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A heterozygous intragenic duplication within the repeated area (CTGCAGCTG)×2 of the NR5A1 gene was found in a 15-year-old 46,XY DSD (disorders/differences of sex development) patient with micropenis and severe proximal hypospadias. This heterozygous duplication has already been described twice in boys with a similar phenotype, whereas a deletion of 3 amino acids at the same position in the protein SF-1 has been described in a 46,XX patient with primary ovarian failure and short stature. These data suggest that this region within the NR5A1 gene has an important role for SF-1 protein function in gonads and is a hotspot for intragenic rearrangements., (© 2018 S. Karger AG, Basel.)

Background: A questionnaire-based survey was conducted to assess attitudes toward a reusable self-injection system (SurePal™) among pediatric patients with growth disturbances who were prescribed treatment with Omnitrope(®) within routine clinical practice., Methods: This was a multicenter, observational study, incorporated into the noninterventional PAtients TReated with Omnitrope(®) (PATRO) Children study. Included subjects, or their caregivers, completed a questionnaire on the following five main areas: attractiveness of SurePal™, training received, using the device, the low drug wastage system, and experience versus other devices used previously (pretreated patients). Responses were based on a 5-point scale, with 2 being the best possible outcome and -2 the worst possible outcome., Results: In total, 550 patients were included in this study (338 from France, 169 from Germany, and 43 from the UK). The mean age ± standard deviation of participants was 10.8±3.5 years; the majority (57%) were male and growth hormone treatment naïve (88%). Almost half (49.8%) of children prepared their SurePal™ for injection themselves and 45.5% performed injections themselves. As patients progressed into their teens, the majority (≥75%) favored preparing SurePal™ and performing injections themselves, rather than seeking assistance. The attractiveness of SurePal™ was rated as excellent/good by 84.7% of patients overall; this rating was similarly high (≥79%) across countries and age-groups. Preparing (88.8%) and using (83.3%) SurePal™ were rated as very easy/easy by most patients; these ratings were similarly high, irrespective of country or age-group. The dose-memory function was rated as very helpful/helpful by 66.2% of patients. Among 246 patients who reported using the low drug-waste feature, 87.4% found it helpful. Among pretreated patients (n=64), 78.2% reported that SurePal™ was much better/better than their previous device., Conclusion: These data confirm the ease of use and patient preference for SurePal™ among pediatric patients with growth disturbances.

Context and Objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations., Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients., Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01)., Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis., (© 2016 European Society of Endocrinology.)

The authors describe a case of a 5 cm mixed desmoplastic melanoma occurring on the cheek of an 88-year-old white woman. The epidermis showed the features of lentigo maligna. Within the dermis, there was a mixed desmoplastic melanoma with 2 components. The first component consisted of infiltrative malignant spindled cells with prominent stromal fibrosis and had the typical appearance of desmoplastic melanoma. The second component was within the deep half of the tumor and consisted of a densely cellular nodule composed of spindled melanocytes admixed with many osteoclast-like giant cells. There was a peripheral neurotropism and tumor invaded bone. The Breslow thickness was 14 mm. On followup, a sacral metastasis was discovered, which had a similar morphology to the deep cellular nodule. Immunohistochemistry of spindled cells both inside and outside the nodule showed S100 positivity with the absence of other melanocytic markers (HMB-45, Melan-A). Smooth muscle actin and p63 were focally positive. The osteoclast-like giant cells expressed CD68 and MiTF. Array comparative genomic hybridization of the typical desmoplastic melanoma region had a flat profile, whereas the cellular osteoclast-like giant cell–rich region displayed important cytogenetic anomalies, some of which have been previously described in melanomas. The main array comparative genomic hybridization findings were confirmed by fluorescence in situ hybridization using specific probes. The differences in morphology and molecular cytogenetics between the 2 areas suggest that these might represent the progression or emergence of a more aggressive clone within the tumor. Subsequent metastatic spread to the bone may be a result of accumulated cytogenetic abnormalities.

Crizotinib, a small molecule tyrosine kinase inhibitor, has shown tremendous promise in the treatment of lung adenocarcinomas harboring either ALK or ROS1 rearrangements. Recently, small studies of colorectal carcinomas (CRCs) have suggested an incidence of EML4-ALK translocations of 0.4% to 2.4% and FIG-ROS1 translocations of 0.8%. In lung cancer, screening immunohistochemical staining for ALK and ROS1 has been validated as highly sensitive for these translocations, but this has not been investigated in CRC. We therefore sought to investigate the incidence of ALK and ROS1 overexpression as detected by immunohistochemical staining in a large cohort of CRCs. Of the 1889 CRCs, only 1 case (0.05%) demonstrated diffuse strong positive staining for ALK, whereas 14 (0.7%) showed weak nonspecific staining; the remainder were negative. The 1 positive case was confirmed to harbor an ALK rearrangement by fluorescent in situ hybridization (FISH), whereas the 14 tumors with weak staining were FISH-negative. The ALK positive case demonstrated positive expression in all dysplastic and malignant cells indicating that the translocation was an early clonal event. No cases were positive for ROS1 by immunohistochemical staining, although 2 cases did show some nonspecific staining and were shown to be negative for ROS1 translocation by FISH. We conclude that although diffuse strong positive staining for ALK is likely to be highly specific for ALK rearrangement in CRC, both ALK and ROS1 immunohistochemical staining are very low-yield tests and difficult to justify in the routine clinical setting.

