Schanze D.,University Hospital Magdeburg |
Harakalova M.,University Utrecht |
Stevens C.A.,Tc Thompson Childrens Hospital |
Brancati F.,IRCCS Casa Sollievo della Sofferenza Hospital |
And 12 more authors.
American Journal of Medical Genetics, Part A | Year: 2013
Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners. No mutation in either of these genes was found in a cohort of 11 patients with AMS from 10 unrelated families. These findings demonstrate that AMS is genetically distinct from FS. It is proposed that it constitutes a separate entity within the group of FRAS-FREM complex disorders. © 2013 Wiley Periodicals, Inc.
Marchegiani S.,U.S. National Institutes of Health |
Davis T.,U.S. National Institutes of Health |
Tessadori F.,University Utrecht |
Van Haaften G.,University Utrecht |
And 45 more authors.
American Journal of Human Genetics | Year: 2015
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding. © 2015 The American Society of Human Genetics.
Strehle E.-M.,Institute of Human Genetics |
Yu L.,University of California at Irvine |
Rosenfeld J.A.,Signature |
Donkervoort S.,University of California at Irvine |
And 19 more authors.
American Journal of Medical Genetics, Part A | Year: 2012
Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes. © 2012 Wiley Periodicals, Inc.
Zielinski J.,Tc Thompson Childrens Hospital |
Lacy T.A.,TLC Pediatric Adolescent Medicine |
Phillips J.H.,Orlando Health
Spine Deformity | Year: 2014
Study Design Retrospective case report. Objective To report the first known case of immunological camouflage of a metal spinal implant with carbon coating. Summary of Background Data Metal sensitivity is common and is a consideration when choosing orthopedic implants in susceptible individuals. The sensitivity often is to nickel, cobalt, or chromium, and titanium is used as a safe alternative. However, when the allergy is also to titanium, solutions may be much more difficult. This case describes an innovative solution to a complex metal allergy that includes titanium in a child requiring spinal instrumentation for early-onset scoliosis. Methods At age 6 years 7 months, the patient underwent an uncomplicated placement of bilateral posterior Vertical Expandable Prosthetic Titanium Ribs (VEPTRs; Synthes, Inc., West Chester, PA). At that time, there were no known metal allergies. At 3 weeks, the right side had become erythematous and had serosanguineous drainage. It briefly improved after each of 2 surgical debridements and a course of intravenous antibiotics, but within 6 weeks of the index procedure, the pain was still worsening. A titanium allergy was suspected and blood was sent for allergy testing. A test confirmed hypersensitivity to titanium, niobium, molybdenum, iron, and aluminum, among others. The remaining rod was removed. An in vivo trial for tolerance to high-grade stainless-steel implants was done. The implant was removed after 2 weeks because of systemic symptoms that occurred. Results A plasma-spray, carbon-coated VEPTR rod was designed. A rod sample was inserted into the patient's forearm for trial. After 3 months, there was no appreciable reaction. Carbon-coated VEPTRs were placed without complications. The patient has undergone multiple lengthening using the carbon-coated VEPTRs. Conclusions In the rare patient with multiple allergies, choosing orthopedic implants can be challenging. An innovative carbon coating was applied by plasma spray to the VEPTR system, with good results. © 2014 Scoliosis Research Society.
Gratias E.J.,Tc Thompson Childrens Hospital |
Jennings L.J.,Ann And Robert H Lurie Childrens Hospital |
Anderson J.R.,University of Nebraska Medical Center |
Dome J.S.,Childrens National Medical Center |
And 2 more authors.
Cancer | Year: 2013
BACKGROUND Wilms tumor is the most common childhood renal tumor. Although the majority of patients with favorable histology Wilms tumor (FHWT) have good outcomes, some patients still experience disease recurrence and death from disease. The goal of the current study was to determine whether tumor-specific chromosome 1q gain is associated with event-free survival (EFS) and overall survival (OS) in patients with FHWT. METHODS Unilateral FHWT samples were obtained from patients enrolled on National Wilms Tumor Study-4 and Pediatric Oncology Group Wilms Biology Study (POG 9046). 1q gain, 1p loss, and 16q loss were determined using multiplex ligation-dependent probe amplification. RESULTS The 8-year EFS rate was 87% (95% confidence interval [95% CI], 82%-91%) for the entire cohort of 212 patients. Tumors from 58 of 212 patients (27%) displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The 8-year EFS rate was 76% (95% CI, 63%-85%) for patients with 1q gain and 93% (95% CI, 87%-96%) for those lacking 1q gain (P =.0024). The 8-year OS rate was 89% (95% CI, 78%-95%) for those with 1q gain and 98% (95% CI, 94%-99%) for those lacking 1q gain (P =.0075). Gain of 1q was not found to correlate with disease stage (P =.16). After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence (risk ratio estimate: 2.72; P =.0089). CONCLUSIONS Gain of 1q may provide a valuable prognostic marker with which to stratify therapy for patients with FHWT. A confirmatory study is necessary before this biomarker is incorporated into the risk stratification schema of future therapeutic studies. Cancer 2013;119:3887-3894. © 2013 American Cancer Society.
