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Am J Med Genet A ; 182(11): 2646-2661, 2020 11.
Article En | MEDLINE | ID: mdl-32924308

Several recurrent malformation associations affecting the development of the embryo have been described in which a genetic etiology has not been found, including LBWC, MURCS, OAVS, OEIS, POC, VACTERL, referred to here as "recurrent constellations of embryonic malformations" (RCEM). All are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence. We performed a comprehensive review of published twin data across all six phenotypes to allow a more robust assessment of the association with twinning and potential embryologic timing of a disruptive event. We recorded the type of twinning, any overlapping features of another RCEM, maternal characteristics, and the use of ART. Statistically significant associations included an excess of monozygotic twins and 80% discordance rate for the phenotype across all twins. There was an 18.5% rate of ART and no consistently reported maternal adverse events during pregnancy. We found 24 instances of co-occurrence of two RCEM, suggesting a shared pathogenesis across all RCEM phenotypes. We hypothesize the following timing for RCEM phenotypes from the earliest perturbation in development to the latest: LBWC, POC, OEIS, VACTERL, OAVS, then MURCS. The RCEM group of conditions should be considered a spectrum that could be studied as a group.

Abnormalities, Multiple/classification , Abnormalities, Multiple/diagnosis , 46, XX Disorders of Sex Development/complications , Abnormalities, Multiple/epidemiology , Anus, Imperforate/complications , Bladder Exstrophy/complications , Cloaca/abnormalities , Congenital Abnormalities , Esophageal Atresia/complications , Female , Heart Defects, Congenital/complications , Hernia, Umbilical/complications , Humans , Infant, Newborn , Male , Mullerian Ducts/abnormalities , Phenotype , Pregnancy , Recurrence , Tracheoesophageal Fistula/complications , Twin Studies as Topic , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics
Mol Genet Genomic Med ; 8(6): e1227, 2020 06.
Article En | MEDLINE | ID: mdl-32281290

The presence of body wall closing defects (abdominoschisis and thoracoabdominoschisis) in combination with other congenital malformations was studied in the pig (Sus scrofa domesticus). After clinical examination and literature review, body wall defects with multiple congenital anomalies in eight pigs were described, and classified using anatomical and embryological criteria. Several BSA presentations were identified and classified as follows: (a) BSA Type I: fetus with spinal and UC defects, thoracoabdominoschisis, anal atresia and/or other internal organs structural defects, and structural limb defects; (b) BSA Type II: fetus with spinal and UC defects, thoracoabdominoschisis, anal atresia and/or other internal organs structural defects, and nonstructural limb defects; (c) BSA Type III: fetus with spinal and UC defects, abdominoschisis, anal atresia and/or other internal organs structural defects, and structural limb defects; and (d) BSA Type IV: fetus with spinal and UC defects, abdominoschisis, anal atresia and/or other internal organs structural defects, and nonstructural limb defects. Two types of LBWC were differentiated: LBWC Type I: characterized by thoracoabdominoschisis and structural limb defects, and LBWC Type II: characterized by abdominoschisis and structural limb defects, corresponding to BSA type I and type III. This is the first report on BSA and LBWC in the pig.

Abnormalities, Multiple/veterinary , Swine Diseases/pathology , Abdomen/abnormalities , Abnormalities, Multiple/classification , Abnormalities, Multiple/pathology , Animals , Spine/abnormalities , Swine , Swine Diseases/classification , Thorax/abnormalities
Int J Mol Sci ; 20(5)2019 Mar 04.
Article En | MEDLINE | ID: mdl-30836598

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.

Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 16/genetics , Comparative Genomic Hybridization , Developmental Disabilities/genetics , Abnormalities, Multiple/classification , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Child , Child, Preschool , Chromosome Aberrations , Chromosome Deletion , DNA Copy Number Variations/genetics , Developmental Disabilities/classification , Developmental Disabilities/physiopathology , Female , Homologous Recombination/genetics , Humans , Infant , Infant, Newborn , Karyotype , Male , Phenotype , Segmental Duplications, Genomic/genetics , Young Adult
Z Geburtshilfe Neonatol ; 223(1): 15-25, 2019 Feb.
Article De | MEDLINE | ID: mdl-30791067

Oesophageal atresia causes a dysplasia of the oesophagus with or without a connection to the adjoining trachea. Prenatal ultrasound results are not specific enough to confirm a suspected diagnosis. In addition to polyhydramnios and a small or absent stomach, the so-called "pouch sign" reinforces the suspected diagnosis. An MRI increases the prenatal detection rate. Due to the lack of reliable sonografic markers, ultrasonic testing is advised during pregnancy. Particularly, further causes for the polyhydramnios should be categorically excluded. Postnatally, children present with classic symptoms. Surgical treatment results in a very high quality of life and a very good prognosis. Nevertheless lifelong monitoring and follow-up of the patient is required.

