Decreased calcium permeability caused by biallelic TRPV5 mutation leads to autosomal recessive renal calcium-wasting hypercalciuria.

Hypercalciuria is the most common metabolic risk factor in people with kidney stone disease. Its etiology is mostly multifactorial, although monogenetic causes of hypercalciuria have also been described. Despite the increased availability of genetic diagnostic tests, the vast majority of individuals with familial hypercalciuria remain unsolved. In this study, we investigated a consanguineous pedigree with idiopathic hypercalciuria. The proband additionally exhibited severe skeletal deformities and hyperparathyroidism. Whole-exome sequencing of the proband revealed a homozygous ultra-rare variant in TRPV5 (NM_019841.7:c.1792G>A; p.(Val598Met)), which encodes for a renal Ca2+-selective ion channel. The variant segregates with the three individuals with hypercalciuria. The skeletal phenotype unique to the proband was due to an additional pathogenic somatic mutation in GNAS (NM_000516.7:c.601C>T; p.(Arg201Cys)), which leads to polyostotic fibrous dysplasia. The variant in TRPV5 is located in the TRP helix, a characteristic amphipathic helix that is indispensable for the gating movements of TRP channels. Biochemical characterization of the TRPV5 p.(Val598Met) channel revealed a complete loss of Ca2+ transport capability. This defect is caused by reduced expression of the mutant channel, due to misfolding and preferential targeting to the proteasome for degradation. Based on these findings, we conclude that biallelic loss of TRPV5 function causes a novel form of monogenic autosomal recessive hypercalciuria, which we name renal Ca2+-wasting hypercalciuria (RCWH). The recessive inheritance pattern explains the rarity of RCWH and underscores the potential prevalence of RCWH in highly consanguineous populations, emphasizing the importance of exploration of this disorder within such communities.

De novo interstitial deletion of 11q14.3q22 in a boy with mild intellectual disability and short stature.

BACKGROUND: Interstitial deletions of the 11q region are infrequent. Nonrecurrent chromosomal rearrangements are observed with high variability in size and precise breakpoints of the deleted area. Moreover heterogeneous clinical findings are observed in those harboring 11q interstitial deletions. Main clinical features associated with these deletions include mild dysmorphic findings intellectual disability and moderate developmental or speech delay . METHOD: Conventional high-resolution karyotyping along with microarray studies were performed for the index patient who was found to be a carrier of a de novo interstitial deletion in the long arm of chromosome 11 which is located between the 11q14 and 11q22 band regions. We also investigated the homologous chromosome with next-generation sequencing technology to search for unmasked recessive variants in genes on the nondeleted contralateral allele. RESULTS: Cytogenetic analysis revealed a de novo interstitial deletion on the long arm of chromosome 11 46 XY del(11) (q14q22). Microarray analysis confirmed the deletion of 11.2 Mb in length mapping from 11q14.3 to 11q22.2 [arr (GRCh37) 11q14.3q22.1(90549863_101833022)x1 dn]. Whole-exome sequencing did not detect any other genetic variant (single nucleotide variant ) on the nondeleted allele. CONCLUSION: This study gave us the opportunity for an attempt to define the smallest region of overlap for frequently observed clinical findings by reviewing the literature.

Hypergonadotrophic hypogonadism in a patient with transaldolase deficiency: novel mutation in the pentose phosphate pathway.

BACKGROUND: Transaldolase (TALDO) deficiency (OMIM #606003) is a rare autosomal recessive multi-systemic disorder of carbohydrate metabolism. It has a vast phenotypic spectrum ranging from neonatal liver failure to slowly progressive liver cirrhosis and is characterized by intrauterine growth restriction, hepatosplenomegaly, bicytopenia, nephrolithiasis, and congenital heart disease. METHODS AND RESULTS: We report a patient with a late-onset form of TALDO deficiency characterized by hypergonadotropic hypogonadism and slightly elevated levels of alpha-fetoprotein (AFP). A novel TALDO1 mutation was detected through the application of reverse genetics with the use of clinical exome sequencing (CES). CONCLUSION: This report provides further evidence that reverse genetics is a useful approach in patients who do not manifest the hallmark features of known and recognizable syndromes. TALDO deficiency should be considered in the differential diagnosis of unexplained elevated AFP levels and hypergonadotropic hypogonadism with microlithiasis.