Mutations in EGFR guide treatment in non-small cell lung cancer (NSCLC). The most common mutations, exon 19 (delE746-A750) and exon 21 (L858R), can be identified by mutation specific immunohistochemistry (IHC). We present our prospective experience of universal reflex IHC and molecular testing in non-squamous NSCLC in the routine clinical setting.A total of 411 specimens from 332 patients were encountered over two years. Of these, 326 (98%) patients underwent EGFR IHC, 15 (5%) were positive for exon 19 deletions and 27 (8%) for exon 21 (L858R); 244 (73%) patients underwent molecular testing. Seventy-six mutations in 64 patients (19% of all patients encountered; 26% with sufficient material for testing) were identified. These comprised nine exon 18 (G719X) mutations, three also with exon 20 mutations; 24 exon 19 deletions, six also with exon 20 mutations; 23 exon 21 (L858R), three also with exon 20 mutations; and 8 exon 20 alone.All 15 exon 19 IHC positive patients were proven mutated (100% specificity, 63% sensitivity). Twenty-two of 27 exon 21 IHC positive cases were proven mutated while three patients had insufficient material for molecular testing (92% specificity, 96% sensitivity). The overall specificity and sensitivity of IHC for any EGFR mutation was 95% and 58%. Five patients initially thought to be wild type for EGFR but IHC positive underwent repeat molecular testing because of the discrepancy which confirmed the IHC result in three cases (60%).We conclude IHC is very specific but not sensitive. Whilst IHC cannot replace molecular testing, it is a useful adjunct which requires minimal tissue and identifies false negative molecular results which occurred in 5% of our patients with eventually confirmed EGFR mutations.

Trichoblastoma is a benign cutaneous adnexal tumor, composed mostly of follicular germinative cells. Its pigmented variant is colonized by numerous dendritic melanocytes. So far, only one case in the literature describes a combination of trichoblastoma and melanoma. We report the case of a 62-year-old man who had a slow-growing mass of the left flank present since childhood. This 8-cm mass was surgically removed when it became ulcerated and associated with axillary lymph nodes. Histologically, this tumor was strictly dermal and composed of 2 intermingled components. Large sheets of atypical, proliferating epithelioid cells predominated. Dispersed solid nests or cribriform epithelial islets encased in fibrous tissue were also seen. Some nests displayed a massive colonization by pigmented dendritic melanocytes. On immunohistochemical staining, the sheets of atypical cells expressed focally but strongly S100 protein, MelanA, HMB45, and MiTF. Epithelial structures diffusely expressed pancytokeratin AE1/AE3, KL1, and pleckstrin homology-like domain, family A, member 1. Based on these results, we diagnosed an intradermal melanoma, possibly developed from dendritic melanocytes colonizing a giant pigmented trichoblastoma. Direct sequencing of the melanoma revealed a rarely described NRAS mutation c.34G>T (G12C). Array comparative genomic hybridization displayed a complex profile somewhat divergent from standard melanoma profiles. The patient died of widespread metastatic disease 8 months after initial diagnosis.

Fluorescence in situ hybridisation (FISH) is considered the gold standard for the detection of ALK gene rearrangements in lung adenocarcinoma. The presence of ALK gene rearrangement predicts response to specific targeted therapy, but these rearrangements are relatively rare and FISH studies are expensive, not widely available, potentially challenging to interpret and therefore difficult to undertake in all patients with non-small cell lung cancer. We developed and then deployed into the routine clinical setting a screening program for ALK gene rearrangement in all non-small cell lung cancer patients based on immunohistochemistry (IHC) with a mouse monoclonal antibody (clone 5A4).ALK IHC was strongly positive in 12 (4%) of 307 tumours from consecutive patients. Only 10 of these cancers were initially thought to be rearranged by diagnostic FISH studies. The two tumours which were IHC positive but initially interpreted as FISH negative underwent repeat FISH testing because of the discrepancy. Repeat FISH testing confirmed the presence of ALK gene rearrangement with the discrepancy being attributable to an atypical FISH pattern.Therefore, in our experienced hands, IHC for ALK performed on initial diagnosis of lung cancer is 100% specific for the presence of ALK gene rearrangement. When ALK IHC and FISH studies are discrepant, IHC may outperform FISH. Although our study was not intended to formally assess the sensitivity of ALK IHC, the 4% rate of gene rearrangements identified by this approach is consistent with the expected incidence in our population.We conclude that reflex ALK IHC followed by confirmatory FISH testing can be readily integrated into the routine clinical setting and represents a cost effective and practical approach to screening for these clinically significant gene rearrangements.

ARID1A is a tumor suppressor gene involved in chromatin remodelling. ARID1A mutations and loss of protein expression occur commonly in endometrioid and gynecological clear cell carcinoma where they are associated with mismatch repair (MMR) deficiency. We assessed ARID1A expression in a large cohort of colorectal carcinomas (CRCs). Immunohistochemistry for ARID1A was performed on whole sections from 100 CRCs and on 1876 CRCs in tissue microarray format. There was complete concordance between the staining on whole slides and tissue microarray sections. Loss of staining was found in 110 (5.9%) of 1876 CRCs and was strongly associated with older age, right sided location, large size, BRAF V600E mutation, MMR deficiency, high histological grade and medullary morphology, (all P < .01). There was a trend towards loss of expression being more common in females (P = .06). When subclassified by combined BRAF V600E mutation and MMR status, loss of ARID1A expression was found most commonly in CRCs with the BRAF V600E mutated, MMR- deficient phenotype (58 of 232 cases, 25%, P < .01). In univariate and multivariate analysis, loss of ARID1A expression was not associated with overall survival-hazard ratio 1.05 (0.68-1.64) and 0.60 (0.24-1.44), respectively. All carcinomas arising in patients with known Lynch syndrome (n = 12) were ARID1A positive. We conclude that loss of ARID1A expression occurs in a small but significant proportion of CRCs where it is strongly correlated with mismatch repair deficiency and other clinical and pathological features associated with somatic hypermethylation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Context: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions., Objective: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test)., Design and Setting: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice., Patients: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included., Intervention: DEX was offered after informed consent to pregnant women., Main Outcome Measure: The sensitivity of an early SRY test was evaluated after data collection., Results: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero., Conclusions: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported.

