Chromosomal findings and sequence analysis of target exons of calcium-sensingreceptor (CaSR) gene in patients with Sagliker syndrome.

BACKGROUND/AIM: Sagliker syndrome (SS) develops as a continuation of chronic kidney disease and secondary hyperparathyroidism conditions. It was thought that there are some genetic predisposition factors leading to SS. The calcium-sensing receptor (CaSR) is essential for calcium homeostasis in the body. We aimed to examine SS patients for chromosome aberrations (CAs) and CaSR gene abnormalities in exons 2 and 3. MATERIALS AND METHODS: Twenty-three patients and 23 control subjects were admitted to Balcali Hospital of the Medical Faculty of Çukurova University in Turkey between 2009 and 2011. Chromosomal analysis was performed according to standard cytogenetic methods. Full sequencing of exons 2 and 3 of the CaSR gene was done. RESULTS: We found base alterations and deletions in exons 2 and 3 of the CaSR gene. We also found a statistically significant increase in the rate of CAs in patients compared to controls. In total we evaluated 639 metaphase plaques in 23 patients and found 241 CAs, of which 88% were structural and 12% were numerical abnormalities. CONCLUSION: There is no relation between the etiology of SS and nucleotide alterations that we could find in exons 2 and 3 of the CaSR gene. Our data suggest that there may be a correlation between CAs and the progression of SS.

Gene mutations in chronic kidney disease patients with secondary hyperparathyroidism and Sagliker syndrome.

Sagliker syndrome (SS) develops particularly before puberty while chronic kidney disease (CKD) reaches stage 3 with overt secondary hyperparathyroidism. We conducted screening for mutations in all the 13 exons of GNAS1 gene, all 3 exons of FGF23, and all 18 exons in FGFR3 genes in 23 patients. In 73.9% (17 of 23) patients, 17 genetic abnormalities in GNAS1 were detected. Seven (58.3%) of 12 nucleotide alterations comprised novel missense mutations and 3 nonsense. Mismutations were in different manner. There were also 6 heterozygous transversion polymorphisms in exons. Six were introngenic mutations (introns 65626, 70387, 70817). We found 10 mutations with different manner in FGF23 gene. Two were defined previously but remaining 8 were novel mutations. Three were in intronic region near exon 2. We sequenced all exons and intronic regions near exon-exon junction regions of FGFR3 gene. We found 22 mutations with different manner. Six were defined previously and remaining 16 were novel mutations. Eight of them were in intronic region near exon 11 and the last 2 were in noncoding exonic region of exons. One was in the exon-exon junction region between exon 11 and 12, therefore this mutation might be preventing splicing of this intron. Because the incidence of CKD late stage 3 is around 8% but the incidence of SS is around 0.5% in CKD, these gene mismutations might be responsible for bone deformities such as McCune-Albright syndrome and achondroplasias. Although our patients were not resembling any of them, they could be in between, and SS might be a combination-compulsion of bone dysplasias-hereditary osteodystrophies and CKD.

Low Serum Phosphorus Level in Massry's Phosphate Depletion Syndrome May Be One of the Causes of Acute Heart Failure.

Hypophosphatemia has been found to be associated with multiple organ dysfunction. In this study we aimed to investigate the association between low serum phosphorus and acute heart failure. A total of 213 subjects, 101 patients with acute heart failure and 112 healthy subjects were included in this case-control study. Serum phosphorus levels, calcium levels, and PTH concentrations were measured. Ejection fraction percentages, pulse rates, systolic and diastolic blood pressures were recorded. The groups were similar in terms of age and gender (p=0.067 and 0.995, respectively). The phosphorus levels and ejection fraction percentages of the patients with heart failure were lower than for the healthy subjects (p<0.001). Frequency of hypophosphatemia was higher in the heart failure group (p<0.001). There was a strong relationship between low serum phosphorus level and acute heart failure (OR 9.85, CI 95% 3.6-26.3, p<0.001). The phosphorus level of patients with acute heart failure was found to be low in this study. Therefore, the phosphorus level should be controlled in patients with acute heart failure and phosphorus supplementation can be a complimentary treatment for these patients.

International evaluation of unrecognizably uglifying human faces in late and severe secondary hyperparathyroidism in chronic kidney disease. Sagliker syndrome. A unique catastrophic entity, cytogenetic studies for chromosomal abnormalities, calcium-sensing receptor gene and GNAS1 mutations. Striking and promising missense mutations on the GNAS1 gene exons 1, 4, 10, 4.