An intronic variant in BRAT1 creates a cryptic splice site, causing epileptic encephalopathy without prominent rigidity.

BRAT1-related neurodevelopmental disorders are characterized by heterogeneous phenotypes with varying levels of clinical severity. Since the discovery of BRAT1 variants as the molecular etiology of lethal neonatal rigidity and multifocal seizure syndrome (RMFSL, OMIM 614498), these variants have also been identified in patients with milder clinical forms including neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS, OMIM 618056), epilepsy of infancy with migrating focal seizures (EIMFS), and congenital ataxia (CA). This study aims to examine the consequences and pathogenicity of a novel homozygous splice site variant in BRAT1 in a patient presenting with migrating focal seizures since birth without prominent rigidity. The patient was born from a consanguineous marriage and has had seizures since the neonatal period. He presented with dysmorphic features, pontocerebellar hypoplasia, and migrating focal seizures. Despite supportive treatment, his symptoms rapidly progressed to intractable myoclonic seizures, bouts of apnea and bradycardia, and arrest of head growth, with no acquisition of developmental milestones. Clinical exome sequencing yielded a novel homozygous splice variant in BRAT1. Genetic analysis based on reverse transcription of the patient's RNA followed by PCR amplifications performed on synthesized cDNA and Sanger sequencing was undertaken, and the functional effect of a BRAT1 variant on splicing machinery was demonstrated for the first time. The severe clinical presentation of migrating focal seizures and pontocerebellar hypoplasia in the absence of rigidity further expands the genotypic and phenotypic spectrum of BRAT1-related neurodevelopmental disorders.

Renpenning Syndrome in a Turkish Patient: de novo Variant c.607C>T in PACS1 and Hypogammaglobulinemia Phenotype.

Renpenning syndrome is an X-linked intellectual disability syndrome caused by mutations in the human polyglutamine binding protein 1 (PQBP1) gene characterized by intellectual disability (ID), microcephaly, and dysmorphic facial features. We report a Turkish child with a novel pathogenic variant in PQBP1 and a likely pathogenic variant in the PACS1 gene presenting with growth restriction, microcephaly, ID, micropenis, bilateral iris coloboma, and hypogammaglobulinemia. Cytogenetic investigations, including a high-resolution-banded karyotype, were normal. Clinical exome sequencing was performed. We found the novel PQBP1 variant, c.640C>T; p.(Arg214Trp), and the known PACS1 variant, c.607C>T; p.(Arg203Trp), in the proband. The patient's hypogammaglobulinemia did not respond to treatment. This condition was detected for the first time in a patient with Renpenning syndrome.

Successful management of acute pancreatitis due to apolipoprotein C-II deficiency in a 37-day-old infant.

Familial chylomicronemia is caused by deficiency of lipoprotein lipase or its co-activators. Here, we report an infant with apolipoprotein C-II (APOC2) deficiency, who developed acute pancreatitis 37 days after birth. He presented as abdominal sepsis with fever, irritability and abdominal distention. Amylase levels were low, but lipase levels and imaging findings were consistent with acute pancreatitis. He had severe hypertriglyceridemia (1091 mg/dl). Keeping him nil orally for two days resulted in rapid decrease in triglyceride levels and resolution of the clinical findings. APOC2 gene sequencing revealed a homozygous splice-site mutation (c.55+1G>C). To the best of our knowledge, this patient is not only the youngest reported patient with APOC2 deficiency, but also the youngest such patient who developed pancreatitis. Although he had a severe presentation, invasive methods to treat hypertriglyceridemia were not necessary. We emphasize that clinical findings and amylase levels are not reliable to diagnose pancreatitis in this age group.

The choice of multi-beam IMRT for whole breast radiotherapy in early-stage right breast cancer.

