NIVOLUMAB ASSOCIATED ENDOCRINE ABNORMALITIES: CHALLENGING CASES FROM A REFERENCE CLINIC.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. Antibodies directed against programmed cell death receptor 1 (PD-1) interrupt the ability of the cancerous cell to depress the immune system. Methods and results: We report three patients who developed different endocrine abnormalities after treatment with nivolumab, a monoclonal antibody directed against PD-1. First, we report a 76-year-old male presenting with generalized fat loss after treatment with nivolumab which predominantly affected his face and trunk. Second, we described the development of thyroiditis that presented with thyrotoxicosis and the expression of thyroid-stimulating hormone receptor antibodies (TRAb). Finally, we observed the emergence of adrenal insufficiency due to hypophysitis in another case. Conclusion: Although immune checkpoint inhibitors are an effective anticancer treatment modality, adverse effects are evident that can affect the endocrine system. These adverse events may relate to different endocrine systems that include the thyroid and pituitary glands. Also, acquired generalized lipodystrophy should be suspected in patients developing unusual fat loss after treatment with ICIs.

The impact of sarcopenia on morbidity and long-term survival among patients with peritoneal metastases of colorectal origin treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a 10-year longitudinal analysis of a single-center experience.

BACKGROUND: The aim of this study was to evaluate the prognostic value of preoperative sarcopenia with regard to postoperative morbidity and long-term survival in patients with peritoneal metastasis from colorectal cancer treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A longitudinal cohort study was conducted on patients with peritoneal metastases of colorectal origin treated with CRS-HIPEC between 2008 and 2018. Data on patient demographics, body mass index, operative characteristics, perioperative morbidity and survivorship status and oncological follow-up were obtained from the hospital registry. Sarcopenia was assessed using preoperative computed tomography (CT) findings. RESULTS: Sixty-five patients [mean (SD) age: 54.4 (13.4) years, 64.6% females] were included in the study. Sarcopenia was evident in 30.8% of patients, while mortality rate was 66.2% with median survival time of 33.6 months. Presence of sarcopenia was associated with older age (59.6 (9.2) vs. 52.1 (14.4) years, p = 0.038), higher likelihood of morbidity (70.0% vs. 35.6%, p = 0.015) and mortality (90.0% vs. 55.6%, p = 0.010) and shorter survival time (17.7 vs. 37.9 months, p = 0.005). Cox regression analysis revealed that the presence of sarcopenia (HR 2.245, 95% CI 0.996-5.067, p = 0.050) was a significant predictor of increased likelihood of mortality. CONCLUSIONS: Preoperative sarcopenia is an independent prognostic factor of postoperative morbidity and shorter survival in CRC peritoneal metastasis patients treated with CRS-HIPEC. Our findings support the importance of preoperative screening for sarcopenia as part of preoperative risk assessment for better selection of CRS-HIPEC candidates or treatment modifications in CRC patients with peritoneal metastasis.

Adult-onset still's disease, an unusual cause of severe acute liver injury: A case report.

Adult-onset Still's disease is a systemic inflammatory disease that often presents with spiking fever, typical rash, arthritis, and serositis. However, adult-onset-Still's-disease associated liver injury and acute liver failure are rare. Herein, we report a case of acute liver injury in a 23-year-old female patient with adult-onset Still's disease. She presented to the emergency department with a high fever and sore throat. She was then admitted to the department of infectious diseases with a preliminary diagnosis of an atypical respiratory infection. After being treated with antibiotics and antiviral agents, she was discharged. A few days later, she returned to the emergency department with jaundice and was rehospitalized. This time, she was admitted to the department of gastroenterology, where she was diagnosed with adult-onset Still's disease-associated acute liver injury. Eventually, the patient responded to immunosuppressive treatment with significant clinical improvement.

Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -γ (PPARG) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations.

