refractory SHPT undergoing PTX, the prevalence of SS was 9.5%. This elevated prevalence of SS observed in this cohort likely reflects referral bias, because the study was specifically restricted to patients with severe, treatment-refractory SHPT. SS is characterized by a spectrum of craniofacial and skeletal abnormalities, including severe disfigurement, height loss, irregular skull and facial bone remodeling, maxilla and mandible destruction, benign intraoral soft tissue neoplasms, upward-curved fingertips, and deformities of the knees and scapulae.^4,5 In addition, patients with SS develop complications such as spontaneous fractures, hearing loss, neurological impairment, and psychological disorders.^9,16,17 These structural abnormalities substantially impair QOL and increase morbidity.^9,18 In China, the large dialysis population and persistent challenges in chronic kidney disease–mineral and bone disorder management may contribute to delayed recognition of SS in clinical practice. In our 2020 study, only 22.7% of hemodialysis patients in Anhui achieved target iPTH levels,¹⁹ indicating a treatment gap that may predispose patients to SS. However, the pathophysiology of SS remains incompletely understood and is likely multifactorial, involving genetic susceptibility and delayed treatment.¹⁸

Accurate case ascertainment remains a major challenge in SS research. Because previous studies have relied primarily on clinical features rather than standardized morphometric criteria, SS was defined here as a structured clinical phenotype. Classification incorporated a predefined assessment form, dual-physician confirmation, and review of archived photographs or craniofacial imaging when available. In a small subset with available lateral cephalometric radiographs, exploratory analysis showed a pattern consistent with previous reports, including higher A point–nasion–B point and Articulare–Gonion–Menton angles, larger total anterior facial height, and skeletal class II malocclusion in the SS group. However, because cephalometric radiographs were not available for the full cohort, these findings were considered supportive rather than diagnostic.

Consistent with previous evidence that prolonged dialysis vintage, as well as elevated ALP and iPTH levels are potential risk factors,^6,9,20 multivariate analysis identified longer dialysis vintage, higher ALP levels, hypoalbuminemia, and vascular calcification as correlates of SS. Each additional year of dialysis increased SS risk by 1.21-fold, aligning with evidence linking dialysis vintage to SHPT severity.¹⁶ In our cohort, iPTH was measured using an assay capped at 2500 pg/ml, which likely truncated values in patients with SS. After ceiling-adjusted categorization of iPTH, between-group differences were clearer; however, the univariable association did not persist after multivariable adjustment. This finding indicates that a single preoperative iPTH value may not adequately represent cumulative parathyroid burden and may overlap with dialysis vintage, ALP, and other indicators of chronic disease severity.

Consistent with previous studies,21, 22, 23 patients with SS demonstrated lower body mass index, albumin, hemoglobin, and phosphorus levels, along with higher CRP levels at baseline, suggesting a malnutrition-inflammation burden in this group. Hypoalbuminemia was independently associated with SS, supporting a possible link between malnutrition-inflammation burden and this phenotype and the integration of nutritional interventions in high-risk patients. Although CRP levels were elevated in the SS group, they were not significantly associated with SS in univariate logistic analysis when treated as a continuous variable; thus, CRP should be interpreted as a marker of inflammatory burden rather than an independent predictor. In contrast to earlier reports suggesting higher susceptibility in younger populations,^9,21 no significant differences in age or sex distribution were observed between groups. This discrepancy may reflect selection bias in smaller previous studies. Notably, hypophosphatemia in patients with SS contrasts with the conventional hyperphosphatemia-driven SHPT model. This finding may result from severe bone turnover and mineral redistribution, as well as from malnutrition. Craniofacial deformities in SS may impair mastication, thereby limiting protein and phosphorus intake. Given the retrospective design and incomplete CRP data, the contribution of inflammation to SS pathogenesis requires confirmation in prospective studies with comprehensive inflammatory profiling.

The prevalence of cardiac valve calcification was markedly higher in patients with SS than in those without SS. This finding is consistent with the bone-vascular axis theory, in which severe bone resorption, characteristic of SS, driven by markedly elevated ALP and iPTH, increases circulating calcium and phosphate levels and promotes hydroxyapatite deposition in the vascular media.^24,25 Because vascular calcification, including both cardiac valve calcification^26,27 and abdominal aortic calcification,²⁸ strongly predicts cardiovascular mortality in dialysis populations,²⁹ its high prevalence may partially explain the increased cardiovascular mortality observed in patients with SS after PTX. However, residual confounding cannot be excluded.