Hypotheses explaining pathogenesis of secondary hyperparathyroidism (SH) in late and severe CKD as a unique entity called Sagliker syndrome (SS) are still unclear. This international study contains 60 patients from Turkey, India, Malaysia, China, Romania, Egypt, Tunisia, Taiwan, Mexico, Algeria, Poland, Russia, and Iran. We examined patients and first degree relatives for cytogenetic chromosomal abnormalities, calcium sensing receptor (Ca SR) genes in exons 2 and 3 abnormalities and GNAS1 genes mutations in exons 1, 4, 5, 7, 10, 13. Our syndrome could be a new syndrome in between SH, CKD, and hereditary bone dystrophies. We could not find chromosomal abnormalities in cytogenetics and on Ca SR gene exons 2 and 3. Interestingly, we did find promising missense mutations on the GNAS1 gene exons 1, 4, 10, 4. We finally thought that those catastrophic bone diseases were severe SH and its late treatments due to monetary deficiencies and iatrogenic mistreatments not started as early as possible. This was a sine qua non humanity task. Those brand new striking GNAS1 genes missense mutations have to be considered from now on for the genesis of SS.

A controlled study of psychiatric manifestations and electroencephalography findings in chronic kidney disease patients with Sagliker syndrome.

Sagliker syndrome (SS) is a novel syndrome that was described in 2004 in patients with chronic kidney disease (CKD). The aim of this study was to assess psychiatric evaluations and electroencephalography (EEG) findings of patients with CKD and SS to compare them with patients with CKD having characteristics similar to that of the study group, in terms of age and gender. The study group comprised 13 patients with CKD and SS. The control group included 13 patients with CKD. Psychiatric diseases were diagnosed using the Structure Clinical Interview. Beck Depression Inventory, Beck Anxiety Inventory, Social Comparison Scale, Hopelessness Scale, and Mini Mental State Examination (MMSE) were administered to the groups. Moreover, EEG recording for all the patients was performed. According to the results obtained from the Structure Clinical Interview, 69.2% of patients with CKD and SS were diagnosed with a mental disease, as compared with only 3 (23.1%) patients with CKD. There was a significant difference between the study and the control group (P < .001). As compared with the control group, patients with CKD and SS had significantly higher scores on the Beck Depression Inventory, the Beck Anxiety Inventory, and the Hopelessness Scale. However, patients with CKD and SS had significantly lower scores on the Social Comparison Scale. The MMSE scores were not significantly different between the 2 groups. When the 2 groups were evaluated separately, no significant differences were found between the EEG abnormalities and psychiatric diagnosis of both the groups. However, an evaluation of EEG abnormalities in all cases with CKD suggested a statistically significant difference between them. In the EEG recordings, electrical seizures activity was not enrolled in any of the cases. In the present study, psychiatric morbidity for patients with CKD and SS was worse than for patients with only CKD. These results indicate a need to develop an effective psychologic strategy for dealing with psychiatric disorders among patients with CKD and SS.

Audiological findings in chronic kidney disease patients with Sagliker syndrome.

Potential hearing loss was found to be high in a 10 patients with chronic kidney disease and Sagliker syndrome. The cause of hearing loss in these subjects remains unknown. We do not know whether those are the results of preexisting renal disease, hemodialysis, or other factors. Thus, future studies will include more subjects with Sagliker syndrome to determine the frequency of hearing loss and to investigate the etiologic factors that cause loss of hearing.

Is survival enough for quality of life in Sagliker Syndrome-uglifying human face appearances in chronic kidney disease?

BACKGROUND: It is known that secondary hyperparathyroidism (SH) and particularly skeletal changes is a severe condition in chronic kidney disease (CKD). Sagliker syndrome (SS) is a very prominent feature in CKD including uglifying human face appearances, short stature, extremely severe maxillary and mandibulary changes, soft tissues in the mouth, teeth-dental abnormalities, finger tip changes and severe psychological problems. METHODS: In the last 8 years we have confronted 36 extremely incredible SS cases in CKD by performing an international study in Turkey, India, Malaysia, Romania and Egypt. RESULTS: In addition to the uglifying human face appearance, we found extremely severe X-ray and tomographical, pantomographical, histo-pathological changes in the head and whole body. Finally, we compared previous face pictures with recent ones. Just a few years earlier they had been pretty and good-looking young boys and girls. By investigating their history, we understood they had not received proper therapy and were in the late-irreversible period. CONCLUSION: SS is a serious and severe complication of CKD. Late and improper treatment leads to abnormalities throughout skeleton particularly in the skull and face. Changes particularly in children and teens become irreversible-disastrous for appearance and psychological health. Appropriate treatment must begin as early as possible in specialized centers. It is possible that SS patients may survive long-term with dialysis, but with all those particular changes could anyone claim this type of life would continue in an acceptable way without extending their height, correcting all the changes in the skull and face, remodeling new faces and most particularly convincing the patients to deal with all those tragi-dramatic psychological problems?