AIMS: To describe the phenotype associated with a novel heterozygous missense PPARG mutation discovered in a Turkish family and to compare the fat distribution and metabolic characteristics of subjects with the peroxisome proliferator activator receptor -γ (PPARG) mutation with those of a cluster of patients with familial partial lipodystrophy with classic codon 482 Lamin A/C (LMNA) mutations. METHODS: The study involved four subjects with familial partial lipodystrophy who had a novel PPARG mutation (H449L) and six subjects with classic codon 482 LMNA mutations (R482W). RESULTS: Compared with subjects with LMNA R482W mutation, fat loss was generally less prominent in subjects with the PPARG H449L mutation. Partial fat loss was limited to the extremities, whilst truncal fat mass was preserved. The PPARG H449L mutation was associated with insulin resistance, hypertriglyceridaemia and non-alcoholic fatty liver disease in all affected subjects, but the severity was variable. Three out of four mutation carriers had overt diabetes or impaired glucose tolerance. Pioglitazone therapy in these three individuals resulted in a modest improvement in their metabolic control, and regular menstrual cycles in the two female subjects. CONCLUSIONS: We suggest that relatively modest fat loss in patients with PPARG mutations may render the recognition of the syndrome more difficult in routine clinical practice. The PPARG H449L mutation is associated with insulin resistance and metabolic complications, but their severity is variable among the affected subjects.

Risk factors for diabetic foot ulcers in metreleptin naïve patients with lipodystrophy.

AIM: Patients with lipodystrophy are at high risk for chronic complications of diabetes. Recently, we have reported 18 diabetic foot ulcer episodes in 9 subjects with lipodystrophy. This current study aims to determine risk factors associated with foot ulcer development in this rare disease population. METHODS: Ninety metreleptin naïve patients with diabetes registered in our national lipodystrophy database were included in this observational retrospective cohort study (9 with and 81 without foot ulcers). RESULTS: Patients with lipodystrophy developing foot ulcers had longer diabetes duration (p = 0.007), longer time since lipodystrophy diagnosis (p = 0.008), and higher HbA1c levels (p = 0.041). Insulin use was more prevalent (p = 0.003). The time from diagnosis of diabetes to first foot ulcer was shorter for patients with generalized lipodystrophy compared to partial lipodystrophy (p = 0.036). Retinopathy (p < 0.001), neuropathy (p < 0.001), peripheral artery disease (p = 0.001), and kidney failure (p = 0.003) were more commonly detected in patients with foot ulcers. Patients with foot ulcers tended to have lower leptin levels (p = 0.052). Multiple logistic regression estimated significant associations between foot ulcers and generalized lipodystrophy (OR: 40.81, 95% CI: 3.31-503.93, p = 0.004), long-term diabetes (≥ 15 years; OR: 27.07, 95% CI: 2.97-246.39, p = 0.003), and decreased eGFR (OR: 13.35, 95% CI: 1.96-90.67, p = 0.008). CONCLUSIONS: Our study identified several clinical factors associated with foot ulceration among patients with lipodystrophy and diabetes. Preventive measures and effective treatment of metabolic consequences of lipodystrophy are essential to prevent the occurrence of foot ulcers in these high-risk individuals.

Comparison of Patients With and Without Anterior Sector Venous Drainage in Right Lobe Liver Transplantation From Live Donors in Terms of Complications, Rejections, and Graft Survival: Single-Center Experience.