Esophageal Atresia/diagnosis , Esophageal Atresia/surgery , Prenatal Care , Prenatal Diagnosis , Abnormalities, Multiple/classification , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/surgery , Esophageal Atresia/classification , Female , Humans , Polyhydramnios/diagnosis , Polyhydramnios/surgery , Postoperative Care , Pregnancy , Tracheoesophageal Fistula/congenital , Tracheoesophageal Fistula/diagnosis , Tracheoesophageal Fistula/surgery , Treatment Outcome , Ultrasonography, Prenatal
J Pediatr Endocrinol Metab ; 32(2): 191-196, 2019 Feb 25.
Article En | MEDLINE | ID: mdl-30676999

Background Silver-Russell syndrome (SRS) is characterized by growth retardation and variable features including macrocephaly, body asymmetry, and genital manifestations such as cryptorchidism in 46,XY patients. Case presentation The patient was born at 39 weeks with a birth weight of 1344 g. Subtle clitoromegaly warranted a thorough evaluation, which disclosed 46,XY karyotype, bilateral undescended testes, and a rudimentary uterus. Because of severe under-virilization, the patient was assigned as female. Failure to thrive, macrocephaly, and body asymmetry led to the diagnosis of SRS, confirmed by marked hypomethylation of H19/IGF2 intergenic differentially methylated region (IG-DMR). From age 9 years, progressive virilization occurred, which necessitated luteinizing hormone-releasing hormone analog (LHRHa) treatment. Gonadal resection at 15 years revealed immature testes with mostly Sertoli-cell-only tubules. Panel analysis for 46,XY-differences of sex development (DSD) failed to detect any pathogenic variants. Conclusions This is the second reported case of molecularly proven 46,XY SRS accompanied by severe under-virilization. SRS should be included in the differential diagnosis of 46,XY-DSD.

Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 11 , DNA Methylation , Genitalia/abnormalities , Silver-Russell Syndrome/pathology , Virilism , Abnormalities, Multiple/classification , Female , Genitalia/growth & development , Gestational Age , Humans , Infant, Newborn , Male , Phenotype , Pregnancy , Prognosis , Severity of Illness Index , Silver-Russell Syndrome/genetics
Am J Med Genet C Semin Med Genet ; 178(4): 447-457, 2018 12.
Article En | MEDLINE | ID: mdl-30580486

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.

Abnormalities, Multiple/classification , Abnormalities, Multiple/diagnosis , Blepharophimosis/classification , Blepharophimosis/diagnosis , Craniofacial Abnormalities/classification , Craniofacial Abnormalities/diagnosis , Developmental Disabilities/diagnosis , Abnormalities, Multiple/therapy , Blepharophimosis/therapy , Craniofacial Abnormalities/therapy , Developmental Disabilities/classification , Developmental Disabilities/therapy , Humans , Meta-Analysis as Topic , Phenotype
BMC Med Imaging ; 18(1): 37, 2018 10 30.
Article En | MEDLINE | ID: mdl-30376819

BACK GROUND: Lung agenesis is a rare congenital anomaly. The main etiology of the disease is unknown whereas genetic, iatrogenic and viral factors as well as vitamin A deficiency during early pregnancy may result in developmental failure of primitive lung bud causing unilateral pulmonary agenesis. Affected patients usually present with variable respiratory symptoms and recurrent chest infection at any age. Plain film demonstrates opaque unilateral lung while chest CT scan can definitely diagnosis the disease. The anomaly has three types. Type I is pulmonary agenesis, type II is called pulmonary aplasia and type III is pulmonary hypoplasia. CASES' PRESENTATION: Six patients with main complaint of dyspnea underwent contrast enhanced chest CT in radiology department of French Medical Institute for Mothers and children, Kabul and were diagnosed lung agenesis. Three patients were categorized as type II pulmonary agenesis (aplasia). Two patients, three months old boy and a seven year- old girl demonstrated right lung aplasia. Another patient boy of eighteen years old presented with left lung aplasia. Two boys of four and seven months of age were classified as type I pulmonary agenesis (agenesis). A boy of one year old was diagnosed pulmonary agenesis type III, right lung hypoplasia. CONCLUSION: Six patients were diagnosed with pulmonary agenesis by Chest CT scan. The clinicians should consider possibility of congenital pulmonary agenesis in dyspneic patients with opaque unilateral hemithorax in plain film.

