Parry-Romberg syndrome is a rare, slowly progressive, autolimitated disease, characterized by unilateral facial atrophy. It is usually manifested in childhood and young adulthood. Because of the degree of atrophy and the variety of symptoms, the diagnosis, prognosis, and treatment of Parry-Romberg syndrome are a major challenge. The purpose of this case presentation is to highlight the difficulty of establishing the diagnosis, furthermore, to present the steps of examining the patient and to draw attention to the importance of proper timing of the surgery. Moreover, it wants to emphasize the importance of looking for diseases that often occur with the mentioned syndrome. Orv Hetil. 2020; 161(28): 1181-1185.

Parry-Romberg syndrome (PRS) is a rare disorder of uncertain etiology that is characterized by progressive atrophy of the soft and hard tissues of face, typically occurring in the first 2 decades of life. It is more commonly seen in females. The disease progresses slowly with gradual atrophy, frequently associated with neurological, ophthalmological, and other system involvement, resulting in secondary complications. The severity of deformity varies depending on the age of onset of disease. Those in whom the disease starts at an earlier age will have more severe deformity. Due to the visible facial deformity, such patients usually suffer from social and psychological trauma. Management is mainly cosmetic, which is carried out after disease progression has stopped and stabilized. This brief review describes PRS in detail and compares it with linear morphea en coup de sabre (ECDS), its close differential, which is likely to be a milder variant sharing the same spectrum of disease.

Parry-Romberg syndrome, or progressive hemifacial atrophy, is a rare disorder of unknown etiology. Patients present with unilateral atrophy of skin that may progress to involve underlying fat, muscle, and osseocartilaginous structures. Neurologic complications are common. After self-limited disease stabilization, various reconstructive options may be used to restore patients' facial symmetry. Serial autologous fat grafting has shown favorable results in reconstruction of mild or moderate soft tissue deficiency, but free tissue transfer remains the treatment of choice for severe disease.

In obesity, elevated fat mass and ectopic fat accumulation are associated with changes in adipokine secretion, which may link obesity to inflammation and the development of insulin resistance. However, relationships among individual adipokines and between adipokines and parameters of obesity, glucose metabolism or inflammation are largely unknown. Serum concentrations of 20 adipokines were measured in 141 Caucasian obese men (n = 67) and women (n = 74) with a wide range of body weight, glycemia and insulin sensitivity. Unbiased, distance-based hierarchical cluster analyses were performed to recognize patterns among adipokines and their relationship with parameters of obesity, glucose metabolism, insulin sensitivity and inflammation. We identified two major adipokine clusters related to either (1) body fat mass and inflammation (leptin, ANGPTL3, DLL1, chemerin, Nampt, resistin) or insulin sensitivity/hyperglycemia, and lipid metabolism (vaspin, clusterin, glypican 4, progranulin, ANGPTL6, GPX3, RBP4, DLK1, SFRP5, BMP7, adiponectin, CTRP3 and 5, omentin). In addition, we found distinct adipokine clusters in subgroups of patients with or without type 2 diabetes (T2D). Logistic regression analyses revealed ANGPTL6, DLK1, Nampt and progranulin as strongest adipokine correlates of T2D in obese individuals. The panel of 20 adipokines predicted T2D compared to a combination of HbA1c, HOMA-IR and fasting plasma glucose with lower sensitivity (78% versus 91%) and specificity (76% versus 94%). Therefore, adipokine patterns may currently not be clinically useful for the diagnosis of metabolic diseases. Whether adipokine patterns are relevant for the predictive assessment of intervention outcomes needs to be further investigated.