AIM: The issue of performing an anastomosis of the anterior sector veins to the vena cava in living donor liver transplantation is still controversial. We aimed to research whether there was any difference in terms of complications, rejections, and graft survival between patients with and without anterior sector venous drainage to the vena cava. PATIENTS AND METHODS: Patients were retrospectively investigated for demographic data and ratio of graft needed to available graft weight. Donors had volumetric calculations and middle hepatic vein anterior sector drainage documented in detail. RESULTS: Seventy-three donors with middle hepatic vein drainage were included. Thirty-five had anterior sector venous drainage performed and 38 patients did not have drainage procedures performed. The incidence of general complications was higher in the group without anterior sector drainage (78.3% and P = .002). Biloma linked to bile leaks were observed in 8 patients without drainage (72.8%) and 3 patients with drainage (27.2%). Late acute rejection occurring during follow up after transplantation was identified in 28 patients (11.6%). Of these, 1 (14.3%) had anterior sector drainage and 6 (85.7%) were in the patient group without drainage (P = .067). CONCLUSION: As a result of this study, for patients with grafts at the volume limit (graft weight to receiver weight ratio <0.8) and with congestion observed in the anterior sector after liver implantation and for patients with outflow problems identified on Doppler ultrasonography, anterior sector veins >5 mm should definitely be drained into the vena cava. Hence, both complication and rejection rates will reduce, and we can lengthen the graft, and thus patient, survival.

The Analysis of Posthepatectomy Liver Failure Incidence and Risk Factors Among Right Liver Living Donors According to International Study Group of Liver Surgery Definition.

AIM: There is a well-known risk of the emergence of hepatic failure in living donor transplant cases on whom are performed a right donor hepatectomy (RDH). There are different prevalence ratios in literature on this phenomenon. In our study, we aim to depict the prevalence of hepatic failure and risk factors in our cases regarding the most recent description criteria related to hepatic failure. PATIENTS AND METHODS: We included right liver donor hepatectomy cases who fit the donor evaluation algorithm at the Dokuz Eylul University Liver Transplantation Unit between the period of June 2000 and September 2017. The patients were evaluated regarding preoperative data. Liver failure was defined according to the International Study Group of Liver Surgery (ISGLS) criteria. We also included statistical analysis of risk factors that are potentially related to liver failure. RESULTS: We included a total of 276 patients. In 27 (9.7%) patients, we observed posthepatectomy liver failure (PHLF). In 26 (9.4%) patients, we observed Grade A liver failure; in 1 (0.3%) patient, we observed Grade B liver failure. We did not observe any Grade C hepatic failure. In patients with hepatic failure, we observed a significantly longer period of hospitalization (P = .007). Old age (odds ratio = 1.065, 95% confidence interval, 1.135-29.108, P = .035) and preoperatory red blood cell (RBC) transfusion (odds ratio = 5.749, 95% confidence interval, 1.019-1.113, P = .005) were shown as independent risk factors for PHLF. CONCLUSION: Posthepatectomy liver failure is a vital complication of RDH. The risk can be decreased by careful selection of donor candidates. Elderly donor candidates and intraoperative RBC are independent risk factors for PHLF.

Preventing parastomal hernia with modified stapled mesh stoma reinforcement technique (SMART) in patients who underwent surgery for rectal cancer: a case-control study.

PURPOSE: Parastomal hernia is a frequent complication of an abdominal wall stoma. Surgical repairs have high complication and recurrence rates. Several different techniques have been suggested to prevent parastomal hernia during stoma creation. The aim of the present case-control study was to evaluate the efficacy of modified Stapled Mesh stomA Reinforcement Technique (SMART) for prevention of parastomal hernia compared with conventional colostomy formation in patients who underwent open or laparoscopic rectal resection and end colostomy for cancer. METHODS AND MATERIALS: Between January 2014 and May 2016, all consecutive patients who underwent open or laparoscopic resection and end colostomy for primary or recurrent rectal cancer were identified from a prospectively collected database. Since January 2014, one surgeon in our team has routinely offered modified SMART procedure to all patients who are candidates for permanent terminal colostomy. In the SMART group patients, while creating an end colostomy, we placed a standard polypropylene mesh in the retromuscular position, fixed and cut the mesh by firing a 31- or 33-mm-diameter circular stapler and constructed the stoma. In the control group, a stoma was created conventionally by a longitudinal or transverse incision of the rectus abdominis sheath sufficiently large for the colon to pass through. RESULTS: Twenty-nine patients underwent parastomal hernia prophylaxis with modified SMART and 38 patients underwent end-colostomy formation without prophylaxis (control group). Groups were similar in terms of age, sex and underlying conditions predisposing to herniation. Median follow-up time is 27 (range 12-41) months. Nineteen patients (28.4%) developed parastomal herniation. In the SMART group, 4 patients (13.8%) developed parastomal herniation which is significantly lower than the control group in which 15 patients (39.5%) developed parastomal herniation (p = 0.029). We did not observe mesh infection, stenosis, erosion or fistulation in the SMART group. One patient in the control group underwent surgical correction of stoma stricture, another patient underwent surgery for stoma prolapse and four patients underwent surgery for parastomal herniation. CONCLUSION: New systemic reviews and meta-analysis support parastomal hernia prevention with the use of a prophylactic mesh. Until more evidence is available, prophylactic mesh should be routinely offered to all patients undergoing permanent stoma formation. SMART is easy to use, safe and effective for paracolostomy hernia prophylaxis.

