Nailfold capillaroscopy as diagnostic test in patients with psoriasis and psoriatic arthritis: A systematic review.

Up to 30 % of patients with psoriasis (PsO) develop psoriatic arthritis (PsA), and diagnosis can be difficult. Nailfold capillaroscopy (NC) is an easily applicable, non-invasive procedure to assess skin microcirculation. This systematic review investigates NC as diagnostic tool for PsO and PsA, including correlations between NC outcome measures to clinical and laboratory outcome measures. This systematic review was built on the PICO and PRISMA guidelines. In total 22 relevant studies were found Searching in the Web of Science, PubMed and Embase, latest update June 13th, 2022. The following NC outcome measures are found to be significantly more prevalent in PsO patients than healthy controls: reduced density, reduced length and more abnormal morphology. Likewise, in PsA patients, reduced density, more abnormal morphology, more microhaemorrhages and fewer hairpin shapes are found to be significantly more prevalent. Results were non-conclusive in terms of disease activity and duration with NC findings. Random-effects meta-analysis showed a significant reduction of density in PsO patients compared to healthy controls (studies: 6, n = 249; SMD = -0.91; 95 % CI [-1.41, -0.40], p = 0.0058, heterogeneity I2=74 %, AUC = 0.740) and in PsA patients compared to healthy controls (studies: 5, n = 130; SMD = -1.22; 95 % CI [-2.38, -0.06], p = 0.0432, heterogeneity I2=89 %, AUC = 0.806). No NC outcome measures were overall conclusive in differentiating PsO from PsA. Considering the conflicting results and small sample sizes further large-scale research on the identification of capillaroscopic changes in PsO and PsA and correlations with standardised clinical and laboratory outcome measures are necessary.

Domain Wall Patterning and Giant Response Functions in Ferrimagnetic Spinels.

The manipulation of mesoscale domain wall phenomena has emerged as a powerful strategy for designing ferroelectric responses in functional devices, but its full potential is not yet realized in the field of magnetism. This work shows a direct connection between magnetic response functions in mechanically strained samples of Mn3 O4 and MnV2 O4 and stripe-like patternings of the bulk magnetization which appear below known magnetostructural transitions. Building off previous magnetic force microscopy data, a small-angle neutron scattering is used to show that these patterns represent distinctive magnetic phenomena which extend throughout the bulk of two separate materials, and further are controllable via applied magnetic field and mechanical stress. These results are unambiguously connected to the anomalously large magnetoelastic and magnetodielectric response functions reported for these materials, by performing susceptibility measurements on the same crystals and directly correlating local and macroscopic data.

The influence of diet therapeutic intervention on the sarcopenic index of patients with metabolic syndrome.

INTRODUCTION: The published data showed the importance of metabolic control in preventing complications in metabolic syndrome (MS) and the role of nutritional medical therapy in glycemic control and in the control of dyslipidemia, hypertension, weight loss/normalization (in overweight or malnourished subjects). OBJECTIVES: This study follows the evolution of sarcopenic index (SI) and other clinical parameters (body mass index (BMI), homeostasis evaluation index (HOMA index)) correlated with MS after diet therapy or diet therapy combined with sports, in patients with MS. PATIENTS AND METHODS: Our research was conducted during 12 months, on 110 patients >18 years of age, with HOMA index>2, divided into three groups: control group (CG, N=20), diet therapy group (DTG, N=58), diet therapy and sports group (DTSG, N=32). HOMA index for insulin resistance was calculated as the product of resting plasma insulin (in microunits/milliliter) and plasma glucose (in millimoles/liter), divided by 22.5. SI was determined using BIA, as being the ratio between muscle mass and fat mass, measured in cm2/m2. RESULTS: A significant decrease of BMI (p<0.05) in DTG (from 31.63 to 24.50) and DTSG (from 30.18 to 24.17) vs. CG was observed (Pearson coefficient r=0.281, p<0.001). Weight status changed significantly (p<0.05) in the high-risk patients. There was a significant decrease of HOMA index (p<0.05) in DTG (from 5.93 to 2.57), DTSG (from 3.93 to 2.23), and in CG an increase was observed (from 3.15 to 3.37). CONCLUSION: The best results in the prevention/ treatment of sarcopenia in MS patients were obtained for DTSG, which benefited from both the positive effect of diet and physical activity.