BACKGROUND:Secreted frizzled-related protein 5 (SFRP5) is a recently identified adipokine; however, its functions during pathogenesis of T2DM and obesity remain unclear. This research attempted to investigate associations between circulating SFRP5 and obesity/T2DM. MATERIALS AND METHODS:According to diagnosis, 107 patients were assigned as impaired-glucose regulation (IGR) and 111 patients newly-diagnosed as T2DM were assigned as the T2DM group. Meanwhile, 132 subjects with normal-glucose tolerance (NGT) were assigned as the NGT group. Differences in plasma SFRP5 levels among three groups were compared. Correlation between SFRP5 levels and different metabolic markers was analyzed. Multiple-linear stepwise regression analyses were performed to determine independent factors for SFRP5. Patients in the T2DM group were administrated with metformin for 12 weeks. Meanwhile, changes in plasma SFRP5 levels were also analyzed. RESULTS:Plasma SFRP5 level of the IGR group was significantly lower compared to the NGT group (219.1±39.7 pg/mL vs 236.7±72.6 pg/mL, <0.05), however, that of the T2DM group was significantly lower compared to the IGR group (203.5±42.1 pg/mL vs 219.1±39.7 pg/mL, <0.01). Level of plasma SFRP5 was negatively correlated with fasting plasma glucose, BMI, waist circumference (WC), normalized WC (waist-to-height ratio) (WHtR), 2h plasma glucose, fasting insulin, glycosylated hemoglobin (HbA1c), fasting C-peptide, HOMA-IR, and hs-CRP (<0.01). Among the above factors, HbA1c and fasting insulin levels (FIns) were two independent factors. Plasma SFRP5 levels were increased after 12-week metformin treatment (201.0±34.8 pg/mL vs 213.1±34.4 pg/mL, <0.05), while insulin resistance was alleviated (ln(HOMA-IR): 1.35±0.55 vs 1.07±0.49, <0.01). CONCLUSION:Metformin reduced circulating levels of secreted frizzled-related protein 5 and improved pathophysiological parameters of T2DM.

To investigate the relationship between serum secreted frizzled-related protein 5(sfrp5) levels, insulin resistance, and airway inflammation in patients with chronic obstructive pulmonary disease(COPD). A total of 178 COPD patients visiting our respiratory outpatient clinic from February 2015 to January 2017 were enrolled, and 99 healthy control subjects from the same time period were selected. Serum sfrp5 levels were compared between the 2 groups. Serum sfrp5 and inflammatory cytokines in induced sputum were observed in the 4 subgroups: insulin resistant COPD group [homeostasis model assessment of insulin resistance (HOMA-IR)≥2.29], non-insulin resistant COPD group, non-COPD insulin resistant group, and healthy control group. Serum sfrp5 levels were found to be significantly higher in the COPD group as compared to the healthy control group (=-14.29, <0.001). Serum sfrp5 levels in the insulin resistant COPD group [(8±3)ng/ml] were significantly lower than that of the non-insulin resistant COPD group [(10±5)ng/ml], non-COPD insulin resistant group [(13±3)ng/ml], and normal control group [(14±4)ng/ml, =35.85, <0.01]. The insulin resistant COPD group had higher levels of In(Homa-IR), as well as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in induced sputum as compared to the non-insulin resistant COPD group, non-COPD insulin resistant group, and healthy control group ( values were 64.968, 41.40, 64.15, respectively, value <0.01 for all items). The non-insulin resistant COPD group had higher levels of In(HOMA-IR) as well as TNF-α and IL-6 in induced sputum as compared to the non-COPD insulin resistant group and healthy control group. FEV(1)/FVC and FEV(1)% predicted were significantly lower in the insulin resistant COPD group as compared to those of non-insulin resistant COPD group and non-COPD insulin resistant group, and healthy control group ( values were 2.481 and 8.37, respectively, value<0.05 for all items). FEV(1)/FVC and FEV(1)% predicted were significantly lower in the non-insulin resistant COPD group as compared to those of the healthy control group and non-COPD insulin-resistant group. Serum sfrp5 levels were positively correlated to FEV(1)/FVC and FEV(1) predicted ( values were 0.466 and 0.412, respectively; values were <0.001 and 0.007, respectively) and inversely correlated to In(HOMA-IR) and TNF-α and IL-6 in induced sputum ( values were -0.304, -0.459, -0.517, respectively; values were <0.001, 0.002, <0.001, respectively). BMI, ln(HOMA-IR), and IL-6 in induced sputum were independent related factors ((2) values were 0.286, 0.176, 14.69, respectively; values were <0.01 for all items) Sfrp5 may be concurrently associated with COPD and insulin resistance; insulin resistance may be associated with airway inflammation and airflow limitation. Sfrp5 may be involved in the development of COPD and may be the key link by which insulin resistance exerts its effects on airway inflammation.