Brooks-Worrell B.M.,University of Washington |
Brooks-Worrell B.M.,DVA Puget Sound Health Care System |
Brooks-Worrell B.M.,Seattle Biomedical Research Institute |
Brooks-Worrell B.M.,Diabetes Endocrinology Research Center |
And 8 more authors.
Diabetes Care | Year: 2011
OBJECTIVE - Islet autoimmunity has long been recognized in the pathogenesis of type 1 diabetes and is becoming increasingly acknowledged as a component in the pathogenesis of type 2 diabetes. Islet reactive T cells and autoantibodies have been demonstrated in type 1 diabetes, whereas islet autoimmunity in type 2 diabetes has been limited to islet autoantibodies. In this study, we investigated whether islet reactive T cells might also be present in type 2 diabetic patients and how islet reactive T cells correlate with β-cell function. RESEARCH DESIGN AND METHODS - Adult phenotypic type 2 diabetic patients (n=36) were screened for islet reactive T-cell responses using cellular immunoblotting and five islet autoantibodies (islet cell antibody, GADA, insulin autoantibody, insulinoma-associated protein-2 autoantibody, and zinc transporter autoantibody). RESULTS - We identified four subgroups of adult phenotypic type 2 diabetic patients based on their immunological status (Ab -T-, Ab+T-, Ab-T +, and Ab+T+). The Ab-T+ type 2 diabetic patients demonstrated T-cell responses similar to those of the Ab+T+ type 2 diabetic patients. Data were adjusted for BMI, insulin resistance, and duration of diabetes. Significant differences (P < 0.02) were observed among groups for fasting and glucagon-stimulated C-peptide responses. T-cell responses to islet proteins were also demonstrated to fluctuate less than autoantibody responses. CONCLUSIONS - We have identified a group of adult autoimmune phenotypic type 2 diabetic patients who are Ab -T+ and thus would not be detected using autoantibody testing alone. We conclude that islet autoimmunity may be more prevalent in adult phenotypic type 2 diabetic patients than previously estimated. © 2011 by the American Diabetes Association.
Frangoul H.,Vanderbilt University |
Keates-Baleeiro J.,Tc Thompson Childrens Hospital |
Calder C.,Vanderbilt University |
Manes B.,Vanderbilt University |
And 3 more authors.
Pediatric Transplantation | Year: 2010
CAMT is a very rare cause of thrombocytopenia in infants. Most of the patients will progress to marrow failure. Allogeneic stem cell transplant remains the only curative therapy. We present two patients with CAMT who underwent an unrelated donor bone marrow transplant, one after developing marrow failure and another early in the course of the disease. Both patients tolerated the transplant with minimal toxicity and durable engraftment. We also present a comprehensive review of the literature for unrelated donor transplant for this condition. © 2009 John Wiley & Sons A/S.
Bockenhauer D.,Great Ormond Street Hospital for Children |
Van'T Hoff W.,Great Ormond Street Hospital for Children |
Dattani M.,Great Ormond Street Hospital for Children |
Lehnhardt A.,University of Hamburg |
And 3 more authors.
Nephron - Physiology | Year: 2010
Background/Aims: Nephrogenic diabetes insipidus (NDI) is a serious condition with large water losses in the urine and the risk of hypernatremic dehydration. Unrecognized, repeated episodes of hypernatremic dehydration can lead to permanent brain damage. Primary NDI is due to mutations in either AVPR2 or AQP2. NDI can also occur as a secondary complication, most commonly from obstructive uropathy or chronic lithium therapy. We observed NDI in patients with inherited tubulopathies and aimed to define the clinical and molecular phenotype. Methods: We reviewed the medical notes of 4 patients with clinical NDI and an underlying molecularly confirmed diagnosis of nephropathic cystinosis, Bartter syndrome, nephronophthisis and apparent mineralocorticoid excess, respectively. Results: The patients all failed to concentrate their urine after administration of 1-desamino[8-D-arginine] vasopressin. None had an identifiable mutation in AVPR2 or AQP2, consistent with secondary NDI. Patients experienced repeated episodes of hypernatremic dehydration, and in 2 cases, NDI was initially thought to be the primary diagnosis, delaying recognition of the underlying problem. Conclusion: The recognition of this potential complication is important as it has direct implications for clinical management. The occurrence of NDI in association with these conditions provides clues for the etiology of aquaporin deficiency. Copyright © 2010 S. Karger AG, Basel.