Vascular endothelial growth factor (VEGF) levels in short, GH treated children: a distinct pattern of VEGF-C in Noonan syndrome.

CONTEXT: Noonan syndrome (NS) is characterized by short stature and elevated risk of lymphedema. The mechanism underlying lymphedema may be mediated by vascular endothelial growth factors (VEGFs). OBJECTIVE: To assess the effect of growth hormone (GH) treatment on plasma insulin-like growth factor (IGF)-1, VEGF-A and VEGF-C levels in patients with NS as compared to short GH-sufficient children. DESIGN: Retrospective, comparative. SETTING: Endocrinology department of a tertiary pediatric medical center. PATIENTS AND METHODS: Plasma IGF-1, VEGF-A and VEGF-C levels were measured before and during GH treatment in 6 patients with NS and 18 age-matched short subjects (Turner, idiopathic short stature and small for gestational age). MAIN OUTCOME MEASURES: Changes in plasma VEGF and IGF-1 levels. RESULTS: Baseline IGF-1 SDS levels were slightly lower in NS patients compared with controls; IGF-1 response to GH therapy was markedly lower in NS patients compared with controls (p = 0.017). Mean baseline VEGF-A levels were similar in NS patients and controls whilst mean baseline VEGF-C levels were significantly lower in the NS group as compared with controls (p = 0.022). Plasma VEGF-A and VEGF-C levels did not significantly change during GH treatment in the study cohort. No correlation was found between VEGF-C levels and levels of IGF-1, VEGF-A and auxological parameters, either before or during GH administration. CONCLUSION: Children with NS have a distinct growth factor profile including low basal VEGF-C and flattened IGF-1 response to GH. Further studies are needed to confirm our findings and to elucidate the interaction between VEGF-C levels and lymphedema.

Changes in weight and BMI following the diagnosis of type 1 diabetes in children and adolescents.

The aim of this study was to study weight and body mass index (BMI) before, at, and after diagnosis of type 1 diabetes (T1D) and to identify factors associated with weight gain. Studied retrospectively were 209 children <18 years with T1D followed for 6 years. Data collected included clinical and laboratory data before diagnosis, at diagnosis, and during 6 years of follow-up. Anthropometric parameters of patients were compared along follow-up and with those of their parents and siblings. Mean BMI-standard deviation score (SDS) was below average at diagnosis (-0.66 ± 1.27), had increased to 0.37 ± 0.93 at 3 months, and decreased to a nadir at 6 months in females and 12 months in males; between 1 and 3 years, there was a slight increase and between 3 and 6 years a further increase only in the females. BMI-SDS at 6 years was significantly higher than pre-diabetes BMI-SDS (0.35 ± 0.83 vs. -0.04 ± 1.23, p < 0.001). Patients' BMI-SDS at 6 years was similar to that of their parents and siblings, was higher in the females (0.53 ± 0.74 vs. 0.27 ± 0.82, p = 0.02) and in those keeping diabetes a secret (0.66 ± 0.82 vs. 0.33 ± 0.78, p = 0.027), and was not associated with age or pubertal stage at diagnosis, ethnicity, or metabolic control. A longer duration of insulin pump therapy was associated with a lower BMI-SDS (r = -0.2375, p < 0.025). BMI-SDS increased during the 6 years following diagnosis of T1D in pediatric patients, especially in the females, but remained in the normal range and was similar to that of other family members.

Factors associated with diabetic ketoacidosis at onset of Type 1 diabetes in children and adolescents.