Considering the role of sFRP5 in Wnt signalling, an important group of pathways regulating adipogenesis and inflammation, we performed a genetic association study on sFRP5 polymorphisms in a population of obese and lean individuals. Using information from the HapMap, two tagSNPs were identified in the sFRP5 gene region and genotyped on a population of 1,014 obese, non-diabetic individuals and 606 lean controls. We performed logistic and linear regression analysis including a wide variety of obesity parameters (BMI, waist circumference, height, WHR, fat mass, fat mass percentage and visceral, subcutaneous and total abdominal fat), in addition to OGTT and HOMA-IR values. We were able to show a significant association of sFRP5 with both total abdominal and subcutaneous fat. The association signal was only seen in obese males, and in this population, the minor allele of rs7072751 explains 1.8 % of variance in total abdominal fat. In addition, we saw a trend towards an association of rs10748709 with glucose metabolism. Although further research is necessary, we can conclude that sFRP5 is a significant regulator of fat development and distribution in obese males. We postulate that altered transcription factor binding on the rs7072751 surrounding sequence might play a role in the associations we found with both total abdominal and subcutaneous fat. In addition, although no conclusive evidence was found, our results indicate that sFRP5 genetic variation may affect glucose metabolism and it would be interesting to investigate this further.

BACKGROUND:Obesity is associated with macrophage infiltration of adipose tissue. These inflammatory cells affect adipocytes not only by classical cytokines but also by the secreted glycopeptide wnt5a. Healthy adipocytes are able to release the wnt5a inhibitor sFRP5. This protective effect, however, was found to be diminished in obesity. The aim of the present study was to examine (1) whether obese human subjects exhibit increased serum concentrations of wnt5a and (2) whether wnt5a and/or sFRP5 serum concentrations in obese subjects can be influenced by caloric restriction. METHODOLOGY:23 obese human subjects (BMI 44.1 ± 1.1 kg/m(2)) and 12 age- and sex-matched lean controls (BMI 22.3 ± 0.4 kg/m(2)) were included in the study. Obese subjects were treated with a very low-calorie diet (approximately 800 kcal/d) for 12 weeks. Body composition was assessed by impedance analysis, insulin sensitivity was estimated by HOMA-IR and the leptin-to-adiponectin ratio and wnt5a and sFRP5 serum concentrations were measured by ELISA. sFRP5 expression in human adipose tissue biopsies was further determined on protein level by immunohistology. PRINCIPAL FINDINGS:Pro-inflammatory wnt5a was not measurable in any serum sample of lean control subjects. In patients with obesity, however, wnt5a became significantly detectable consistent with low grade inflammation in such subjects. Caloric restriction resulted in a weight loss from 131.9 ± 4.0 to 112.3 ± 3.2 kg in the obese patients group. This was accompanied by a significant decrease of HOMA-IR and leptin-to-adiponectin ratio, indicating improved insulin sensitivity. Interestingly, these metabolic improvements were associated with a significant increase in serum concentrations of the anti-inflammatory factor and wnt5a-inhibitor sFRP5. CONCLUSIONS/SIGNIFICANCE:Obesity is associated with elevated serum levels of pro-inflammatory wnt5a in humans. Furthermore, caloric restriction beneficially affects serum concentrations of anti-inflammatory sFRP5 in such subjects. These findings suggest a novel regulatory system in low grade inflammation in obesity, which can be influenced by nutritional therapy.