MYC over-expression as determined by molecular means has been reported as a favorable prognostic biomarker in colorectal carcinoma (CRC). However MYC expression analysis is not available in the routine clinical setting. We investigated whether immunohistochemistry (IHC) for the myc protein using a novel commercially available rabbit monoclonal antibody [clone Y69] which is currently in widespread clinical use for lymphoma diagnosis could be used to predict outcome in resected CRC. Myc IHC was performed on a tissue microarray (TMA) comprising a retrospective cohort of 1421 CRC patients and scored blinded as to all clinical and pathological data. IHC was also performed on a subcohort of whole section CRCs to assess staining characteristics and concordance with TMA expression. MYC over-expression was found in 980 (69%) of CRCs and was associated with tumor stage and DNA mismatch repair/BRAF status. There was substantial agreement between TMA and whole section myc IHC (kappa = 0.742, p<0.01). CRCs with MYC over-expression demonstrated improved 5-year survival (93.2% vs. 57.3%), with the effect significantly modulated by the dominant effect of tumor stage, age at diagnosis and lymphovascular space invasion status on survival. We conclude that myc status as determined by IHC alone can be used to predict overall survival in patients with CRC undergoing surgical resection.

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis., (© 2013.)

KISS1R and its ligand, the kisspeptins, are key hypothalamic factors that regulate GnRH hypothalamic secretion and therefore the pubertal timing. During studies analysing KiSS1 as a candidate gene in pubertal onset disorders, two SNP and one nucleotide insertion were observed in a 23 nucleotides G-rich sequence located 65 nucleotides downstream of the stop codon. The polymorphisms formed four haplotypes. Biophysical experiments revealed the ability of this G-rich sequence to fold into G-quadruplex structures and demonstrated that the three DNA polymorphisms did not perturb the folding into G-quadruplex but affected G-quadruplex conformation. A functional luciferase reporter-based assay revealed functional differences between 3'UTR haplotypes. These data show that polymorphisms in a G-rich sequence of the 3'UTR of KISS1, able to fold into G-quadruplex structures, can modulate gene expression. They highlight the potential role of this G-quadruplex in the regulation of KISS1 expression and in the timing of pubertal onset., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We determined whether super selective radio embolization of the porcine kidney was technically feasible and evaluated histopathological changes in the treatment target zone (upper or lower renal pole), adjacent nontargeted kidney, and adjacent and distant organs after administering (90)Y labeled vs bland resin microspheres., Materials and Methods: We performed super selective radio embolization with (90)Y resin microspheres in 1 kidney and with an equivalent number of bland microspheres in the corresponding pole of the contralateral kidney as a control. The aim was to achieve radio embolization of a target zone equivalent to approximately a third of the kidney volume. A pathologist independently graded macroscopic and microscopic changes in the kidney, and adjacent and distant tissue resulting from incremental increases (0.15 to 0.35 GBq) in implanted activity in 6 pigs., Results: We recorded grade 4 histological changes in the treatment target zone (upper or lower renal pole) in 5 of 6 pigs after injecting (90)Y resin microspheres with evidence of nephron sparing effects in the adjacent renal tissue at the lowest activity. At activity greater than 0.3 GBq increasing damage was noted to adjacent renal tissue beyond the treatment target zone. No toxicity was evident in adjacent or distant organs., Conclusions: Delivery of highly targeted intra-arterial radiotherapy to the kidney is feasible and safe in the pig model. Further evaluation is warranted as a potential treatment for advanced renal cell carcinoma or for localized disease in patients who are not candidates for surgery., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Study Design: Case report., Objective: To report a previously undescribed association between complex regional pain syndrome (CRPS) and surgery for cervical disc protrusion., Summary of Background Data: Although CRPS has been associated with disc protrusion and lumbar spine surgery, there is no record in the literature of a similar association with cervical disc protrusion., Methods: Description of a clinical case., Results: A patient with radicular pain due to cervical disc protrusions underwent posterior foraminotomy, which did not relieve his pain. Within 3-4 weeks, he developed features of CRPS. Review at 16, 22, and 34 months revealed some, but limited, improvement., Conclusions: This case provides circumstantial evidence of a hitherto undescribed association between CRPS and cervical disc protrusion. The mechanism is elusive, but may involve damage to small nerves in or near the intervertebral foramina., (Wiley Periodicals, Inc.)

Studies have reported the incidence of anatomical variants of the paranasal sinuses for specific populations with a view to helping surgeons avoid possible complications during functional endoscopic sinus surgery. Some have found significant variation when comparing different populations. The current study has used computed tomography (CT) scans to observe variations in the paranasal sinuses in a non-random sample of museum skulls of Melanesians, a racial group that has not previously been studied in this respect. The incidence of variants found were: agger nasi cells 59.5%, concha bullosa 41.5%/o, Haller's air cells 31.7%, internal carotid artery bulge in the sphenoid sinus 23.8%/, supraorbital cells 16. 7%, paradoxical curvature of the mid-dle turbinate 7.5% and pneumatization of crista galli 7.1%.Because of contradictory findings in the literature as to the incidence of such variations between racial groups the authors are able to make only limited meaningful comparisons between their subjects and other such groups.