The aim of this study was to identify a rational strategy for the selection of multi-beam IMRT in patients with right breast cancer through the comparison of dosimetric parameters of the planning target volume (PTV) and organs at risk (OARs) using five different radiotherapy modalities. This was a retrospective study using computed tomography scans from ten patients with early-stage right breast cancer who had been treated previously. Three dimensional conformal radiotherapy (3DCRT), forward-planned IMRT (for-IMRT), inverse-planned IMRT (inv-IMRT), helical tomotherapy (HT), and volumetric-modulated arc therapy (VMAT) were planned for each patient. The plans were compared according to dose-volume histogram analysis. The most significant impact of inverse-planned multi-beam modalities for right breast cancer was the reduction of Dmax, Dmean, V53.5 and prescribed dose volume (cc) outside of the PTV (breast) (OB-V50) of the PTV. HT decreased the ipsilateral OAR volumes receiving higher doses. In exchange, HT also increased the volumes receiving low doses, which is known to lead to an increased rate of radiation-induced secondary malignancies. The heart, LAD, and contralateral doses for 3DCRT and for-IMRT were significantly lower than those for inv-IMRT, HT, and VMAT. In addition, inv-IMRT demonstrated an increase in exposed volume of heart, LAD, ipsilateral lung, and contralateral lung compared with those parameters for HT or VMAT. Although it is known to reduce cardiac toxicity with breath hold technique in left sided breast cancer, similarly it is possible for 3DCRT and for-IMRT techniques in right sided breast cancer even in free breathing.

Prospective Randomized Comparison of the Effectiveness of Radiation Therapy and Local Steroid Injection for the Treatment of Plantar Fasciitis.

PURPOSE: The purpose of this study was to conduct a randomized trial of radiation therapy for plantar fasciitis and to compare radiation therapy with local steroid injections. METHODS AND MATERIALS: Between March 2013 and April 2014, 128 patients with plantar fasciitis were randomized to receive radiation therapy (total dose of 6.0 Gy applied in 6 fractions of 1.0 Gy three times a week) or local corticosteroid injections a 1 ml injection of 40 mg methylprednisolone and 0.5 ml 1% lidocaine under the guidance of palpation. The results were measured using a visual analog scale, a modified von Pannewitz scale, and a 5-level function score. The fundamental phase of the study was 3 months, with a follow-up period of up to 6 months. RESULTS: The median follow-up period for all patients was 12.5 months (range, 6.5-18.6 months). For the radiation therapy patients, the median follow-up period was 13 months (range, 6.5-18.5 months), whereas in the palpation-guided (PG) steroid injection arm, it was 12.1 months (range, 6.5-18.6 months). After 3 months, results in the radiation therapy arm were significantly superior to those in the PG steroid injection arm (visual analog scale, P<.001; modified von Pannewitz scale, P<.001; 5-level function score, P<.001). Requirements for a second treatment did not significantly differ between the 2 groups, but the time interval for the second treatment was significantly shorter in the PG steroid injection group (P=.045). CONCLUSION: This study confirms the superior analgesic effect of radiation therapy compared to mean PG steroid injection on plantar fasciitis for at least 6 months after treatment.

A Glutamine Repeat Variant of the RUNX2 Gene Causes Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD), an autosomal dominant skeletal dysplasia characterized by hypoplastic clavicles and delayed closure of the cranial sutures, is caused by mutations of the runt-related transcription factor 2 (RUNX2) gene. The RUNX2 gene consists of a glutamine and alanine repeat domain (Q/A domain, 23Q/17A), a DNA-binding Runt domain and a proline/serine/threonine-rich domain. We report on a familial case of CCD with a novel mutation within the Q/A domain of the RUNX2 gene, which is an insertion in exon 1 (p.Q71_E72insQQQQ) representing the Q-repeat variant (27Q/17A). Functional analysis of the 27Q variant revealed abolished transactivation capacity of the mutated RUNX2 protein. This is the first case report that demonstrated a glutamine repeat variant of the RUNX2 gene causes CCD.

Comparison of dose distributions hippocampus in high grade gliomas irradiation with linac-based imrt and volumetric arc therapy: a dosimetric study.