AIMS:To detect plasma secreted frizzled-related protein (SFRP) 5 levels in Chinese healthy, obese and type 2 diabetes mellitus (T2DM) subjects and to investigate the relationships between plasma SFRP5 levels and body fat parameters, insulin resistance, glucolipid metabolism and inflammation. METHODS:Eighty-nine subjects with normal glucose tolerance (NGT) and 87 subjects with T2DM were enrolled in this study. NGT and T2DM groups were divided into normal weight (NW) and obese (OB) subgroups separately. Anthropometric parameters such as body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) were examined. Plasma levels of SFRP5, IL-6, glucose, serum lipid, glycated hemoglobin (HbA1C) and fasting insulin (FINS) levels were measured. Insulin resistance index (IR) was assessed by homeostasis model assessment (HOMA). RESULTS:Plasma SFRP5 levels were lower in T2DM group than in NGT group. The levels of plasma SFRP5 in subjects with obesity were also lower than those in subjects with NW in both NGT and T2DM groups. T2DM-OB subgroup had lower plasma SFRP5 levels than that in NGT-OB subgroup. Plasma SFRP5 levels were negatively correlated with BMI, WC, WHR, fasting plasma glucose, HbA1C, triglyceride (TG), FINS, HOMA-IR and IL-6. Multiple stepwise regression analysis showed that HOMA-IR, BMI and TG were independently related with plasma SFRP5 levels. CONCLUSIONS:Plasma levels of SFRP5 were decreased in Chinese obese and T2DM subjects. SFRP5 was an independent factor affecting glucolipid metabolism, inflammation and IR. It may play an important role in the pathogenesis of obesity and T2DM.

BACKGROUND:Secreted frizzled-related protein 5 (Sfrp5) has been described as novel adipokine in mice with insulin-sensitising and anti-inflammatory properties similar to adiponectin. The aim of this study was to compare serum concentrations and determinants of Sfrp5, its pro-inflammatory antagonist wingless-type MMTV integration site family member (Wnt)5a and adiponectin in humans and their regulation by coffee. MATERIAL AND METHODS:Serum concentrations of Sfrp5, Wnt5a and adiponectin were measured in 47 individuals who participated in a coffee intervention study. Associations with demographic, metabolic and immunological variables and regulation of serum levels by different amounts of daily coffee intake were analysed. RESULTS:At baseline, fasting serum Sfrp5 levels ranged between 96 and 4056 ng/mL. Sfrp5 was directly correlated with a surrogate of insulin resistance (homeostasis model assessment of insulin resistance/HOMA-IR; r = 0·32, P < 0·05) and with the oxidative stress markers 8-isoprostane (r = 0·44, P < 0·01) and nitrotyrosine (r = 0·52, P < 0·001). Adiponectin showed inverse correlations with several indices of insulin resistance (e.g. HOMA-IR, Stumvoll index; all P < 0·05) and a direct correlation with the anti-atherogenic apolipoprotein A-I (r = 0·56, P < 0·001). Coffee did not affect serum concentrations of Sfrp5. Serum Wnt5a concentrations were below the detection limit (0·02 ng/mL) in 81% of the study participants. CONCLUSIONS:In contrast to obese mouse models, serum Sfrp5 was directly related to HOMA-IR and oxidative stress in humans, but not with apolipoproteins, and thus, associations differed from those found for circulating adiponectin. These differences between Sfrp5 and adiponectin might be explained by differences in the investigated species.