Abnormalities, Multiple/classification , Abnormalities, Multiple/diagnostic imaging , Lung Diseases/classification , Lung Diseases/diagnostic imaging , Lung/abnormalities , Lung/diagnostic imaging , Adolescent , Child , Dyspnea/etiology , Female , Humans , Infant , Male , Tomography, X-Ray Computed
Actas Dermosifiliogr (Engl Ed) ; 109(8): 677-686, 2018 Oct.
Article En, Es | MEDLINE | ID: mdl-29983155

Epidermal nevi are hamartomatous lesions derived from the epidermis and/or adnexal structures of the skin; they have traditionally been classified according to their morphology. New variants have been described in recent years and advances in genetics have contributed to better characterization of these lesions and an improved understanding of their relationship with certain extracutaneous manifestations. In the first part of this review article, we will look at nevi derived specifically from the epidermis and associated syndromes.

Epidermis/pathology , Keratinocytes/pathology , Nevus/classification , Skin Neoplasms/classification , Abnormalities, Multiple/classification , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Darier Disease/classification , Darier Disease/pathology , Genetic Association Studies , Genetic Diseases, X-Linked/classification , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Humans , Ichthyosiform Erythroderma, Congenital/classification , Ichthyosiform Erythroderma, Congenital/genetics , Ichthyosiform Erythroderma, Congenital/pathology , Limb Deformities, Congenital/classification , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/pathology , Mosaicism , Mutation , Nevus/genetics , Nevus/pathology , Pemphigus, Benign Familial/classification , Pemphigus, Benign Familial/pathology , Proteus Syndrome/classification , Proteus Syndrome/genetics , Proteus Syndrome/pathology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Syndrome
Rofo ; 190(9): 825-835, 2018 Sep.
Article En | MEDLINE | ID: mdl-29874693

BACKGROUND: Vascular anomalies are a diagnostic and therapeutic challenge. They require dedicated interdisciplinary management. Optimal patient care relies on integral medical evaluation and a classification system established by experts in the field, to provide a better understanding of these complex vascular entities. METHOD: A dedicated classification system according to the International Society for the Study of Vascular Anomalies (ISSVA) and the German Interdisciplinary Society of Vascular Anomalies (DiGGefA) is presented. The vast spectrum of diagnostic modalities, ranging from ultrasound with color Doppler, conventional X-ray, CT with 4 D imaging and MRI as well as catheter angiography for appropriate assessment is discussed. RESULTS: Congenital vascular anomalies are comprised of vascular tumors, based on endothelial cell proliferation and vascular malformations with underlying mesenchymal and angiogenetic disorder. Vascular tumors tend to regress with patient's age, vascular malformations increase in size and are subdivided into capillary, venous, lymphatic, arterio-venous and combined malformations, depending on their dominant vasculature. According to their appearance, venous malformations are the most common representative of vascular anomalies (70 %), followed by lymphatic malformations (12 %), arterio-venous malformations (8 %), combined malformation syndromes (6 %) and capillary malformations (4 %). CONCLUSION: The aim is to provide an overview of the current classification system and diagnostic characterization of vascular anomalies in order to facilitate interdisciplinary management of vascular anomalies. KEY POINTS: · Vascular anomalies are comprised of vascular tumors and vascular malformations, both considered to be rare diseases.. · Appropriate treatment depends on correct classification and diagnosis of vascular anomalies, which is based on established national and international classification systems, recommendations and guidelines.. · In the classification, diagnosis and treatment of congenital vascular anomalies, radiology plays an integral part in patient management.. CITATION FORMAT: · Sadick M, Müller-Wille R, Wildgruber M et al. Vascular Anomalies (Part I): Classification and Diagnostics of Vascular Anomalies. Fortschr Röntgenstr 2018; 190: 825 - 835.