Deletion of the A gamma-globin gene in G gamma-delta beta-thalassemia.

In an individual homozygous for G gamma-delta beta-thalassemia, a physical alteration in gamma-globin gene organization was detected by restriction enzyme mapping. The data indicated that the absence of A gamma-globin chains resulted from extension of the DNA deletion from the delta beta-globin gene region into the gamma-globin gene region rather than a functional disturbance of gamma-gene expression.

Evaluation of ureteral jet dynamics in pediatric kidney stone formers: A cross-sectional study.

INTRODUCTION: The risk of kidney stone formation increases with urinary stasis, which is associated with decreased peristaltism. The relationship between nonobstructive kidney stone formation and ureteral jet dynamics, which can be measured with Doppler ultrasonography (US) and provide information about ureteral peristaltism, has been demonstrated in adults. OBJECTIVE: To investigate the relationship between ureteral jet dynamics, which provide information about ureteral peristaltism, and stone formation in children. STUDY DESIGN: Children admitted to Dokuz Eylul University Hospital with flank pain, and asymptomatic age-matched children for the control group, were prospectively enrolled and underwent Doppler US for diagnostic reasons and bilateral ureteral jet flow measurements. Children diagnosed with unilateral nonobstructive lower pole kidney stones formed Group 1, and the control group, without any evidence of stone disease, formed Group 2. Ureteral jet dynamics were compared between the affected renal units in Group 1, and healthy renal units in Group 1 and Group 2. RESULTS: A total of 32 children were included for each group. The mean average jet flow-rate (JETave (cm/second)) in affected renal units in Group 1 was found to be significantly lower than in the healthy renal units in Group 1 and left and right healthy renal units in Group 2 (P < 0.05). The continuous JETpattern rate in affected renal units in Group 1 was found to be significantly higher compared with healthy renal units in Groups 1 and 2 (P = 0.012) (Table). The odds ratio for kidney stone formation was 5.6 for renal units with JETave <9.5 cm/s when compared with renal units with JETave ≥9.5 cm/s. DISCUSSION: In a recent study, it was demonstrated in adults that low ureteral jet flow-rate and continuous JETpattern were significantly higher in affected renal units. The findings in children were also similar to adults: the mean JETave was significantly lower and determination rate of continuous flow pattern was significantly higher in affected renal units. CONCLUSIONS: Children with low JETave and continuous JETpattern as a sign of decreased ureteral peristaltism are at an increased risk of kidney stone formation. However, it is vital that further studies are conducted to elaborate on this topic.

Hb J-Antakya or alpha 2 beta (2)65(E9)Lys----Met in a Turkish family and Hb complutense or alpha 2 beta (2)127(H5)Gln----Glu in a Spanish family; correction of a previously published identification.

Almost 10 years ago we reported in this journal the characterization of Hb Hacettepe or alpha 2 beta (2)127(H5)Gln----Glu. Unfortunately, we have to conclude that the original characterization of this Turkish variant was in error. The corrected data are presented in this short communication. The variant (alpha 2 beta (2)65(E9)Lys----Met) was (re)named Hb J-Antakya, after the city where the family resides. An abnormal Hb, observed in a Spanish family and named Hb Complutense, had the beta 127 Gln----Glu substitution, erroneously assigned to the Turkish variant.