AIMS: To identify risk factors for diabetic ketoacidosis at diagnosis of Type 1 diabetes in children and adolescents. METHODS: In three time periods (1986-1987, 1996-1997 and 2006-2007) 75, 86 and 245 patients, respectively, aged < 20 years were newly diagnosed with Type 1 diabetes in one tertiary care centre. In this retrospective comparative study, data of clinical characteristics, laboratory evaluation at diagnosis, as well as demographic data were retrieved from the patients' files. Comparative analyses were performed between patients presenting with or without diabetic ketoacidosis and between the three time periods. RESULTS: Patients presenting with diabetic ketoacidosis were younger (9.2 ± 4.7 vs. 10.4 ± 4.7 years; P < 0.02), thinner (weight standard deviation score -0.59 ± 1.2 vs. -0.25 ± 1.1; P = 0.002) and less frequently had a first- and/or second-degree relative with Type 1 diabetes compared with those without diabetic ketoacidosis at presentation (16.0 vs. 31.2%, respectively; P = 0.001). Children with diabetic ketoacidosis were less likely to have had relevant testing before diagnosis than children without diabetic ketoacidosis. Children aged < 2 years presented more often with diabetic ketoacidosis than the older children (85 vs. 32%; P < 0.001). Children of Ethiopian origin had a higher rate of diabetic ketoacidosis at diagnosis than the rest of the cohort (57.8 vs. 33%; P = 0.04). CONCLUSIONS: Factors affecting the risk of developing diabetic ketoacidosis at diagnosis of Type 1 diabetes may be related to the degree of awareness of symptoms of diabetes among parents and primary care physicians. Prevention programmes should aim at increasing awareness and consider the application of special measures to avoid diabetic ketoacidosis in children aged < 2 years and high-risk ethnic groups.

Decrease in frequency of ketoacidosis at diabetes onset over the past two decades - perspectives of a paediatric tertiary care centre.

AIMS: To determine whether the frequency and severity of diabetic ketoacidosis and the clinical characteristics of children at diagnosis of Type 1 diabetes mellitus have changed over the past decades among patients under surveillance of a tertiary paediatric centre. METHODS: In three time-periods, 75 (1986-1987), 86 (1996-1997) and 245 (2006-2007) patients at mean age 10.1 ± 4.7 years (0.6-20.0) were diagnosed with new-onset Type 1 diabetes. Data on clinical characteristics and laboratory evaluation at diagnosis retrieved from the patients' files . Comparative analysis was performed between the three time periods. RESULTS: The frequency of diabetic ketoacidosis at diagnosis was 40% in 1986-1987, 41.8% in 1996-1997 and 29.4% in 2006-2007; the last rate was significantly lower (P=0.04). No significant differences in the proportions of patients with severe or moderate diabetic ketoacidosis were found over time. Mean weight standard deviation score significantly increased from -0.72 ± 1.8 in 1986-1987 to -0.27 ± 1.2 in 2006-2007 (P<0.05), while percentage weight loss (∼6.5%) before diagnosis remained unchanged. In 2006-2007 a higher proportion of children had glucose testing at the community clinic before diagnosis, than in the earlier years (73.1 vs. 59.6%, P=0.003). CONCLUSIONS: The overall frequency of diabetic ketoacidosis in children with newly diagnosed Type 1 diabetes has decreased in the past decade, although the degree of metabolic decompensation has remained unchanged.

PP004. Study of the methylenetetrahydrofolate reductase and the reduced-folate carrier-1 gene polymorphism in healthy and severe pre-eclamptic patients.

INTRODUCTION: One-carbon cycle is involved in two essential physiological processes: The synthesis of purins and pyrimidines required for DNA synthesis and repair. The other is the methylation with the methionine cycle. These one-carbon groups are served by the tetrahydrofolate and the S-adenosylmethionine. Deficiencies of the folate, or other abnormalities within the methionine pathway lead to elevated homocysteine levels. These disorders have been implicated in placental diseases. Earlier studies have shown that homocysteine levels are elevated by patients with severe pre-eclampsia than by healthy pregnant normotensive women. Methylenetetrahydrofolate reductase (MTHFR) gene C677T missense mutation has a high frequency by patients with HELLP syndrome and connected with elevated serum homocysteine levels. The reduced-folate carrier (RFC-1) facilitates the internalization of 5-methyltetrahydrofolate from the blood into peripheral cells. The mutation G80A this gene leads to higher plasma folate. OBJECTIVES: Our aim was to identify the polymorphism of these two genes in samples of severe pre-eclamptic patients and healthy controls. METHODS: Blood samples were collected from healthy pregnant normotensive women (n=82) and women with pre-eclampsia (n=75). DNA was isolated and quantitative real-time PCR method combined with melting curve analysis was performed for the detection of the two polymorphisms. Statistical analysis was performed with the STATISTICA software package. RESULTS: The frequency of the A allele in the RFC-1 gene was 46.57% by healthy pregnant and 41% by severe pre-eclamptic patients. The overall distribution of genotypes was not significantly different between the control and pre-eclamptic groups (p=0.58). In the study groups by the MTHFR gene the frequency of the T was 32% in pre-eclamptics, and 35.92% in controls. Similarly the overall distribution of genotypes was not significantly different between the two study groups (p=0.15). CONCLUSION: In hypertensive disorders of the pregnancy the one-carbon cycle is disturbed. We studied single nucleotide mutations in the genes of two enzymes involved in the cycle. We determined the allele and genotype frequencies in healthy control and pre-eclamptic patients and found no significant differences. Further examinations of other genetical compounds can help to understand the elevated homocysteine levels in pre-eclampsia.