OBJECTIVE:Secreted frizzled-related protein 5 (sfrp5), like adiponectin, has been identified as a novel insulin-sensitising and anti-inflammatory adipokine. Our objective was to determine whether differences of circulating plasma sfrp5 concentration exist among type 2 diabetes (T2D), latent autoimmune diabetes in adults (LADA) and healthy population. METHODS:Enzyme-linked immuno sorbent assay was employed to detect the circulating sfrp5 level in plasma, and other lab tests such as fasting glucose and creatinine were also examined. Correlation analysis between sfrp5 and characteristics of subjects was conducted IBM SPSS Statistics and GraphPad Prism. RESULTS:Circulating sfrp5 level was significantly decreased in T2D and LADA patients plasma compared with that in healthy control (14.14±11.91ng/mL, 14.82±11.27ng/mL, 22.98±12.36ng/mL, respectively), although no differences was observed between LADA and T2D groups. Furthermore, we found sfrp5 was correlated with homeostasis model assessment of insulin resistance (HOMA-IR), diabetes duration and BMI. Finally we found sfrp5 was still negatively correlated with HOMA-IR after being adjusted for disease duration and BMI(r= -0.315, P< 0.05). CONCLUSIONS:Our results support a role for SFRP5 as a protective factor in the pathogenesis of autoimmune diabetes and facilitate a novel aspect for diabetes research.

Our study focused on investigating the clinical significance of serum Sfrp5/Wnt-5a levels as a risk marker in metabolic syndrome (MetS). The study involved a total of 107 treatment-naive MetS cases and 100 controls with similar age and sex belonging to northern India. The profiling of clinical, biochemical, and anthropometric variables was done. ELISA methods were employed for serum cytokine estimation. Serum Sfrp5 was inversely correlated with BMI, WC, SBP, DBP, FPG, TG, fasting insulin level, and HOMA-IR in both males and females. The best cutoff value for Sfrp5 to predict MetS in males was ≤40.48 ng/ml (sensitivity 53.70% and specificity 90.48%), while in female, it was ≤66.67 ng/ml (sensitivity 98.11% and specificity 34.48%). MetS occurrence decreased with increasing concentration of Sfrp5 with an odds ratio (OR) of 0.95 (95% CI = 0.92-0.98, < .001) in male and 0.93 (95% CI = 0.91-0.97, < .001) in female. Quartile analysis revealed that odds of MetS significantly decreased in quartile 4 vs. 1, 0.06 (95% CI = 0.01-0.25), = .001 and 0.13 (95% CI = 0.04-0.44), = .001, respectively, in male and female. The inverse association of serum concentration of Sfrp5 with MetS might have a useful addition to the available risk marker as well as a therapeutic target for MetS.

BACKGROUND:Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder of heterogeneous nature. Secreted frizzled-related protein (SFRP) 5 is an anti-inflammatory adipokine implicated in metabolic homeostasis. We aimed to confirm the correlation between SFRP5, metabolic inflammation and PCOS, investigate the predictive value of SFRP5 for PCOS and the involvement of SFRP5 in metformin treated PCOS. METHODS:This retrospective case-control study included 140 PCOS and 33 control women. Sixty seven PCOS women were included for detecting serum SFRP5 level and its correlation with metabolic inflammation. Predictive value of SFRP5 for PCOS was evaluated by logistic regression and receiver operating characteristic (ROC) analyses. Seventy three PCOS women complicated with impaired glucose tolerance (IGT)/insulin resistance (IR) were included for investigating the effects of metformin (37 with metformin vs. 36 without metformin) on SFRP5, pro-inflammatory cytokines, ovulation and pregnancy rate. RESULTS:Plasma SFRP5 levels were decreased in PCOS (odds ratio: 0.78, 95% confidence interval (CI):0.703-0.866, P < 0.001) independent of obesity. SFRP5 was negatively associated with IL-6, TNFα, FAI and HOMA-IR. The cut-off point of SFRP5 < 46.13 ng/ml was optimal to identify PCOS with a higher specificity of 96.87% and a relatively lower sensitivity compared to AMH. SFRP5 increased specificity of AMH for predicting PCOS, especially which with relatively decreased AMH (< 4.7 ng/ml). Metformin promoted SFRP5 and decreased leptin, IL-6 and TNFα secretion in PCOS women with metabolic abnormality in a time dependent manner and with improved ovulation rate and pregnancy rate. CONCLUSION:Decreased SFRP5 was associated with metabolic inflammation in PCOS and has a potential role for the supplement of AMH in predicting PCOS. The reverse of serum SFRP5 by metformin indicated that SFRP5 participated in the improvment of follicular development by metformin. Further prospective investigations are needed to confirm these preliminary data.