The relative levels of alpha 2-, alpha 1-, and zeta-mRNA in HB H patients with different deletional and nondeletional alpha-thalassemia determinants.

We have analyzed the alpha 2/alpha 1-, alpha/beta-, zeta/(alpha + zeta)-mRNA ratios in the retic-ulocytes of 40 patients with Hb H disease. 21 patients had deletional Hb H disease (- -/- alpha), namely combinations of one of four types of alpha-thal-1 (MED-I, MED-II, -(alpha)20.5, SEA) and one of two types of alpha-thal-2 (-3.7 or -4.2 kb); 13 had Hb H disease because of combinations of one of these alpha-thal-1 deletions with either a 5 nt deletion at the 5' splicing site of IVS-I, or a terminating codon mutation (Hb CS), or a poly(A) mutation, and six were homozygous for either a poly(A) mutation or the 5 nt deletion. Significant differences were observed between the deletional types (- -/- alpha; alpha 2/alpha 1 ratio of zero; alpha/beta ratio of approximately 1) and non-deletional types (- -/alpha T alpha; alpha 2/alpha 1 ratio of 0.05-0.3 for those with T = the 5 nt deletion or the terminating codon mutant, and approximately 1.0 for those with T = a poly(A) mutation; alpha/beta ratio in all types of approximately 0.7). Comparable data were found for the nondeletional alpha-thal-2 homozygotes. The noted differences were highly significant and the determination of the two ratios may be diagnostically of considerable value. The low alpha 2/alpha 1-mRNA ratio in the two patients with - -/alpha-5nt alpha and the one patient with alpha-5nt alpha/alpha-5nt alpha indicates the presence of minute amounts of alpha 2-mRNA; apparently splicing at the donor site is greatly impaired by this deletion but not eliminated. The high alpha 2/alpha 1-mRNA ratio in the four patients with - -/alpha PA-2 alpha and the five patients with alpha PA-1 alpha/ alpha PA-1 alpha (PA-1 and PA-2 are poly(A) mutations) is due to the presence of an elongated alpha 2-mRNA which uses an alternate location as polyadenylation site. The relative levels zeta-mRNA varied considerably; the highest levels were found in patients with the -(alpha)20.5/-alpha or - -SEA/-alpha deletional types but not in those with the -(alpha)20.5/alphaPA-2 alpha, -(alpha)20.5/alpha-5nt alpha, or - -SEA/alphaCS alpha nondeletional types. No definitive explanation can be given for these differences; perhaps certain sequences that are part of some of the alpha-thal-1 deletions are important for the suppression of the zeta-globin gene.

High cystine in platelets from patients with nephropathic cystinosis: a chemical, ultrastructural, and functional evaluation.

AIM: To investigate the morphology and function of platelets in nephropathic cystinosis (NC). METHODS: Seven patients (mean age, 6.5 years; SD, 20 months) with NC were investigated. Their platelets were examined by transmission electron microscopy (TEM) and the characteristics of the dense granules (DGs) were determined by mepacrine labelling and the uranaffin reaction. Bleeding time, turbidometric aggregation, and luminescence aggregation were studied and intraplatelet cystine was measured. RESULTS: Increased intraplatelet cystine, primary and secondary aggregation defects, and the absence of ATP release were demonstrated. TEM revealed DGs of various shapes and sizes and lamellary or amorphous cytoplasmic inclusions. Viscous material had been released into the vacuolar spaces and enlarged open canalicular system. Mepacrine labelling revealed that the numbers of DGs/platelet were comparable between the patients and the controls (mean, 2.9 (SD, 0.22) v 3.32 (0.18); p = 0.34). The uranaffin reaction revealed that the numbers of type 1, 3, and 4 DGs were comparable between the patients and the controls, but that there were fewer type 2 DGs in the patients (mean, 8.5 (SD, 1.95) v 17.22 (1.58); p = 0.01). TEM for platelet aggregation revealed a lack of induction and/or defective execution and/or delayed transmission. The patients' intraplatelet cystine concentrations were higher than the controls (mean, 1.56 (SD, 0.84) v 0.08 (0.01) nmol/mg protein; p = 0.009). CONCLUSIONS: This is the first report to demonstrate raised intraplatelet cystine, abnormal platelet ultrastructural findings, and defective aggregation in NC.