Relative value of clinical, laboratory and imaging tools in diagnosing pediatric acute appendicitis.

OBJECTIVE: Aim of the study was to evaluate the relative value of the tools used to diagnose suspected acute appendicitis (AA) in children. METHODS: A retrospective review of data from 1 848 children admitted to the Pediatric Surgery Department between 2004 and 2008 in our university-affiliated medical center was conducted. A total of 780 children underwent appendectomy at first presentation. Of these patients, 75 children required removal of their appendix during laparotomy for other reasons and 19 had appendectomy following peri-appendicular abscess and were excluded from the study. The study included 686 children (2-16 years of age) with presumed AA managed by appendectomy. Clinical, laboratory, and imaging data were collected and compared to pathology results. RESULTS: Of the 686 children who underwent surgery for suspected AA, 34 (5%) had a normal appendix (negative appendectomy rate). No statistical differences were found between normal and AA groups with regard to vomiting, diarrhea, pain duration, and peritoneal signs on admission. Children in the AA group were younger (10.9±3.2 vs. 12.1±2.3 years, p=0.004), had higher fever (36.9±0.7°C vs. 37.4±0.8°C, p=0.004), WBC (14.8±4.8 vs. 10.5±4.6×103/mL, p<0.0005), and neutrophil counts (77.2±11.1% vs. 64.0±15.9%, p<0.0005) on admission, and larger appendicular diameters on ultrasound (US) examination (0.9±0.2 cm vs. 0.7±0.08 cm, p<0.0005). The parameters with the highest positive predictive values for AA were WBC (>10×10 (3)/mL), neutrophil (>66%) count on admission (positive predictive value [PPV]=0.971 and 0.975, respectively), and appendicular diameter on US (>6 mm; PPV=0.968). These 3 parameters combined had a PPV of 0.991. CONCLUSIONS: The results of laboratory tests (WBC, neutrophils) and imaging (US) contributed far more than clinical signs and symptoms (pain duration, vomiting, diarrhea, fever, and peritoneal signs at first physical examination) to the correct diagnosis of AA in children. When these 3 parameters were positive, the probability of a false positive (normal appendix) was only 1%. The contribution of US was particularly high as it was used primarily in patients in whom the diagnosis was in doubt and its results matched the final diagnosis better than diagnoses based on clinical signs and symptoms alone. It provides the additional benefit of no radiation exposure.

The histopathological study of osteoporosis.

The osteoporosis is characterized by the imbalance between the activity of the osteoblasts, the bone forming cells, and the osteoclasts, the cells that resorb the bone tissue, imbalance that favors the osteoclasts. As a conclusion, in the case of osteoporosis, for the same volume, the bone is less compact and more fragile. The objective of our study is to make a histological evaluation of the different elements of the bone tissue in many 47 bone samples: 27 bone fragments were collected from the head and the femoral head of patients who required hip arthroplasty and 20 bone fragments were collected from the vertebral body of dead patients. The results of our study emphasized the thinned trabeculae of the bone that lost continuity, the preferential resorption of the horizontal trabeculae, the consecutive trabecular anisotropy and the reduction of the trabecular connectivity with enlarged areolae and the adipose degeneration of the marrow. One notices in the osteoporosis a reduction of the trabecular network connectivity directly proportional with the stage of the illness; thus, we determined a strong reduction of the trabecular connectivity in advanced osteoporosis stages. The growth aspects of the medular adiposity, associated with the intratrabecular connectivity concurs to highlight the functional connection between bone and marrow. The diminution of the medullar cellularity together with its enrichment in fat cells has negative outcomes on the bone.