Rare Diseases , Vascular Malformations/classification , Vascular Malformations/diagnostic imaging , Vascular Neoplasms/diagnostic imaging , Abnormalities, Multiple/classification , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/therapy , Adult , Arteriovenous Malformations/classification , Arteriovenous Malformations/diagnostic imaging , Arteriovenous Malformations/therapy , Child , Diagnosis, Differential , Diagnostic Imaging/methods , Humans , Lymphatic Abnormalities/classification , Lymphatic Abnormalities/diagnostic imaging , Lymphatic Abnormalities/therapy , Syndrome , Vascular Malformations/therapy , Vascular Neoplasms/classification , Vascular Neoplasms/therapy
Med Princ Pract ; 27(3): 293-296, 2018.
Article En | MEDLINE | ID: mdl-29533933

OBJECTIVES: The aim of this report is to describe the orofacial manifestations and dental management of a girl with Sanjad-Sakati syndrome. CLINICAL PRESENTATION AND INTERVENTION: The facial features included microcephaly, thin lips, beaked nose, low set ears, and a retrognathic mandible. An oral examination revealed oligodontia/hypodontia, small dental arches, a high arched palate, and a deep overbite and increased overjet. Oral rehabilitation involved full coverage prosthetic crowns on the upper central incisors, stainless steel crowns on the lower molars, and removable partial prostheses to replace missing teeth. CONCLUSION: Recognition of orofacial features might help in the diagnosis of Sanjad-Sakati syndrome. Dental management of affected patients might be complicated by intellectual, neurological, and endocrine abnormalities.

Abnormalities, Multiple/diagnosis , Child Health , Growth Disorders/diagnosis , Hypoparathyroidism/diagnosis , Intellectual Disability/diagnosis , Osteochondrodysplasias/diagnosis , Seizures/diagnosis , Abnormalities, Multiple/classification , Child , Female , Growth Disorders/classification , Humans , Hypoparathyroidism/classification , Intellectual Disability/classification , Oral Health , Osteochondrodysplasias/classification , Seizures/classification
Rev Neurol ; 66(7): 241-250, 2018 Apr 01.
Article Es, En | MEDLINE | ID: mdl-29557550

Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the brainstem. This generic term has the advantage over the eponyms Moebius 'expanded' or 'unrestricted', Robin, Cogan or Carey-Fineman-Ziter syndromes in that it has a less restrictive view and provides a frame work that enables a systematic approach to diagnosis and research of most developmental disorders involving the brainstem. The review of the literature and our experience shows that infants with a predominant rombencephalic involvement are due to brainstem prenatal disruptive vascular accidents, while cases with midbrain and cerebellar involvement and widespread malformative syndromes have most likely an underlying genetic cause. Due to phenotypic heterogeneity associated with brainstem dysgenesis, it is crucial to evaluate each case individually and to establish a specific therapeutic plan. Intervention programs should start soon after diagnosis and directed to improve functions needed for daily life activities. Even though the prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved, in most patients with brainstem dysgenesis, the prognosis is better than the initial clinical manifestations would indicate.

Abnormalities, Multiple/classification , Brain Stem/abnormalities , Abnormalities, Multiple/embryology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/rehabilitation , Brain Stem/embryology , Cerebral Cortex/abnormalities , Cerebral Cortex/embryology , Disease Progression , Early Diagnosis , Eponyms , Humans , Infant, Newborn , Mesencephalon/abnormalities , Mesencephalon/embryology , Phenotype , Precision Medicine , Prognosis , Rhombencephalon/abnormalities , Rhombencephalon/embryology , Syndrome
J Pediatr Orthop ; 38(4): 217-222, 2018 Apr.
Article En | MEDLINE | ID: mdl-27280892