Context: IGF-I is essential for fetal and postnatal development. Only three IGF1 defects leading to dramatic loss of binding to its type 1 receptor, IGF-1R, have been reported., Patient: We describe a very lean boy who has intrauterine growth restriction and progressive postnatal growth failure associated with normal hearing, microcephaly, and mild intellectual impairment. He had markedly reduced concentrations of IGF-I, with IGFBP-3 and ALS serum levels in the upper normal range or above. IGF-I serum concentrations differed according to the immunoassay used. A higher than average GH dose was required for catch-up growth. Given the mismatch between IGF-I and IGFBP-3 levels, we sequenced his IGF1 gene., Result: We identified a homozygous missense IGF1 mutation. This causes the replacement of a highly conserved amino acid (arginine 36) by a glutamine (R36Q) in the C domain of the predicted peptide. We showed that the abnormal IGF-I peptide has reduced mitogenic activity and partial loss of binding to its receptor IGF-1R. The patient's IGF-I level was undetectable in a highly specific monoclonal assay but elevated in a polyclonal assay., Conclusion: This first report of mild deficiency of IGF-I activity demonstrates that the integrity of IGF-I signaling is important for normal growth and brain development. Molecular defects leading to partial loss of IGF-I activity may not be uncommon in patients born small for gestational age. The characterization of this complex phenotype and identification of such molecular defects have therapeutic implications, particularly now that, in addition to GH, recombinant IGF-I is available for clinical use.

We report on two sporadic and two familial new cases with sensorineural hearing impairment and ovarian dysgenesis which are the cardinal signs of Perrault syndrome in females. Only one of them has a nervous system defect. We reviewed all the published cases of Perrault syndrome in order to define the clinical variability and to evaluate the frequency of the neurological anomalies in this clinical entity. Moreover we excluded GJB2, POLG, and FOXL2 as candidate genes in Perrault syndrome., ((c) 2008 Wiley-Liss, Inc.)

A case of endometrioma of the right inguinal canal region, diagnosed preoperatively, is presented. The diagnosis was made on the basis of cyclical symptoms relating to menstrual periods, in combination with demonstration of blood products within an enhancing focal lesion in the inguinal region with magnetic resonance imaging. The case presented here is unique, as it is the first case, to our knowledge, of an endometriotic lesion in the inguinal canal to demonstrate the characteristic 'shading sign' at magnetic resonance imaging.

The phenotype of monosomy 18p varies widely, the main clinical manifestations being mental and growth retardation, and craniofacial dysmorphism. Clinical features also include growth hormone (GH) deficiency, or holoprosencephaly (HPE). Haploinsufficiency for TGIF, mapped to 18p11.3, is not generally sufficient to cause HPE. To perform a genotype-phenotype correlation, and delineate the region involved in GH deficiency, we carried out a molecular characterization of the 18p deletions, in three patients with midline defects. Two unrelated children, a 7-month-old girl and a 2-month-old boy had del(18p) syndrome and GH deficiency. In addition, the boy had HPE. HPE genes, SHH, ZIC2, SIX3, and TGIF, were tested by denaturing high-performance liquid chromatography and quantitative multiplex of PCR short fluorescent fragments analyses. A deletion of TGIF was confirmed, without any associated mutation for the tested HPE genes, suggesting the role of other genetic or environmental factors. The third patient was his moderately retarded mother. A set of chromosome 18p-specific BACs clones was used as fluorescence in-situ hybridization probes to define the breakpoints. Recently, it was found that there seem to be a breakpoint cluster in the centromeric region at 18p11.1, which was not observed in our patients. The girl was found to have a deletion of 10.3 Mb, with a breakpoint in 18p11.22. The boy and his mother had a smaller deletion (8 Mb), with a breakpoint in 18p11.23. These findings suggest that the distal region on 18p is involved in the main clinical features, and GH deficiency, in 18p deletions.

Context: Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth retardation, dysmorphic features, and frequent body asymmetry, spares cranial growth. Maternal uniparental disomy for chromosome 7 (mUPD7) is found in 5-10% of cases. We identified loss of methylation (LOM) of 11p15 Imprinting Center Region 1 (ICR1) domain (including IGF-II) as a mechanism leading to RSS., Objective: The aim was to screen for 11p15 epimutation and mUPD7 in RSS and non-RSS small-for-gestational-age (SGA) patients and identify epigenetic-phenotypic correlations. STUDIED POPULATION AND METHODS: A total of 127 SGA patients were analyzed. Clinical diagnosis of RSS was established when the criterion of being SGA was associated with at least three of five criteria: postnatal growth retardation, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties. Serum IGF-II was evaluated for 82 patients., Results: Of the 127 SGA patients, 58 were diagnosed with RSS; 37 of these (63.8%) displayed partial LOM of the 11p15 ICR1 domain, and three (5.2%) had mUPD7. No molecular abnormalities were found in the non-RSS SGA group (n = 69). Birth weight, birth length, and postnatal body mass index (BMI) were lower in the abnormal 11p15 RSS group (ab-ICR1-RSS) than in the normal 11p15 RSS group [-3.4 vs.-2.6 SD score (SDS), -4.4 vs.-3.4 SDS, and -2.5 vs.-1.6 SDS, respectively; P < 0.05]. Among RSS patients, prominent forehead, relative macrocephaly, body asymmetry, and low BMI were significantly associated with ICR1 LOM. All ab-ICR1-RSS patients had at least four of five criteria of the scoring system. Postnatal IGF-II levels were within normal values., Conclusion: The 11p15 ICR1 epimutation is a major, specific cause of RSS exhibiting failure to thrive. We propose a clinical scoring system (including a BMI < -2 SDS), highly predictive of 11p15 ICR1 LOM, for the diagnosis of RSS.