Although the pathogenesis of SS remains incompletely defined, current evidence supports a multifactorial etiology. Recent studies have identified chromosomal abnormalities as potential drivers of disease progression.²⁰ An international multicenter study of 60 patients with SS reported GNAS1 missense mutations in 40% of analyzed cases, specifically involving exons 1, 4, and 10, after excluding genomic abnormalities and calcium-sensing receptor gene mutations.¹⁸ These findings suggest that a genetic susceptibility may profoundly disrupt bone and mineral homeostasis, particularly in the setting of prolonged SHPT. However, molecular and genetic analyses were not performed in the present cohort because of financial constraints.

Recent pharmacological advances, particularly calcimimetics, have shown potential in slowing the progression of uremic bone disease, with the long-term objective of eliminating SS as a clinical entity.^30,31 According to the Kidney Disease: Improving Global Outcomes guidelines, PTX is recommended for patients with advanced chronic kidney disease and medically refractory SHPT.³ Early integrated management, including pharmacological optimization, dialysis modification, and timely surgical referral, is essential to interrupt the cycle of bone and metabolic dysfunction.²⁴ Such strategies may improve biochemical control and prevent irreversible deformities associated with SS.

SS-related skeletal diseases can result in permanent damage, particularly in younger patients.³² Clinical evidence indicates that PTX may halt facial deformity progression and prevent further height loss in patients with SS. In a small study, Pineda et al.³³ reported that total PTX arrested musculoskeletal progression in 5 patients with SS, although the interpretation was limited by a 14-month follow-up. Because advanced skeletal deformities are largely irreversible, the primary therapeutic objective should be early control of SHPT to prevent progression and improve QOL. In the present cohort, exploratory analyses from limited paired follow-up data suggested that PTX may slow deformity progression, stabilize height loss, and reduce bone pain in some patients with SS. These findings support the importance of timely surgical intervention; however, they remain hypothesis-generating because of small sample sizes.

In addition to physical complications, SS imposes a substantial neuropsychiatric burden, including depression, anxiety, insomnia, and paresthesia.³² In this study, patients with available paired postoperative data demonstrated improvements across all KDQOL-36 domains and reductions in bone pain. These results indicate that PTX may improve both physical and psychological outcomes, potentially through alleviation of metabolic imbalance and chronic pain. Although the mechanisms linking biochemical abnormalities to mental health remain unclear, consistent postoperative QOL improvements highlight the role of surgery in reducing SS-related disability.

Large-scale studies have consistently shown that PTX is associated with improved long-term survival in patients with refractory SHPT.34, 35, 36 Despite these benefits, patients with SS in our PTX-treated cohort exhibited significantly higher risks of all-cause and CVD mortality than those without SS. This observation suggests that SS reflects a higher preexisting systemic burden, particularly cardiovascular involvement, that may not be fully reversible after PTX. The association remained consistent in sensitivity and subgroup analyses. However, because all participants underwent PTX and no nonsurgical comparator was included, causal inference regarding the survival benefit of PTX in SS is not possible. The persistent excess risk likely reflects irreversible systemic and cardiovascular damage accumulated during the prolonged uncontrolled hyperparathyroidism, which continues to influence long-term outcomes despite the successful biochemical correction following PTX.

This study has several limitations. The retrospective single-center design, highly selected PTX-treated cohort, and exclusion of 329 screened patients may have limited generalizability and introduced referral and selection bias. SS classification relied on structured dual-physician clinical phenotyping rather than standardized cephalometric or morphometric criteria, introducing potential misclassification. Postoperative QOL and symptom analyses were based on small paired subsets and should be interpreted as exploratory. Incomplete perioperative documentation limited longitudinal analyses, and residual confounding remains possible despite multivariable adjustment and sensitivity analyses. Future multicenter prospective studies with standardized phenotyping and molecular profiling are needed to refine SS classification and clarify underlying mechanisms.

Conclusion

In this PTX-treated cohort, SS represents a severe phenotype of refractory SHPT characterized by extensive skeletal deformity and a high burden of chronic kidney disease–mineral and bone disorder–related abnormalities. Prolonged dialysis vintage, hypoalbuminemia, elevated ALP levels, and vascular calcification were independently associated with its development. Although PTX provided meaningful symptomatic benefit, SS was associated with higher long-term mortality during post-PTX follow-up in this cohort. Early identification and timely intervention may help prevent progression to this advanced phenotype.

Disclosure

All the authors declared no competing interests.

Supplementary Material

Supplementary File (PDF)

Figure S1. Flowchart of cohort assembly and reasons for exclusion. Figure S2. Representative lateral cephalometric radiographs from patients with severe secondary hyperparathyroidism with and without Sagliker syndrome. Table S1. Exploratory lateral cephalometric measurements in the subset with available radiographs among SS and non-SS groups (n = 9). Table S2. Sensitivity analysis of the association between SS and all-cause and CVD mortality excluding patients who died within the first 2 years of follow-up. Table S3. Multivariable Cox regression analysis of the association between SS and all-cause and CVD mortality, adjusted for comprehensive clinical covariates. STROBE Checklist.