PURPOSE:Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that has been associated with various metabolic diseases. However, such relationship among adolescents remains unclear. The purpose of this study was to clarify the relationship between SFRP5 and the components of metabolic syndrome in Chinese adolescents. PATIENTS AND METHODS:In this cross-sectional study, we included a total of 684 adolescents aged 11-16 years old from Liaoyang city, Liaoning province, China. The ELISA kits were implemented to measure the plasma SFRP5 and high-sensitivity C-reactive protein. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), serum uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting plasma glucose (FPG), and fasting serum insulin (FINS) were also measured. RESULTS:The multivariate logistic regression analysis showed that low SFRP5 level were an independent risk factor of high FPG [odds ratio (OR)=5.31, 95% confidence interval (CI): 1.85-15.22, <0.01] and high TC (OR=1.73, 95% CI: 1.01-2.96, <0.05) when adjusting for age, sex, family history of diabetes, body mass index, and high-sensitivity C-reactive protein. CONCLUSION:The lower level of SFRP5 is strongly related to lipid and glucose metabolism among adolescents in Northeast China. The risk of high fasting plasma glucose and high total cholesterol increases significantly as the plasma SFRP5 level decreases.

A 76-year-old woman, presenting with a 4-year history of progressive dysphagia, was submitted to endoscopic examination. The upper endoscopy revealed a proximal esophageal stricture and inflammatory mucosa associated with multiples small orifices in the esophageal wall, some of them fulfilled with white spots suggestive of fungal infection. This was a typical endoscopic finding of esophageal intramural pseudodiverticulosis, a benign and rare condition, related to chronic esophagitis and others comorbid states, such as gastroesophageal reflux disease or infectious esophagitis, diabetes mellitus, alcohol consumption, and achalasia. Dysphagia is the predominant symptom and can be accompanied by esophageal stricture in 80% to 90% of patients. The pathogenesis is unknown, and as the pseudodiverticulosis is an intramural finding, endoscopy biopsies are inconclusive. The main histological finding is dilation of the submucosal glands excretory ducts, probably obstructed by inflammatory cells. The treatment consists in management of the underlying diseases and symptoms relief. In this particular case, the patient was submitted to antifungal drugs followed by endoscopic dilation with thermoplastic bougies, with satisfactory improvement of dysphagia.

Candida albicans is an opportunistic pathogen colonizing the oropharyngeal, esophageal, and gastrointestinal mucosa in most healthy humans. In immunocompromised hosts, this fungal organism can cause mucosal candidiasis in these sites. C. albicans also causes fungemia, a serious consequence of cancer cytotoxic chemotherapy, which is thought to develop from fungal translocation through compromised mucosal barriers. Changes in endogenous bacterial population size or composition as well as changes in the host environment can transform fungal commensals into opportunistic pathogens in the upper and lower GI tract. Pioneering studies from our group have shown that a ubiquitous oral commensal of the mitis streptococcal group (Streptococcus oralis) has a mutualistic relationship with C. albicans, with C. albicans enabling streptococcal biofilm growth at mucosal sites, and S. oralis facilitating invasion of the oral and esophageal mucosa by C. albicans. In these studies, we used a cortisone-induced immunosuppression mouse model. More recently, the development of a novel mouse chemotherapy model has allowed us to examine the interactions of C. albicans with the endogenous bacterial microbiota in the oral and small intestinal mucosa, two sites adversely affected by cytotoxic chemotherapy. In this model, oral inoculation with C. albicans causes severe dysbiosis in the mucosal bacterial composition in both sites. We also found that antibiotic treatment ameliorates invasion of the oral mucosa but aggravates dissemination through the intestinal mucosa. In this chapter, we discuss work from our laboratory and others examining the relationships of C. albicans with oral bacteria and their role in mucosal homeostasis or disease.