Is sex hormone priming in peripubertal children prior to growth hormone stimulation tests still appropriate?

Low growth hormone (GH) secretion during puberty may stem from either a permanent GH axis abnormality or from transient GH deficiency secondary to lack of sex hormones. Although well known to enhance stimulated GH secretion in pre- or early puberty, sex hormone priming for the evaluation of the function of the GH-IGF-I axis remains controversial. Many pediatric endocrinologists consider that omission of such priming during the preadolescent period decreases the specificity of GH stimulation tests and increases the percentage of false-positive diagnosis results. Others believe that it leads only to a temporary augmentation of GH secretion followed by a decrease in spontaneous secretion to levels which may be insufficient for normal pubertal growth; thus priming with sex hormones may lead to underdiagnosis of peripubertal children that could have benefited from GH treatment. The increased availability of biosynthetic GH has enabled expanding the indications for GH therapy and judging and renewing the criteria for the diagnosis of GH deficiency, including the practice of sex hormone priming which was and still is executed in clinical use in many centers in the world. We would like to recommend that priming should not be routinely performed in every peripubertal child undergoing GH evaluation but may be considered in adolescents with pubertal delay--girls aged >11.5-12 years and boys aged >13-13.5 years exhibiting no evidence of puberty or only initial signs.

Growth without growth hormone and similar dysmorphic features in three patients with sporadic combined pituitary hormone deficiencies.

BACKGROUND/AIMS: Mutations in the HESX1 gene are associated with a broad spectrum of phenotypes: septo-optic dysplasia, midline defects, pituitary abnormalities with consequent hypopituitarism, isolated growth hormone (GH) deficiency or combined pituitary hormone deficiencies (CPHD). This study examined the prevalence of mutations in the HESX1 gene in patients with CPHD. PATIENTS/METHODS: Sixty patients with sporadic CPHD without septo-optic dysplasia were screened for mutations in HESX1. RESULTS: Three patients were found to be heterozygous for the same Asn125Ser variant in the HESX1 gene. In all 3, panhypopituitarism was presented in the neonatal period, manifested by severe hypoglycemia and neonatal jaundice in 2 patients and respiratory distress in 1. Remarkable findings from physical examination included coarse face; prominent, large, low-set ears; and skeletal abnormalities. Magnetic resonance imaging, performed in 2 patients, revealed a hypoplastic anterior and ectopic posterior pituitary without other midline anomalies. Despite persistent GH deficiency and undetectable levels of insulin-like growth factor 1, all patients had normal linear growth along the 10-25th percentile without GH therapy. CONCLUSION: The present study expands the clinical picture of HESX1 mutations by demonstrating that patients heterozygous for Asn125Ser may have a severe endocrinologic and neuroradiologic phenotype and similar dysmorphic features appearing very early in life.

Incidence of chromosomal abnormalities in the presence of fetal subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops.

INTRODUCTION: The authors investigated the incidence of chromosomal abnormalities in subcutaneous oedema detected in the fetus by intrauterine ultrasonography. MATERIAL AND METHOD: In the 10-year period, intrauterine karyotyping was performed in pregnancies with positive ultrasound findings for subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops. RESULTS: Intrauterine karyotyping in fetal subcutaneous oedema was carried out in 434 cases. The chromosomal investigation was made in nuchal oedema in 374 cases, in 120 patients the chromosomal examination was made in the first trimester because of nuchal translucency, and in 254 cases in the second trimester because of nuchal thickening. Cystic hygroma cases (27 patients), non-immune hydrops cases (20 patients), and combined cases of non-immune hydrops and cystic hygroma (13 patients) were investigated separately. In nuchal oedema, pathological karyotypes were detected in 8.33% in the first trimester and in 5.51% in the second trimester. Chromosomal abnormality was found in 48.15, 20, and 53.8% in cystic hygroma, non-immune hydrops, and combined occurrence of non-immune hydrops and cystic hygroma, respectively. Considering all of the changes accompanied by subcutaneous oedema, 50, 25 and 18.75% of the pathological karyotypes was X-monosomy, trisomy 18 and trisomy 21, respectively. DISCUSSION: It was important to distinguish nuchal oedema and cystic hygroma, and in the case of non-immune hydrops, it was also important to discuss cases with or without cystic hygroma separately. During the investigations, cases of non-immune hydrops with or without cystic hygroma were evaluated as separate categories. CONCLUSIONS: The authors emphasize the differentiation of the various types of subcutaneous oedema and the importance of precise information about the risks, provided during genetic counselling.