STUDY DESIGN: This is a retrospective cohort study. BACKGROUND: Hemimetameric segmental shift (HMMS) is defined as a hemivertebral deformation in which 2 or more hemivertebrae exist on both sides of the spine and are separated by at least 1 normal vertebra. Reports of HMMS are rare and based on simple anterior x-ray images. No reports have used 3-dimensional computed tomography (3D-CT) to analyze both the anterior and posterior elements. The objective of this study was to analyze the morphology and clinical features of HMMS 3 dimensionally. METHODS: HMMS was confirmed in 32 (6.6%, 16 males and 16 females) of 483 patients diagnosed with congenital scoliosis at the study institution between 1998 and 2013. The average age at the first visit was 6 years and 3 months. 3D-CT imaging was performed for 30 patients older than 2 years (average age: 9 y and 8 mo) and used to classify cases according to posterior elements. RESULTS: With regard to the number of hemivertebrae present, 21 patients had 2 hemivertebrae, 7 patients had 3 hemivertebrae, and 2 patients had 4 hemivertebrae. Patients with 2 hemivertebrae predominantly had hemivertebrae in the thoracolumbar spine. Patients were classified into 2 categories: malformation existing at an equal level in anterior and posterior sides (unison HMMS) and malformation existing at nonequal levels (discordant HMMS). Nine patients had unison HMMS and all of them had 2 hemivertebrae (average: 4.6 vertebrae). Twenty-one patients had discordant HMMS, with 12 having 2 hemivertebrae, 7 having 3 hemivertebrae, and 2 having 4 hemivertebrae. CONCLUSIONS: Through 3D-CT analysis, HMMS was categorized as unison or discordant. Discordant HMMS was observed in 21 of 30 (70%) patients and in all patients with >3 hemivertebrae. Diagnosing HMMS, whether unison or discordant, is clinically important and should be done with careful analysis of bone models and/or radiologic images to determine the correct spinal levels. LEVEL OF EVIDENCE: Level IV-diagnostic study.

Abnormalities, Multiple/diagnostic imaging , Imaging, Three-Dimensional/methods , Lumbar Vertebrae/abnormalities , Musculoskeletal Diseases/diagnostic imaging , Scoliosis/congenital , Synostosis/diagnostic imaging , Thoracic Vertebrae/abnormalities , Abnormalities, Multiple/classification , Abnormalities, Multiple/surgery , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Kyphosis/diagnostic imaging , Kyphosis/surgery , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/surgery , Male , Musculoskeletal Diseases/classification , Musculoskeletal Diseases/surgery , Retrospective Studies , Scoliosis/classification , Scoliosis/diagnostic imaging , Scoliosis/surgery , Synostosis/classification , Synostosis/surgery , Thoracic Vertebrae/diagnostic imaging , Thoracic Vertebrae/surgery , Tomography, X-Ray Computed/methods , Young Adult
J Craniomaxillofac Surg ; 46(1): 22-27, 2018 Jan.
Article En | MEDLINE | ID: mdl-29239768

INTRODUCTION: Craniofacial clefts belong to the most disfiguring and rare congenital malformations of the face and among these, orbito-facial clefts constitute approximately 0.22 % of the cases with Tessier cleft number 5 being the least common. Our aim was to define the phenotypic spectrum for this subgroup to improve clinical management. METHODS: Our study group consisted of four patients which were treated at two different cleft centers. Retrospective chart review and anatomical analysis were conducted for each patient based on clinical evaluation and imaging studies. Morphological anomalies including soft tissue, bone and oral components were recorded. RESULTS: Based on our analysis and literature review, we could define two subtypes of Tessier facial cleft number 5. (1) Medial clefts are the more severe subtype, creating a significant soft tissue and bone defect that runs vertically, through the eyelid, infraorbital rim, maxillary sinus and cheek. They have the poorer esthetic and functional prognosis, due to orbital dystopia and absence of lower eyelid. (2) Lateral clefts are a less severe subtype characterized by the presence of a vertical furrow of the cheek running laterally to the maxillary sinus. CONCLUSIONS: We identified two subtypes of facial cleft number 5 which require an individualized surgical management.

Abnormalities, Multiple/classification , Abnormalities, Multiple/genetics , Face/abnormalities , Facial Bones/abnormalities , Adolescent , Child , Child, Preschool , Humans , Male , Phenotype , Retrospective Studies
Birth Defects Res ; 110(1): 5-11, 2018 01 15.
Article En | MEDLINE | ID: mdl-28925590