Esophageal candidiasis (EC) is the most common type of infectious esophagitis. In the gastrointestinal tract, the esophagus is the second most susceptible to candida infection, only after the oropharynx. Immunocompromised patients are most at risk, including patients with HIV/AIDS, leukemia, diabetics, and those who are receiving corticosteroids, radiation, and chemotherapy. Another group includes those who used antibiotics frequently and those who have esophageal motility disorder (cardiac achalasia and scleroderma). Patients complained of pain on swallowing, difficulty swallowing, and pain behind the sternum. On physical examination, there is a plaque that often occurs together with oral thrush. Endoscopic examination is the best approach to diagnose this disease by directly observing the white mucosal plaque-like lesions and exudates adherent to the mucosa. These adherent lesions cannot be washed off with water from irrigation. This disease is confirmed histologically by taking the biopsy or brushings of yeast and pseudohyphae invading mucosal cells. The treatment is by systemic antifungal drugs given orally in a defined course. It is important to differentiate esophageal candidiasis from other forms of infectious esophagitis such as cytomegalovirus, herpes simplex virus, gastroesophageal reflux disease, medication-induced esophagitis, radiation-induced esophageal injury, and inflammatory conditions such as eosinophilic esophagitis. Except for a few complications such as necrotizing esophageal candidiasis, fistula, and sepsis, the prognosis of esophageal candidiasis has been good.

Alkaline phosphatase activity is a parameter included in biochemical liver test. These isoenzymes are of various cellular origin inducing physiological variations on age and sex. The alkaline phosphatase activity standardization as well as numerous international studies have made it possible to standardize the pediatric reference values. The hyperphosphatasemia etiologies are very well know but the hypophosphatasemia are hardly explored and can allow the diagnosis of pathologies including hypophosphatasia, a rare treatable disease.

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder, which causes a range of physical, cognitive, and medical challenges. To retrospectively analyze the clinical characteristics and genetic variations of Chinese patients, and to provide experience for further diagnosis and treatment of CdLS in Chinese children, we identified 15 unrelated Chinese children who presented with unusual facial features, short stature, developmental delay, limb abnormalities, and a wide range of health conditions. In this study, targeted-next generation sequencing was used to screen for causal variants and the clinically relevant variants were subsequently verified using Sanger sequencing. DNA sequencing identified 15 genetic variations, including 11 NIPBL gene variants, two SMC1A gene variants, one RAD21 gene variant, and one HDAC8 variant. The phenotype of these patients was summarized and differences between this cohort and another four groups were compared. The clinical manifestations of the patients in this cohort were mostly consistent with other ethnicities, but several clinical features in our cohort had different frequencies compared with other groups. We identified 15 deleterious variants of which 11 were novel. Variants in the NIPBL gene were the most common cause in our cohort. Our study not only expands upon the spectrum of genetic variations in CdLS, but also broadens our understanding of the clinical features of CdLS.

BACKGROUND:Cornelia de Lange syndrome (CdLS), a rare, multisystemic disorder, has been linked to genetic alterations in NIPBL, SMC1A, SMC3, HDAC8, and RAD21 genes. Approximately 60% of CdLS patients harbor various NIPBL variants. Genetic changes predicted to affect NIPBL gene splicing represent 15% of all NIPBL genetic abnormalities. Yet, only a few studies have investigated the molecular consequences of such variants. CASE PRESENTATION:This study reports two novel, intronic NIPBL genetic variants in unrelated CdLS patients with the characteristic phenotype. A c.6954 + 3A > C substitution and a c.5862 + 1delG deletion were identified, one of each, in a 6 year-old boy and 39 month-old girl. Further studies confirmed that both variants introduce premature termination codons, resulting in the formation of truncated proteins p.(Ser2255LeufsTer20) and p.(Leu1955Ter), respectively. CONCLUSION:Single nucleotide alterations located within the conserved splice-donor site of intronic regions of the NIPBL gene can give rise to a premature termination of the translation and cause significant changes in the sequence of mRNA transcripts and NIPBL protein structure and function. The latter underline development of Cornelia de Lange syndrome phenotype.