The aim of this study was to assess the feasibility of sparing contralateral hippocampus during partial brain radiotherapy in high grade gliomas. 20 previously treated patients were replanned to 60 Gy in 30 fractions with sparing intensity-modulated radiotherapy (IMRT) and volumetric modulated arctherapy (VMAT) using the following planning objectives: 100 % of PTV covered by 95% isodose without violating organs at risk (OAR) and hot spot dose constraints. For each, standard intensity-modulated radiotherapy (IMRT) plans were generated, as well as sparing IMRT and VMAT plans which spared contralateral (hemispheric cases) hippocampus. When the three plans were compared, there was equivalent PTV coverage, homogeneity, and conformality. Sparing IMRT significantly reduced maximum, mean, V20, V30 and V40 hippocampus doses compared with standart IMRT and VMAT (p < 0.05). VMAT significantly reduced maximum left lens and mean eye doses compared with standart IMRT and sparing IMRT (p < 0.05). Brainstem, chiasm, left and right optic nerves, right eyes and lens doses were similar. VMAT significantly reduced monitor units compared with standart IMRT and sparing IMRT (p < 0.05). It is possible to spare contralateral hippocampus during PBRT for high grade gliomas using IMRT. This approach may reduce late cognitive sequelae of cranial radiotherapy.

Dosimetric comparison of left-sided whole-breast irradiation with 3DCRT, forward-planned IMRT, inverse-planned IMRT, helical tomotherapy, and volumetric arc therapy.

PURPOSE: This study evaluated the dose distribution and homogeneity of four different types of intensity-modulated radiotherapy (IMRT) in comparison with standard wedged tangential-beam three-dimensional conformal radiotherapy (3DCRT) of the left breast in patients who had undergone lumpectomy. MATERIALS AND METHODS: Five radiotherapy treatment plans, including 3DCRT, forward-planned IMRT (for-IMRT), inverse IMRT (inv-IMRT), helical tomotherapy (HT) and volumetric-modulated arc therapy (VMAT), were created for 15 consecutive patients. RESULTS: All modalities presented similar target coverage. Target max doses were reduced with for-IMRT compared to 3DCRT, and these doses were further reduced with inv-IMRT and HT. HT resulted in the lowest max doses delivered to the heart, left anterior descending artery (LAD), and ipsilateral lung, but had higher mean, max, and low doses delivered to contralateral breast. HT resulted in increased low doses to a large volume of healthy tissue. Compared to other techniques, all inverse-planned modalities significantly improved conformity number; however, VMAT had worse homogeneity. The for-IMRT plan significantly lowered monitor unit (MU) compared to the inverse-planned techniques. CONCLUSION: All modalities evaluated provide adequate coverage of the whole breast. For-IMRT improves target homogeneity compared with 3DCRT, but to a lesser degree than the inverse-planned inv-IMRT and HT. HT decreases the ipsilateral OAR volumes receiving higher and mean doses with an increase in the volumes receiving low doses, which is known to lead to an increased rate of radiation-induced secondary malignancies.

Evaluation of prognostic factors and survival results in gastric carcinoma: single center experience from Northeast Turkey.

OBJECTIVE: To evaluate the prognostic factors affecting overall survival (OS), disease-free survival (DFS), and survival among patients undergoing chemoradiotherapy (CRT) for locally advanced gastric carcinoma. METHODS: Between January 2001 and May 2014, 257 patients who presented to our clinic with a diagnosis of stage I-IIIC gastric cancer were evaluated. The male/female ratio of the cases was 2.02:1 and the median age was 55.16±11.8 (20-80) years. Four of the cases (1.6%) were stage IA, 13 (5.1%) were stage 1B, 41 (16%) were stage IIA, 40 (15.6%) were stage IIB, 50 (19.5%) were stage IIIA, 51 (19.8%) were stage IIIB, and 58 (22.6%) were stage IIIC. RESULTS: The mean follow-up time was 22.5 months (3.3-155.0); loco-regional recurrence was noted in 34 (13.2%) patients who underwent postoperative chemoradiotherapy, and metastases were observed in 108 (42%) patients. The median OS duration was 26.7 months (95% confidence interval, 20-33.5) and the 2-, 5-, and 10-year OS was 52.8% (standard error [S.E.] 0.032), 36.1% (S.E. 0.032), and 26.9% (S.E. 0.034) respectively. The median DFS was 53.7 months and the 2-, 5-, and 10-year DFS were 58.9% (S.E. 0.034), 47.4% (S.E. 0.037), and 40.7% (S.E. 0.042), respectively. In multivariate analysis of prognostic factors, advanced T stage (p<0.0001), advanced nodal stage (p=0.001), and surgical margin status (p<0.0001) were related to decreased OS and DFS. CONCLUSION: R1 resection, advanced T stage, and advanced nodal stage were adverse prognostic factors in gastric cancer patients who had undergone CRT after the operation.