Human immunodeficiency virus (HIV)-related lipodystrophy is characterized by adipose tissue redistribution, dyslipidemia, and insulin resistance. We hypothesized that fat redistribution and metabolic abnormalities in HIV-infected children are related to alterations in endocrine function of adipose tissue. A multicenter study was conducted in 130 HIV-infected children. Lipodystrophy definition was based on the central to peripheral skinfold ratio. Fasting adiponectin, leptin, insulin concentrations, glycemia, and lipid profile were measured in all children. Fat redistribution syndrome was apparent in 32 children: 14 with atrophic (LPDA) and 18 with hypertrophic lipodystrophy (LPDH). Mean serum adiponectin levels were significantly decreased in LPDA and LPDH groups compared with the group with no lipodystrophy (LPD-). Fasting insulin concentration was significantly higher in LPDA and LPDH groups versus LPD-. Mean serum leptin concentration was significantly increased only in LPDH compared with LPDA and LPD- groups. Triglyceride levels were significantly increased and high-density lipoprotein (HDL)-cholesterol concentration decreased in the LPDA versus LPD- group. Controlling for puberty stage, gender, percentage of total fat mass, serum lipids, HIV treatment, and disease severity, adiponectin was significantly and inversely associated with central obesity and insulin/glucose ratio. Fat redistribution had no significant effect on leptin concentration, which was directly related to the percentage of body fat, female gender, and insulin/glucose ratio. In conclusion, HIV-infected children with symptoms of fat redistribution have decreased levels of adiponectin, associated with insulin resistance and dyslipidemia.

Sensorineural hearing loss is the most frequent sensory deficit of childhood and is of genetic origin in up to 75% of cases. It has been shown that mutations of the SLC26A4 (PDS) gene were involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established, it remains to be studied in large cohorts of patients with nonsyndromic deafness and detailed clinical informations. In this report, 109 patients from 100 unrelated families, aged from 1 to 32 years (median age: 10 years), with nonsyndromic deafness and enlarged vestibular aqueduct, were genotyped for SLC26A4 using DHPLC molecular screening and sequencing. In all, 91 allelic variants were observed in 100 unrelated families, of which 19 have never been reported. The prevalence of SLC26A4 mutations was 40% (40/100), with biallelic mutation in 24% (24/100), while six families were homozygous. All patients included in this series had documented deafness, associated with EVA and without any evidence of syndromic disease. Among patients with SLC26A4 biallelic mutations, deafness was more severe, fluctuated more than in patients with no mutation. In conclusion, the incidence of SLC26A4 mutations is high in patients with isolated deafness and enlarged vestibular aqueduct and could represent up to 4% of nonsyndromic hearing impairment. SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2, in this Caucasian population.

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the gene AIRE (autoimmune regulator). APECED affects mainly endocrine organs resulting in hypoparathyroidism, adrenocortical failure, diabetes mellitus, hypogonadism, and hypothyroidism. Nonendocrine organ manifestations are autoimmune hepatitis, vitiligo, pernicious anemia, exocrine pancreatic insufficiency, and alopecia. APECED's first manifestation generally is mucocutaneous candidiasis presumably related to T cell dysfunction., Patient: A 5-yr-old Iranian girl presented first with pernicious anemia, exocrine pancreatic insufficiency, and nail candidiasis. She had renal dysfunction due to chronic interstitial nephritis (CIN), which progressed to end-stage renal failure. She was transplanted 1 yr later. Common causes of CIN were excluded. APECED was suspected first because she developed progressively hypoparathyroidism, adrenocortical failure, glucose intolerance, and hypothyroidism., Results: Genetic analysis revealed a large homozygous deletion (g.424&#95;2157del1734), spanning exons 2-4, in the AIRE gene. The predicted protein, if it is produced, has only 44 amino acids (exon 1) in common with the wild-type protein. Immunosuppression after the first renal transplant included prednisone, azathioprine, and cyclosporine A. Multiple acute rejection episodes occurred. Chronic rejection resulted in lost graft and she was retransplanted 2 yr later. Surprisingly, all APECED-related symptoms including candidiasis and autoantibody levels decreased, presumably due to the reinforced immunosuppression (tacrolimus, mycophenolate mofetil, prednisone)., Conclusions: This is the first report of an APECED patient with CIN resulting in end-stage renal failure. Clinical and biological improvement was observed under posttransplant multidrug immunosuppression including tacrolimus and mycophenolate mofetil.