International study on Sagliker syndrome and uglifying human face appearance in severe and late secondary hyperparathyroidism in chronic kidney disease patients.

OBJECTIVE: It is known that skeletal changes due to secondary hyperparathyroidism (SH) can be severe in chronic kidney disease (CKD). Recently described Sagliker syndrome (SS) is a very striking and prominent feature of SH in CKD, including an uglifying appearance to the face, short stature, extremely severe maxillary and mandibulary changes, soft tissue in the mouth, teeth/dental abnormalities, fingertip changes, knee and scapula deformities, hearing abnormalities, and neurological and, more important, severe psychological problems. DESIGN, SETTING, PATIENTS: In the past 8 years, we have encountered 40 cases of SS in SH and CKD by performing an international study in Turkey, India, Romania, Egypt, Maleysia, Tunis, and China. RESULTS: The medical history of these patients showed that they did not receive proper therapy. Changes, particularly in children and teenagers, become irreversible, which was disastrous for the patients both aesthetically and psychologically. CONCLUSION: Treatment must begin early and be the appropriate treatment given in centers with sophisticated skills. Otherwise, the inability to correct all the changes in the skull and face, to remodel a new face, to extending the height, and, most important, to convince the patients to face the dramatic psychological problems can be catastrophic for those patients.

Cephalometric evaluation of patients with Sagliker syndrome: uglifying human face appearance in severe and late secondary hyperparathyroidism in chronic renal failure patients.

It is well known that secondary hyperparathyroidism may be an extremely severe condition in chronic renal failure, and almost all patients with chronic kidney disease, even in the well-developed countries, encounter every kind of bone abnormalities if they are not treated properly. Although some sporadic cases have been reported of unique facial bone changes, the largest collection of this phenomenon has been reported by Sagliker et al. We also have found 6 of 9 patients who have these changes (Sagliker syndrome) to manifest class II malocclusion of the upper and lower jaws according to dental universally accepted criteria by performing cephalometric studies, x-ray plain films, tomographic procedures, and drawing technology.

Neurologic manifestations in Sagliker syndrome: uglifying human face appearance in severe and late secondary hyperparathyroidism in chronic renal failure patients.

Patients with chronic renal failure (CRF) often have signs and symptoms related to fluid and electrolyte disturbances, anemia, malnutrition, bone disease, and gastrointestinal problems. Vascular and neurologic impairment in particular remain an important source of morbidity and mortality in this vulnerable patient population. Sagliker syndrome is a novel syndrome that was recently described in 2004 in patients with CRF and severe and late secondary hyperparathyroidism who suffered from severe skull and facial bone changes, particularly from uglifying human face appearances and neuropsychiatric disorders. The goal of this study was to assess neuropsychiatric manifestations occurring in CRF patients with Sagliker syndrome. Four female and 8 male patients with CRF on regular dialysis at the hemodialysis units of the Internal Medicine Departments around southern Turkey participated in the study. All patients underwent a clinical neurologic examination performed by the same neurologist. Neuropsychiatric signs and symptoms were found in all cases. The results showed that the most frequent neurologic manifestations in CRF patients with Sagliker syndrome were headache, polyneuropathy, cranial neuropathy, fatigue, and psychiatric disorders.

Sagliker syndrome: uglifying human face appearance in late and severe secondary hyperparathyroidism in chronic renal failure.