Comparison of intracavitary brachytherapy and stereotactic body radiotherapy dose distribution for cervical cancer.

PURPOSE: To compare the dose distribution characteristics of stereotactic body radiotherapy (SBRT) with intracavitary high-dose-rate (HDR) brachytherapy in patients with cervical carcinoma. METHODS AND MATERIALS: HDR intracavitary brachytherapy treatment plans for 11 women with cervical carcinoma were evaluated in this analysis. The total HDR brachytherapy dose was 28Gy given in four fractions. HDR brachytherapy was delivered with the microSelectron HDR therapy unit (Nucletron B. V., Veenendaal, The Netherlands). SBRT plans for each patient were generated with MultiPlan for CyberKnife Robotic Radiosurgery System (Accuray Inc., Sunnyvale, CA). The dose distributions, dose-volume histograms, and maximum dose points of the target and critical organs were recorded for both plans. RESULTS: SBRT yielded significantly better target coverage; the median target coverage for the 100% isodose line was 50.7% for HDR brachytherapy plans, whereas it was 99.1% for SBRT plans. The dose distributions for critical organs were similar in both types of plans. The exceptions were the 25% isodose being significantly better in brachytherapy plans for rectum, and the 100% isodose exposure being higher in brachytherapy plans for rectum, bladder, and sigmoid colon. Some significant differences were also found in maximum doses received by a 2-cc volume of bladder in favor of SBRT plans. In addition, maximum bone marrow doses were significantly higher in SBRT plans. CONCLUSION: SBRT plans achieved better target coverage and better dose distributions to critical organs except bone marrow compared with HDR brachytherapy plans in patients with locally advanced cervical cancer.

Accelerated superfractionated radiotherapy with concomitant boost for invasive bladder cancer.

PURPOSE: To determine the toxicity and clinical effectiveness of accelerated superfractionated radiotherapy with delayed concomitant boost (ASCBRT) in locally invasive carcinoma of the bladder. METHODS AND MATERIALS: Between July 1997 and December 2001, 87 patients (unsuitable or refusing cystectomy) with invasive bladder cancer underwent ASCBRT. The mean patient age was 66 years (range 40-90). The stage distribution was as follows: 2 T1, 51 T2, 13 T3, and 21 T4. Initially, the whole pelvis was treated by 1.8-Gy conventional daily fractions up to a total dose of 45 Gy. A small field boost covering gross disease was added as a second daily fraction (1.5 Gy) during the last 3 weeks of the 5-week schedule up to a total dose of 67.5 Gy. The interfraction interval was a minimum of 6 h. The patients were evaluated in follow-up for toxicity, local control, and survival. RESULTS: All but 2 patients completed the study protocol. Grade 3 acute urinary toxicity was observed in 2 patients. Grade 2 and 3 late bladder toxicity was observed in 12 patients and 1 patient, respectively. Grade 2 and 3 late bowel toxicity was observed in 5 and 3 patients, respectively. The 3-year actuarial local control, distant disease control, cause-specific survival, and overall survival rate was 64%, 78%, 58%, and 46%, respectively. Multivariate analysis revealed T stage as independent predictor of complete response. For Stage T2 and T3, the 3-year local control rate was 77% and 48%, respectively. At the last follow-up, 53 patients (61%) were still alive with a survival time between 6 and 62 months. CONCLUSION: ASCBRT is feasible with acceptable tolerance even in relatively old patients with Stage T3 or greater tumor. The encouraging locoregional control and survival results of this institutional experience, favorable compared with conventional radical and other accelerated fractionated (with or without a concomitant boost) RT series, make ASCBRT worthy of further study in a Phase III trial.