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9.

FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in 20 families - 97% of all expected mutant alleles. All mutation types have been found, with the exception of large deletions, the large majority is predicted to lead to shortened proteins. One stop codon mutation, E105X, has been found in several German patients and this founder mutation accounts for 44% of the mutant FANCG alleles in German FA-G patients. Comparison of clinical phenotypes shows that patients homozygous for this mutation have an earlier onset of the haematological disorder than most other FA-G patients. The mouse Fancg sequence was established in order to evaluate missense mutations. A putative missense mutation, L71P, in a possible leucine zipper motif may affect FANCG binding of FANCA and seems to be associated with a milder clinical phenotype.

Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance.

Approximately 25% of patients with Fanconi anemia (FA) have evidence of spontaneously occurring mosaicism as manifest by the presence of two subpopulations of lymphocytes, one of which is hypersensitive to cross-linking agents (e.g. mitomycin C) while the other behaves normally in response to these agents. The molecular basis of this phenotypic reversion has not yet been determined. We have investigated 8 FA patients with evidence of mosaicism. Epstein-Barr virus-immortalized lymphoblastoid cell lines established from these patients exhibited an IC50 for mitomycin C of 25 to > 100 nM compared to a mean of 2 +/- 2 nM for 20 nonmosaic FA patients and 49 +/- 11 nM for 8 healthy controls. In 3 patients who were compound heterozygotes for pathogenic FAC gene mutations the molecular mechanism of the mosaicism was investigated by haplotype analysis. The results indicated that an intragenic mitotic recombination must have occurred leading to a segregation of a wild-type allele in the reverted cells and suggested two patterns of recombination. In 1 patient a single intragenic crossover between the maternally and paternally inherited mutations occurred associated with markers located distally to the FAC gene; in the other 2 patients (sibs) the mechanism appears to have been gene conversion resulting in segregants which have lost one pathogenic mutation. In 6 of the 8 patients the hematological symptoms were relatively mild despite an age range of 9-30 years.

Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.

Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.

The occurrence and identification of alpha-thalassemia-2 among hemoglobin S heterozygotes.

The in-vitro synthesis of hemoglobin (Hb) chains was studied among 60 Hb S heterozygotes (AS) having different quantities of Hb S, including five with an associated alpha-chain heterozygosity (ASAG). Hematologic values and hemoglobin composition were studied in these cases and in 15 other ASAG heterozygotes. The percentages of Hb S (which fell between 27% and 42%) and the mean corpuscular volume values correlated directly with the alpha/non-alpha values, confirming previous suggestions (Huisman, Hemoglobin 1:349, 1977) that the concomitant occurrence of an alpha-thalassemia-2 heterozygosity (alpha alpha(0)/alpha alpha; beta/beta(S)) or homozygosity (alpha(0) alpha/alpha(0) alpha; beta/beta(S)) resulted in intermediate or lower levels of Hb S compared with Hb S heterozygotes having four active alpha-chain genes (alpha alpha/alpha alpha; beta/beta(S)). Among ASAG heterozygotes, the occurrence of low (about 25%), intermediate (about 33%), or high (about 45%) proportions of an alpha-chain variant resulting from a variability in the number of active alpha-chain genes due to alpha-thal-2 coincided with high (39%), intermediate (34%), or low (28%) levels of Hb S, respectively. However, the overlap of biosynthetic data between Hb S heterozygotes with four, three, or two active alpha-chain genes prevents a reliable diagnosis in individual cases.