Almost every patient with chronic renal failure (CRF) eventually develops secondary hyperparathyroidism (SH) unless they are treated with proper and novel medications in advanced medical centers by skilled medical personnel. Every kind of bone abnormality including skull deformities has been described in detail by almost every concerned researcher and textbook, but descriptions of this phenomenon are limited in the medical literature to the years from 1973 to 1977. To our knowledge, extensive data regarding uglifying human face appearances have not been defined so far in the literature. We are therefore making this addition to the clinical nephrology field by accumulating such data. After we found 2 consecutive peculiar and unique patients with uglifying human face appearances in 2000, we attempted to inform and draw attention to this new entity to all hemodialysis (HD) centers in Turkey, as well as in other developing countries around the world to collect data on this phenomenon. Accordingly, we visited dialysis centers and patients' houses to collect detailed information, including medical clinical histories, physical examinations, laboratory data, biographies, current medications, and so forth. We found 25 patients who had CRF, SH, short stature, extremely severe skull changes, maxillary and mandibular bone changes, teeth/dental abnormalities, and soft and innocuous tumoral tissues in the mouth (hence, uglifying the appearance of the face), fingertip changes, severe psychologic problems, and depression. It appears that patients with CRF may have a new syndrome of bone deformities that have long been neglected, ignored, and forgotten since the mid-1970s when they were first described. This is vital and critical information for the clinical status of patients who suffered from the syndrome that we have named Sagliker syndrome (SS), and we believe there are many more patients in the world who are suffering from it.

Effect of tempol (4-hydroxy tempo) on gentamicin-induced nephrotoxicity in rats.

We investigated the effects of tempol (4-hydroxy tempo), a membrane-permeable radical scavenger, on gentamicin-induced renal failure in rats. The rats were given gentamicin (100 mg/kg/day, i.p., once a day); and gentamicin (100 mg/kg/day, i.p.) and tempol (3.5, 7 or 14 mg/kg/day, i.p., once a day). At the end of 7 days, the gentamicin group produced the remarkable nephrotoxicity, characterized by a significantly decreased creatinine clearance and increased serum creatinine, blood urea nitrogen (BUN) and daily urine volume when compared with controls. In control the BUN value was 21.2 +/- 0.07 (mg/100 mL); in comparison, it was 96.9 +/- 6.03 in gentamicin group (P < 0.05). Renal histopathologic examination confirmed acute tubular necrosis in this group. In rats treated with gentamicin and tempol a partial improvement in biochemical and histologic parameters was observed. BUN values were 96.9 +/- 6.03 and 36.3 +/- 2.39 in gentamicin, and gentamicin plus tempol (14 mg/kg) treated groups, respectively (P < 0.05). These results suggest that the administration of tempol may have a protective effect on gentamicin-induced nephrotoxicity in rats.

Heart rate variability, left ventricular functions, and cardiac autonomic neuropathy in patients undergoing chronic hemodialysis.

OBJECTIVE: Autonomic neuropathy and impairment of left ventricular functions (LVF) have been frequently encountered in chronic renal failure (CRF). The aim of the present study was to evaluate the relationship of cardiac autonomic modulation impairments, as assessed by means of heart rate variability (HRV), with clinical characteristics, and left ventricular function in the patients with CRF undergoing hemodialysis (HD). METHODS: Twenty control subjects (Group I) and 22 comparable by age and gender patients with CRF undergoing hemodialysis (Group II) were enrolled in the study. After routine clinical and biochemical evaluations, electrocardiography, and 2 Dimensional, M Mode echocardiography were performed in all participants. Frequency domain HRV analysis was studied by using Kardiosis System. The powers (P1 and P2) and the central frequencies (F1 and F2) of low and of high frequency spectral bands were recorded. RESULTS: End systolic (ESV) and end diastolic volumes (EDV) were significantly higher in Group II (59.3 +/- 21.1mL vs. 34.0 +/- 14.3 mL and 131.5 +/- 37.3 mL vs. 96.9 +/- 18.9 mL, p < 0.01, p < 0.05, respectively) when compared to those of Group I. Ejection fraction (EF) and fractional shortening (FS) were significantly lower in Group II than in control subjects (52.3 +/- 2.4% vs. 63.7 +/- 10.1% and 0.29 +/- 0.01 vs. 0.34 +/- 0.07, p < 0.001, p < 0.05, respectively). P and P2 were decreased in Group II than in Group I (136.2 +/- 173.9 m s2 vs. 911.0 +/- 685.5 and 96.5 +/- 149.6 vs. 499.7 +/- 679.5, p < 0.001, p < 0.01, respectively). Significant correlations were found between high frequency spectral power and dialysis duration (DD), ESV, EDV, EF, FS (r = 0.52 p < 0.01, r = 0.68 p < 0.001, r = 0.65 p < 0.002, r = 0.66 p < 0.02, and r = 0.69 p < 0.01). CONCLUSION: As a result, the dependence of cardiac autonomic neuropathy on the disease duration and degree of left ventricular function impairment was shown in the patients undergoing chronic hemodialysis.