Objective: To assess the rate of progression of lipodystrophy and the associated metabolic disturbances over a 2-year period in children and to assess risk factors associated with lipodystrophy and metabolic disturbances., Design: Multicenter 2-year prospective study with a standardized evaluation., Methods: One hundred thirty children (median age = 10 years, 64 boys and 66 girls) receiving antiretroviral therapy were recruited in 3 pediatric clinics. Lipodystrophy was defined based on 4 skinfold thickness measurements. Fasting lipids and glucose profile were measured in all children., Results: The proportion of children presenting with lipodystrophy was 24.6%. Nineteen percent of children had high-density lipoprotein values less than 1 mmol/L. Twenty-two percent and 15% of children had values greater than 2 standard deviations for age and gender for cholesterol and triglycerides, respectively. A total of 13.2% showed insulin resistance. A total of 42.7% showed at least 1 of these biologic disturbances. Prospective follow-up showed no progression at all over 2 years, except for a doubling of the number of children with insulin resistance. In multivariate analyses, ethnicity, previous severe clinical condition, duration of HIV infection, and nucleoside reverse transcriptase inhibitor treatment were significantly associated with lipodystrophy. Tanner stage V of puberty, severe clinical symptoms and protease inhibitor treatment were independently associated with the risk of metabolic disturbances., Conclusions: Puberty seems to be the time when HIV-infected children taking potent antiretroviral therapy are more likely to develop lipodystrophy and metabolic complications, especially in children with a severe underlying HIV infection. Once developed, lipodystrophy and metabolic changes seem to be extremely stable with time.

Silver-Russell syndrome (SRS, OMIM 180860) is a congenital disorder characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in approximately 10% of affected individuals. Given the crucial role of the 11p15 imprinted region in the control of fetal growth, we hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. We identified an epimutation (demethylation) in the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical SRS. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provide new insight into the pathogenesis of SRS and strongly suggest that the 11p15 imprinted region, in addition to those of 7p11.2-p13 and 7q31-qter, is involved in SRS.

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

Groin dissection was performed in adult male post-mortem subjects to establish the prevalence of inguinal canal "lipoma." Thirty-six body halves (age range 24-92 years) were studied. Of these, 27 (75%) contained a discrete mass of fat within the inguinal canal. This mass was always continuous with the preperitoneal fat through the deep inguinal ring. Nineteen of these 27 masses (70%), displayed a characteristic pedunculated form with a bulbous distal end. Eighteen of the 36 dissections (50%), revealed a mass more than 4 cm in length. Six dissections showed extension of the mass beyond the superficial inguinal ring and three of these six (8% of the 36 groins studied) showed distortion of the proximal spermatic cord with a mass at the superficial inguinal ring. The masses submitted for histology comprised mature adipose tissue and all but two of these were reported as having an adherent capsule. No significant correlation was found between mass length and either subject age or body mass index (BMI) but a statistically significant correlation between the length of the fat mass on the left and right sides was shown. This study demonstrates that the inguinal canal "lipoma" is a common feature in an adult male population and may be of sufficient size to cause clinical misdiagnosis. The high prevalence, characteristic location and appearance of the "lipoma" suggest a developmental etiology., (Copyright 2002 Wiley-Liss, Inc.)

In Mediterranean countries, almost half the incidence of non-syndromic congenital hearing loss is caused by mutations in the gap junction (GJ) connexin 26 gene (GJB2/DFNB1 locus). In this form of deafness the cochlear defect is usually isolated. We describe here the first case of hypogonadotrophic hypogonadism in association with this particular cochlear defect. The male patient had moderate deafness inherited from his deaf parents. All family members had a homozygous 35delG mutation in the connexin 26 gene. This mutation accounts for 70% of all connexin 26 gene mutations. The patient was referred to a paediatric endocrinology unit at 11 years of age for moderate growth retardation. Growth rate was normal until 11 years. The patient then presented delayed puberty (testicular volume 4 ml, penis length 4 cm) and did not undergo the usual pubertal growth spurt. LH and FSH secretory responses to GnRH at the age of 14.5 years (bone age 13.5 years), were: LH baseline level 1.1 IU/l, peak 34 IU/l; FSH baseline level 1.8 IU/l, peak 5.7 IU/l. Testosterone concentration was <0.11 ng/ml. From 11 to 14 years old, testosterone concentration ranged from 0.11 to 0.2 ng/ml. Anti-Mullerian hormone (AMH) level was 38.6 ng/ml (normal for Tanner stage I), cortisol 109 ng/ml, and ACTH 37 pg/ml., Karyotype was 46 XY. On MRI analysis, the anterior pituitary and olfactory bulbs were normal. These data were consistent with partial hypogonadotrophic hypogonadism of hypothalamic origin, and the patient was treated with testosterone. This report supports the possible involvement of connexins in puberty initiation. Connexins may play a part in the co-ordination and synchronisation of GnRH release.

The IGFs, IGF-I and IGF-II, regulate fetal growth by activating IGF type 1 receptors (IGF-IR). We aimed to quantify the binding of IGF-I to its cognate receptors in intrauterine growth-retarded children (IUGR). We measured the affinity of the erythrocyte IGF-IR and the number of IGF-IR receptors in 17 children with retarded growth (mean height, -2.7 SD), normal levels of GH, and a history of idiopathic intrauterine growth retardation (height at birth, -10 to -2 SD; mean, -3.1 SD). These children had reduced receptor affinity (Kd = 0.47 nM; P < 0.01) and more receptors per cell [binding capacity (Bmax) = 11.7 binding sites/cell; P < 0.05)] compared with control children (Kd = 0.32 nM; Bmax = 7.8 binding sites/cell). Moreover, the distributions of Kd and Bmax suggested that there were two groups of IUGR children. Group 1 included subjects with normal receptor binding function (Kd = 0.36 nM; Bmax = 8.2 sites/cell) and normal levels of circulating IGF-I. Group 2 comprised children with low receptor affinity (Kd = 0.56 nM) and increased receptor number (Bmax = 14.7 sites/cell). This group showed significantly decreased IGF-I levels (-2.1 SD; P < 0.01). We investigated these IGF-IR binding parameters in two additional groups of growth-retarded children (Turner syndrome and patients with chronic renal failure), in whom the IGF-I axis was not believed to be the primary cause, and found that Kd and Bmax were normal or nearly normal. We also measured IGF-IR binding parameters in 4 Seckel syndrome patients with IUGR and severely retarded growth (mean height, -7.9 SD). Their receptor affinity was reduced, but not statistically different, from that in controls, and their receptor number was normal, whereas IGF-I levels were elevated. Our results suggest heterogeneous alterations in IGF-IR binding function in IUGR patients.