Beta-thalassemia intermedia in Turkey.

DNA data have been collected for 41 patients with beta-thalassemia intermedia without transfusion dependency. They belonged to 33 families, and 45 of their parents were included in the study. Eight patients were homozygous for the frameshift at codon 8 (-AA), and nine were homozygous for the IVS-2 nt 1 (G----A) mutation; haplotypes IV and III, respectively, were associated with these mutations. Three patients had a G gamma A gamma(delta beta)0-thalassemia homozygosity, characterized by a deletion of 13 kb. Of the remaining subjects, ten had a homozygosity for the IVS-1 nt 6 (T----C) mutation, and five were compound heterozygotes for one mild and one severe thalassemia determinant. Combinations with Hb Knossos, the T----A mutation at nt -30, the C----T mutation at nt -101, the G----A and G----C mutations at IVS-1 nt 5, and the G----A mutation at IVS-1 nt 110 were the other thalassemia determinants resulting in beta-thalassemia intermedia in the six remaining patients. Haplotypes IV and IX were associated with the latter three mutations. The C----T mutation at nt -158 5' to the G gamma gene was characteristic for haplotypes III, IV, and IX. Genotype and phenotype correlation indicated significant differences in some of the hematological parameters among patients with the frameshift at codon 8 (-AA) or with the IVS-2 nt 1 (G----A) mutation, with both the frameshift at codon 8 and the T----C mutation at IVS-1 nt 6, and with both the IVS-2 nt 1 (G----A) and IVS-1 nt 6 (T----C) mutations. Statistically significant differences were found in the mean values for hemoglobin (Hb) A2 in heterozygotes with the frameshift at codon 8 (-AA) and the IVS-1 nt 5 (G----A) mutation. Variations in the number of alpha-globin genes resulted in modifications of the phenotypical expression of the beta-thalassemia intermedia determinants.

Evidence for the existence of the PAF acetylhydrolase mutation (Val279Phe) in non-Japanese populations: a preliminary study in Turkey, Azerbaijan, and Kyrgyzstan.

Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase resulting from a missense mutation (Val279Phe) in exon 9 of the gene has been described exclusively in the Japanese population with a very high frequency. This study describes the distribution of the mutation in Turkey and two other Turkic nations, Kyrgyzstan in central Asia and Azerbaijan bordering the Caspian Sea. Among 358 unrelated healthy subjects studied from Turkish population, only 3 had the mutation in heterozygous state (0.84%). Family studies also revealed the presence of homozygous individuals in close relatives of one of these subjects. Among 143 healthy subjects studied from Kyrgyzstan, 12 were heterozygous for the mutation (8.4%). No mutation was detected among 100 healthy individuals studied from Azerbaijan. However, it was suggested that the number of subjects was not enough to draw any conclusion about the prevalence of the mutation in the populations studied. Contrary to the previous notions, identification of the mutation in Turkey and Kyrgyzstan shows the existence of the mutation in non-Japanese populations as well.

Beta thalassaemia: a report of 20 children.

Beta-thalassaemias have a wide variety of musculoskeletal system manifestations. In this cross-sectional study, we aimed to investigate the frequency and features of musculoskeletal system problems in children with beta-thalassaemia. A total of 20 beta thalassaemic patients with an average age of 13.8 years were enrolled in the study. In all patients studied, detailed history regarding musculoskeletal involvement was taken and locomotor examinations were performed. All patients underwent radiographic examination with standing anteroposterior and lateral X-rays of the spine. Two physicians blinded for the diagnosis used Cobb technique for determining the degree of scoliosis. In 12 of 20 patients (60%) locomotor system involvement was found. Most frequent complaints were arthralgia and low back pain in 30% and 25% of patients respectively. Scoliosis was detected radiologically in 40% of patients with a lateral curve of at least 5 degrees Cobb.