Ismail H.M.,University of Washington |
Rincon M.,Tc Thompson Childrens Hospital
Endocrine Practice | Year: 2014
Objective: Our objective is to present the first case report of X-linked adrenal hypoplasia congenita in a child conceived by a donated egg and which also presented atypically, with initial mineralocorticoid deficiency.Methods: Case report with literature review.Results: A late preterm fraternal twin male, conceived by in vitro fertilization of donated eggs, presented shortly after birth with feeding intolerance, hyponatremia, and hyperkalemia. Testing revealed a low aldosterone level, high plasma renin activity, normal cortisol level, and normal 17-hydroxyprogesterone level. He was diagnosed with 18-hydroxylase deficiency based on low 18-hydroxycorticosterone levels and was treated with mineralocorticoid successfully for 17 months. At age 18 months, he presented with dehydration secondary to herpetic gingivostomatitis and was found to be hypoglycemic, hyponatremic, hyperkalemic, and acidotic, with a low serum cortisol level. An adrenocorticotropic hormone (ACTH) stimulation test revealed low levels of all adrenal cortex products, with an elevated ACTH level. He was started on glucocorticoids. Genetic testing confirmed X-linked adrenal hypoplasia congenita (AHC). His asymptomatic fraternal twin underwent genetic testing and the results were negative. The fertility center records indicated that the mother had donated eggs to other families, but none of the children were known to have this disorder. The egg donor was informed but did not pursue genetic testing.Conclusion: We report a case of X-linked AHC presenting in the context of extraordinary ethical considerations. Our case raises a question unique to the era of assisted reproduction: should routine genetic screening of gamete donors be done for rare but potentially life-threatening conditions? © 2014 AACE.
Alessio A.M.,University of Washington |
Alessio A.M.,Seattle Childrens Hospital |
Sammer M.,Tc Thompson Childrens Hospital |
Phillips G.S.,University of Washington |
And 5 more authors.
Journal of Nuclear Medicine | Year: 2011
Pediatric 18F-FDG dosing and acquisition durations are generally based on coarse extrapolation from adult guidelines. This study sought to determine whether shorter acquisition durations or a lower 18F-FDG injected activity could be used for pediatric 18F-FDG PET/CT examinations while maintaining diagnostic utility. Reduction of overall scan time potentially reduces motion artifacts, improves patient comfort, and decreases length of sedation. Alternatively, decreased 18F-FDG dose minimizes radiation risk. Methods: Fourteen whole-body 18F-FDG PET/CT examinations were performed on 13 patients (weight, 13-109 kg; age range, 1-23 y) with a weight-based injected activity (5.3 MBq/kg [0.144 mCi/kg]), fixed acquisition durations (3 min/field of view [FOV] if < 22 kg, 5 min/FOV if > 22 kg), and list-mode acquisition. For each examination, the list-mode data were truncated to form multiple datasets with shorter acquisition durations down to a minimum of 1 min/FOV (i.e., 1, 2, 3, 4, and 5 min/FOV data were formed from single 5 min/FOV acquisition). Fifty-six image volumes were generated, randomized, and reviewed in a masked manner with corresponding CT image volumes by 5 radiologists. Overall, subjective adequacy and objective lesion detection accuracy by body region were evaluated. Results: All examinations with maximum acquisition duration were graded as adequate and were used as the reference standard for detection accuracy. For patients less than 22 kg, 1 of the 3 PET/CT examinations was graded as inadequate for clinical tasks when acquisition duration was reduced to 2 min/FOV, and all examinations were graded as inadequate when reduced to 1 min/FOV. For patients more than 22 kg, all 3-5 min/FOV studies were graded as adequate, and 2 of the 9 studies were graded as inadequate for 2 min/FOV studies. Lesion detection accuracy was perfect for acquisition times between 3 min/FOV and 5 min/FOV for all regions of the body. However, lesion detection became less accurate when imaging acquisition time was reduced more than 40%. Conclusion: Evaluation of image volumes generated from simulated shorter acquisition durations suggests that imaging times for larger patients (>22 kg) can be reduced from 5 min/FOV to 3 min/FOV without a loss of diagnostic utility. Using decreased acquisition times as a surrogate for 18F-FDG dose, 18F-FDG dose can be reduced by approximately 40% when all patients were scanned for 5 min/FOV. Copyright © 2011 by the Society of Nuclear Medicine, Inc.