Analysis of perioperative morbidity according to whether the uterine cavity is opened or remains closed during abdominal myomectomy--results of 423 abdominal myomectomy cases.

UNLABELLED: For women who desire pregnancy or who wish to retain their uterus, myomectomy is the standard approach for the treatment of fibroids. Abdominal myomectomy seems to be the best choice when there are large subserosal or intramural fibroids (> 5-7 cm), or submucosal fibroids > 3 cm or when multiple fibroids (> 3) are to be removed. When submucosal myomas are present or multiple fibroids are to be removed, opening the uterine cavity during the surgical procedure is more likely to happen. There is lack of published evidence about whether there is any difference in perioperative morbidity and management of those cases where the uterine cavity is opened during the surgical procedure compared with those where the uterine cavity remains closed. METHODS: We undertook a retrospective review of 423 abdominal myomectomies via either an opened or closed uterine cavity. As a primary outcome we assessed the overall perioperative morbidity rate and as a secondary outcome we compared the necessity of pre and postoperative transfusions, intraoperative bleeding, febrile morbidity, unintended surgical interventions, life-threatening events, need for relaparotomies and duration of hospital stay between the opened and non opened uterine cavity groups. RESULTS: The overall perioperative morbidity rate was significantly higher in those cases where the uterine cavity was opened during surgery; however the difference was caused only by the increased risk of intraoperative bleeding. All the other variables, such as febrile morbidity, number of relaparotomies, unintended surgical procedures and life-threatening events did not differ between the two groups. CONCLUSION: Although there is an increased risk of intraoperative bleeding it seems that entering the uterine cavity during abdominal myomectomy can be considered as safe a procedure as in those cases where the uterine cavity remains closed.

Novel mutation in OTC gene causes neonatal death in twin brothers.

Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of the urea cycle. OTC locus is located in the short arm of X-chromosome. Authors report a case of a woman who gave birth to monozygotic male twins who later died because of severe neonatal-onset hyperammonaemic encephalopathy caused by a novel mutation of OTC gene. Post-mortem liver biopsy was taken from the second twin; afterwards, blood was drawn from the mother for examination. DNA sequence data showed that the mother was a carrier of the same novel mutation that was previously detected in the case of her son. In OTC deficiency, detection of female carriers is important for genetic counselling and eventual prenatal diagnosis.

Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a T-cell-mediated autoimmune disease that leads to the destruction of insulin-producing beta cells. Treatment with DiaPep277, a peptide derived from heat-shock protein 60 (hsp60), has been found to slow the deterioration of beta-cell function after clinical onset of diabetes in NOD mice and human adults. Our aim was to evaluate the efficacy and safety of DiaPep277 treatment in attenuating beta-cell destruction in children with recent-onset T1DM. METHODS: A prospective, randomized, double-blind, phase II design was used. The sample included 30 children (19 males) aged 7-14 years who had been diagnosed with T1DM from 53 to 116 days previously, and had basal C-peptide concentrations above 0.1 nmol/L. The children were randomized to receive subcutaneous injections of 1 mg DiaPep277 (15 patients) or 40 mg mannitol (placebo) at entry and at 1, 6, and 12 months. The duration of follow-up was 18 months. The groups were compared for stimulated C-peptide level, exogenous insulin dose, and HbA1c concentration. RESULTS: C-peptide levels similarly decreased over time in the DiaPep277- and placebo-treated patients. There was no significant difference in insulin dose or HbA1c concentration between the groups at any time point. No serious drug-related adverse effects were recorded throughout the study period. CONCLUSIONS: One-year treatment with DiaPep277 at a dosage of 1 mg is safe for use and well tolerated in children with recent-onset T1DM. However, it appears to have no beneficial effect in preserving beta-cell function or improving metabolic control.