Mice deficient in C/EBP alpha have defective development of adipose tissue, but the precise role of C/EBP alpha has not been defined. Fibroblasts from C/EBP alpha(-/-) mice undergo adipose differentiation through expression and activation of PPAR gamma, though several clear defects are apparent. C/EBP alpha-deficient adipocytes accumulates less lipid, and they do not induce endogenous PPAR gamma, indicating that cross-regulation between C/EBP alpha and PPAR gamma is important in maintaining the differentiated state. The cells also show a complete absence of insulin-stimulated glucose transport, secondary to reduced gene expression and tyrosine phosphorylation for the insulin receptor and IRS-1. These results define multiple roles for C/EBP alpha in adipogenesis and show that cross-regulation between PPAR gamma and C/EBP alpha is a key component of the transcriptional control of this cell lineage.

Fanconi anemia (FA) is a rare inherited disease caused by mutations in genes that are primarily involved in DNA damage response or repair. The disease is often characterized by congenital malformations, progressive bone marrow failure, abnormal skin pigmentation patterns and susceptibility to cancer. The present study describes a pair of 4-year-old male twins, both of whom had been suffering from upper respiratory tract infections for >2 years. There was no indication of discomfort including fever, coughing, bleeding or fatigue from either child when the upper respiratory tract infection disappeared. Physical examination of the twins did not reveal anything significant, and no external anomalies were observed. In order to obtain additional diagnostic evidence, next-generation gene sequencing, chromosome breakage analysis and comet assays were performed. The results revealed double heterozygous mutations in the Fanconi Anemia Complementation Group D2 gene of the twins, therefore providing a conclusive diagnosis of FA. The case highlights how difficulties in clinical diagnosis may be overcome by including genetic screening tests into the range of diagnostic tests, which may also reveal unexpected results.

To investigate the clinical features and genetic characteristics of cases with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN). Characteristics of clinical material, immunological data and gene mutation of two cases with XMEN in the same family in China were retrospectively analyzed. The related reports literature were searched by using search terms'MAGT1 gene'or'XMEN'. The proband, a 2-year-eight-month old boy, was admitted due to 'Urine with deepened color for two days and yellow stained skin for one day'. He had suffered from recurrent upper respiratory tract infection and sinusitis previously. Hemoglobin level was 38 g/L. The absolute count of reticulocytes was 223.2×10(9)/L. Urobilinogen level was 38 μmol/L (3-16 μmol/L). Coomb's test was positive. Both total (77.2 μmol/L) and indirect bilirubin (66 μmol/L) levels were elevated. There was an inverted CD4(+)/CD8(+)T cell ratio (0.89). The gene sequencing results showed MAGT1 gene c.472delG, p.D158Mfs*6 mutation. His 1-year-6-month old brother, was also identified to have MAGT1 gene c.472delG, p.D158Mfs*6 mutation.The younger brother mainly suffered from recurrent upper respiratory tract infection, accompanied by an inverted CD4(+)/CD8(+)T cell ratio (0.45), an elevated ratio and number of total B cells (45.7%). A total of 7 reports were retrieved including 11 male cases caused by MAGT1 gene mutation. These 11 cases were characterized by EBV viremia (11 cases), recurrent upper respiratory tract infection, otitis media or sinusitis (10 cases), secondary neoplasia diseases (8 cases), reduction of CD4(+)/CD8(+) T cell ratio (7 cases),and autoimmune thrombocytopenia or hemolytic anemia (2 cases). XMEN often manifests as male onset, recurrent upper respiratory tract infection, otitis media or sinusitis, EBV viremia, lymphoproliferative disease or lymphoma, autoimmune diseases and reduction of CD4(+)/CD8 (+)T cell ratio. NKG2D expression in NK cells is significantly reduced, and gene sequencing analysis shows a pathogenic mutation in MAGT1 gene.