Chronic renal failure in childhood causes severe growth retardation. The aim of the study was to identify whether changes in the IGF system could account for the growth retardation observed in children with chronic renal failure. Insulin-like growth factor (IGF-I) serum concentrations, insulin-like growth factor binding proteins (IGFBP) and/or IGF-I binding to erythrocyte type I receptor of IGF were analysed in 69 children (mean age 11.6 +/- 4.3 years) with chronic renal failure and growth retardation (mean height -2.6 +/- 1.8 SD). The study population was separated into three groups, according to their renal status, children on conservative treatment (CRF group: n = 30), on haemodialysis (ESRD group: n = 26) and those transplanted (RT group: n = 13). Nineteen of these children, some from each of the three groups, received recombinant growth hormone therapy (rhGH). Mean basal IGF-I serum concentrations were -0.7 +/- 1.2 SD in the CRF group, + 2.1 +/- 3 SD in the ESRD group and + 1.1 +/- 2 SD in the RT group. Under rhGH therapy, as height velocity improved, mean IGF-I concentrations increased up to + 3.1 +/- 0.6 SD in the CRF group, to + 6.9 +/- 2.8 SD in the ESRD group and to + 3.9 +/- 2 SD in the RT group. Basal IGFBP-3 levels, studied by Western Ligand Blot were low in the CRF group and high in the ESRD and normal in the RT groups, whereas IGFBP-2 and a 30-32 kDa IGFBP were always high in all cases. Western immunoblot analysis showed that this 30-32 kDa IGFBP was mostly composed of IGFBP-1 and IGFBP-6 in all three groups, but IGFBP-6 was particularly abundant in the ESRD group. IGFBP-6 concentrations assessed by RIA were moderately increased in CRF children (392 +/- 177 ng/mL) and very high in children on ESRD (2094 +/- 1525 ng/mL) when compared to normal values (131 +/- 42 ng/mL). Binding studies of IGF type I receptor showed that there was no particular difference in IGF-I binding between renal failure patients and normal children. In poorly growing children, especially in ESRD children and to a lesser extent in RT children, high concentrations of IGF-I and IGFBP-1, 2, 3 and 6, suggest a resistance mainly by a sequestration mechanism. Moreover, in the CRF group, especially in the younger children, low levels of IGF-I and IGFBP-3 are evocative of an associated resistance at the GH receptor level.

We evaluated the involvement of a possible dysfunction of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the fetal growth retardation and poor growth rates of children born with intrauterine growth retardation (IUGR). Children with IUGR have a nephron deficit and are also at risk of developing cardiovascular diseases, high blood pressure, glucose intolerance, and dyslipidemia later in life. The major site of 11beta-HSD2 production is the kidney and its deficit causes hypertension. We investigated plasma concentrations of cortisol (F) and cortisone (E) and the F/E ratio in 26 control children and in 40 IUGR children without catch-up growth. We also determined cholesterol, HbA1C, insulin, and glucose levels in plasma. Mean F values were 106 +/- 54.2 ng/mL in control children and 114.6 +/- 53.2 ng/mL in IUGR children. Mean E values were 19.5 +/- 7.1 ng/mL in control children and 17.9 +/- 6.85 ng/mL in IUGR children. The mean F/E ratio for control children was 5.5 +/- 1.7. Eight (20%) of the IUGR children (IUGR children of group 1) had high F/E ratios more than 2 SD above the normal mean: 13.15 +/- 4.26, (p < 0.0001) as compared to control children, whereas the other 32 children (IUGR children of group 2) had normal F/E ratios: 5.40 +/- 1.43 (p = 0.68). Childhood height was significantly lower for group 1 than group 2 children (-3.63 SD and -2.92 SD, respectively: p < 0.01) and was negatively correlated with the F/E ratio (p < 0.01). Systolic blood pressure was higher for group 1 (p = 0.005) and for group 2 (p = 0.015) than for control children. The diastolic pressure in IUGR children of group 1 was higher than that in control children (p = 0.013) and slightly higher than that in group 2 (p = 0.1, ns). Cholesterol concentrations were higher in group 1 than in group 2 (p = 0.029), and controls (p = 0.017) and correlated positively with F/E (0.02 < p < 0.05). Fasting insulin concentrations were higher in group 1 than in group 2 (ns) and controls (ns). There was no difference in mean fasting glucose concentrations, or HbA1C between the three groups. Twenty percent of our children with IUGR and poor growth rates had high F/E ratios, suggesting a possible partial 11beta-HSD2 deficit. Whether these children are at high risk of developing cardiovascular diseases as adults remains to be further evaluated.