A new mutation in the growth hormone-releasing hormone receptor gene in two Israeli Arab families.

BACKGROUND: Mutations in the GHRH receptor gene (GHRH-R) are emerging as a common cause of familial isolated GH deficiency (IGHD). DESIGN: We searched for GHRH-R mutations in 10 patients with IGHD of Israeli-Arab origin, belonging to two highly consanguineous families. METHODS: Analysis of the 13 coding exons, the intron-exon boundaries, and the proximal promoter of the GHRH-R was performed by denaturing gradient gel electrophoresis. Abnormally migrating bands were sequenced. The newly found mutation was inserted into GHRH-R cDNA. Wild type and mutant receptor were expressed in Chinese hamster ovary (CHO) cells, and the cAMP response to GHRH was measured. RESULTS: All patients were homozygous for a novel GHRH-R missense mutation in exon 11 that replaces arginine with cysteine (R357C). Functional assay demonstrated complete inactivity of the mutant receptor in vitro. The prevalence of the mutant allele in the Israeli-Arab population was found to be 2%. All the patients had low but detectable GH reserve, proportionate short stature, and growth retardation since early childhood, with good growth response to GH treatment. Magnetic resonance imaging, performed in 3 patients, revealed a normal sized anterior pituitary in one patient evaluated at early childhood, and a borderline hypoplastic gland in the 2 patients evaluated at puberty. CONCLUSIONS: We describe a novel missense mutation in the GHRH-R. The high incidence of the mutant allele in Israeli Arabs suggests that the mutation may be a common cause of familial IGHD in this population.

Effect of sex hormone administration on circulating ghrelin levels in peripubertal children.

BACKGROUND: Ghrelin levels gradually decrease throughout childhood and with advancing pubertal stage. The change during puberty is more pronounced in boys than girls. OBJECTIVE: The objective of the study was to investigate whether the pubertal drop in ghrelin secretion is modified by the increase in sex hormones. PATIENTS AND METHODS: Ghrelin levels were measured in 34 short peripubertal children (17 boys and 17 girls) aged 8-12.5 yr before and after sex hormone priming for GH stimulation testing. RESULTS: In boys, priming with testosterone increased testosterone to pubertal levels (23.7 +/- 7.1 nmol/liter), which in turn induced a marked decrease in ghrelin (from 1615.8 +/- 418.6 to 1390.0 +/- 352.0 pg/ml) and leptin (from 8.0 +/- 4.5 to 5.8 +/- 3.2 ng/ml) and an increase in IGF-I (from 162.7 +/- 52.8 to 291.1 +/- 101.6 ng/ml) (P < 0.001 for all parameters). In girls, priming with estrogen led to a supraphysiological increase in estradiol levels (1313.8 +/- 438.0 pmol/liter), which had no effect on ghrelin, leptin, or IGF-I. There was no correlation between ghrelin levels and levels of sex hormones, leptin, or body mass index in either boys or girls. CONCLUSIONS: A pharmacological increase in sex hormones is associated with a marked decline in circulating levels of ghrelin in boys but not girls. Additional longitudinal studies through puberty are needed to elucidate the physiological interaction between sex hormones and ghrelin.

Three novel mutations in POU1F1 in Israeli patients with combined pituitary hormone deficiency.

BACKGROUND: POU1F1, a pituitary-specific transcription factor of the class 1 POU family, is crucial for the development and differentiation of the anterior pituitary gland. Mutations in the POU1F1 gene have been shown to be responsible for a syndrome of combined pituitary hormone deficiency (CPHD), including prolactin, growth hormone and thyroid-stimulating hormone deficiencies. METHODS: Five patients with CPHD from three families were evaluated. The clinical and biochemical data were taken from the medical records. DNA was analyzed by polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE), and sequencing. RESULTS: Molecular analysis yielded three novel mutations in POU1F1: W193X, Q242R (-2 bp), and F262L. CONCLUSIONS: Three novel POU1F1 mutations were detected in Israeli patients with CPHD. Two of them, a W193X missense mutation and a deletion of two adenine bases at position 242Q, may lead to the production of a truncated protein that lacks the entire POU homeodomain or part of it, respectively. The third mutation, F262L, resides in the POU homeodomain and hence might change the activity of the protein.