The clinical outcomes of seven girls presenting with pseudosexual precocity caused by isolated autonomous ovarian follicular cysts are presented. Six of the seven girls, aged 11 months to 6.9 years, had a unilateral ovarian cyst detected by ultrasound at the first acute episode. Plasma oestradiol was raised in only five of the cases, but all had a low response to luteinising hormone releasing hormone stimulation. Follow up lasted for up to eight years with recurrent episodes of variable frequency and severity in all seven patients. Evidence of McCune-Albright syndrome appeared later in only three patients. It could not be predicted from the initial symptoms or the clinical course. Mutations of the G(s)alpha protein leading to activation were investigated in the lymphocytes and ovarian and bone tissues of four patients. Only one patient showed a mutation in bone tissue. Close follow up with repeated searches for skeletal lesions remains necessary since the distribution of somatic mutations cannot be assessed by molecular studies. Most patients with recurrent ovarian cysts require a conservative approach.

Many factors contribute to the growth failure of chronic renal failure: water and electrolytes disturbances, hypertonicity, phosphate or calcium wasting, secondary hyperparathyroidism, anemia, hypertension, metabolic acidosis, and malnutrition. In addition, the pubertal growth spurt is usually stunted. Growth hormone (GH) resistance is observed with low GH binding protein (GHBP) level, and normal or low IGF I levels despite elevated GH level. Elevated IGFBP levels may contribute to a reduced IGF activity, especially in dialysed patients. Glucocorticoid therapy in transplanted patients further contribute to poor growth and inhibited IGF I activity. As conventional treatments have a limited effect to improve growth, adult height is often far below -2 SD. GH therapy has proved to be successful, especially in young children, overpassing the hormonal resistance so that an adult height within the normal range may be reached.

We observed four families with loss of function mutations of the TSH receptor gene. One patient had a homozygous Pro162 Ala substitution. The three other were compound heterozygotes: 1) Gln324-->Stop and Asp410 Asn2), Cys41 Ser and Phe525 Leu, 3) Cys390 Trp and Trp546-->Stop. In all patients, the plasma TSH concentration was increased, whereas T3 and T4 concentrations were normal. The TSH levels were normal in the heterozygous parents. These results confirmed the recessive character of TSH receptor defects. Expression of the various mutated receptors in transfected COS-7 cells demonstrated the impairment of their function. We studied the expression of the receptors on the cell surface by immunofluorescence, their ability to bind hormone, and their capacity to activate adenylate cyclase. Some mutations allowed us to identify sites that are especially important for receptor function. The substitution Cys390 Trp abolished high affinity hormone binding. Receptor mutated at Asp410 Asn bound the hormone normally, but failed to activate adenylate cyclase. This result underscores the role of this acidic extracellular residue, close to the first transmembrane segment, in signal transmission. The Phe525 Leu substitution also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.

Purpose: To evaluate the presence of central nervous system degeneration in patients with low-tension glaucoma using magnetic resonance imaging., Method: Ten patients with low-tension glaucoma and ten age-matched control subjects underwent magnetic resonance imaging. Cortical atrophy and cerebral infarcts were graded from "0" (normal) to "3," which was done subjectively by two neuroradiologists independently in a masked fashion. Midsagittal corpus callosum section was evaluated by measuring the thickness and cross-sectional area., Results: There was a significantly greater extent of cerebral infarcts in the patients with low-tension glaucoma (P = 0.02). The thickness of the body (P = 0.03) and genu (P = 0.04) of the corpus callosum were thinner in the patients with low-tension glaucoma. The corpus callosum cross-sectional area was smaller in the low-tension glaucoma group (P = 0.04). There were no significant differences in the other parameters in this study., Conclusion: This study suggests a greater extent of cerebral infarcts and corpus callosum atrophy in patients with low-tension glaucoma. This may imply a greater degree of neuronal degeneration, possibly on an ischemic basis in low-tension glaucoma.

Background: Syringomyelia is rare in children aged less than 10 years, and bladder dysfunction is an unlikely first manifestation. This report describes a case of repeated episodes of acute urinary retention in a young girl revealing syringomyelia and Arnold-Chiari malformation., Case Report: A 2.5 year-old girl was admitted because she was suffering from acute urinary retention. Her poor appetite had been treated with cyproheptadine, a histamine type I blocking drug. Clinical investigation revealed no local cause for this bladder dysfunction except moderate spasticity of the legs. Cystography showed no vesicoureteral reflux. Because the episodes of urinary retention recurred each day, magnetic resonance imaging (MRI) was performed; this showed the typical features of syringomyelia extending from C5 to T11 plus Arnold-Chiari malformation. The cyproheptadine was discontinued and the urinary retention disappeared., Conclusion: Cyproheptadine may have revealed latent neurogenic bladder in this case, although urodynamic studies, performed 3 months later, detected no bladder dysfunction.

A case of cutaneous herpes relapse with meningitis is reported in a 1.5 month-old infant treated during the first three weeks of life with acyclovir (ACV) for a neonatal herpes infection. Such a relapse has previously been described in older children as well as in adults. In this case report, there was immunological response to herpes virus infection, 2.5 months after the onset of the infection. The relapse is discussed taking into account the mechanism of action of ACV, the age of the patient and the immunological response profile. Because of the high risk of neurological involvement, we suggest that the relapse should be treated with ACV for a period of time longer than actually recommended.

Objective: To review the first years experience of the only private MRI facility in Australia., Method: Utilisation Review., Results: 1497 scans have been comprehensively analysed, with regard to the efficacy of the procedure in examining the brain, spinal cord, the lumbar region and the knee joint.