BACKGROUND: It is estimated that 20 to 30% of infants with birth defects have two or more birth defects. Among these infants with multiple congenital anomalies (MCA), co-occurring anomalies may represent either chance (i.e., unrelated etiologies) or pathogenically associated patterns of anomalies. While some MCA patterns have been recognized and described (e.g., known syndromes), others have not been identified or characterized. Elucidating these patterns may result in a better understanding of the etiologies of these MCAs. METHODS: This article reviews the literature with regard to analytic methods that have been used to evaluate patterns of MCAs, in particular those using birth defect registry data. RESULTS: A popular method for MCA assessment involves a comparison of the observed to expected ratio for a given combination of MCAs, or one of several modified versions of this comparison. Other methods include use of numerical taxonomy or other clustering techniques, multiple regression analysis, and log-linear analysis. Advantages and disadvantages of these approaches, as well as specific applications, were outlined. CONCLUSION: Despite the availability of multiple analytic approaches, relatively few MCA combinations have been assessed. The availability of large birth defects registries and computing resources that allow for automated, big data strategies for prioritizing MCA patterns may provide for new avenues for better understanding co-occurrence of birth defects. Thus, the selection of an analytic approach may depend on several considerations. Birth Defects Research 110:5-11, 2018. © 2017 Wiley Periodicals, Inc.

Abnormalities, Multiple/classification , Statistics as Topic/methods , Congenital Abnormalities , Humans , Registries
Rev Neurol ; 64(s03): S13-S17, 2017 May 17.
Article Es | MEDLINE | ID: mdl-28524213

INTRODUCTION: The term 'RASopathies' covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include neurofibromatosis type 1, Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome. Involvement of the RAS/MAPK pathway not only increases predisposition to develop tumours, but also determines the presence of phenotypic anomalies and alterations in learning processes. AIM: To review the use of therapeutic strategies with mechanisms that have a selective action on RASopathies. DEVELOPMENT: The fact that the RAS pathway is involved in a third of all neoplasms has led to the development and study of different drugs at this level. Some of these pharmaceutical agents have been tested in RASopathies, mainly in neurofibromatosis type 1. Here we analyse the use of different antitarget treatments: drugs that act on the membrane receptors, such as tyrosine kinase inhibitors, in the mTOR pathway or MEK inhibitors. These latter have shown potential benefits in recent studies conducted on different RASopathies. CONCLUSIONS: Today, thanks to the results from the first studies conducted with MEK inhibitor based mainly on animal models, a number of promising clinical trials are being carried out.

Abnormalities, Multiple/drug therapy , Genes, ras , Genetic Diseases, Inborn/drug therapy , MAP Kinase Signaling System , Molecular Targeted Therapy , ras Proteins/antagonists & inhibitors , Abnormalities, Multiple/classification , Abnormalities, Multiple/genetics , Animals , Clinical Trials as Topic , Drug Evaluation, Preclinical , Genetic Diseases, Inborn/classification , Genetic Diseases, Inborn/genetics , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/genetics , Neurofibromatosis 1/drug therapy , Neurofibromatosis 1/genetics , Noonan Syndrome/drug therapy , Noonan Syndrome/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Syndrome , TOR Serine-Threonine Kinases/antagonists & inhibitors , ras Proteins/genetics
DNA Cell Biol ; 36(7): 589-595, 2017 Jul.
Article En | MEDLINE | ID: mdl-28436679

Conotruncal heart defects (CTDs) are severe malformations of outflow tract with heterogeneous morphology. Several missense variants of CITED2 have been identified to cause CTDs in recent researches. In this study, we screened the coding regions of CITED2 in 605 Chinese children with CTDs and found two possible pathogenic mutant sites: p.Q117L and p.T257A, both located in the conserved regions of CITED2. Then, we investigated the biological and functional alterations of them. Western blotting showed low level of protein expression of mutant Q117 and T257A compared with wild-type CITED2. Dual-luciferase reporter assay demonstrated that mutant Q117 and T257A decreased the ability of CITED2 to modulate the expression of paired-like homeodomain transcription factor 2 gamma (PITX2C), which are closely related to cardiac growth and left-right patterning. Meanwhile, T257A also exhibited impaired ability to mediate vascular endothelial growth factor expression, another gene closely associated with the normal development of cardiovascular system. Three-dimensional molecular conformation showed reduced hydrogen bond between Asp254 and mutant Thr257, indicating the weakened stability and binding ability of CITED2. All these results suggest that CITED2 mutations in conserved regions lead to disease-causing biological and functional changes and may contribute to the occurrence of CTDs.

Abnormalities, Multiple/genetics , Heart Defects, Congenital/genetics , Homeodomain Proteins/genetics , Meningomyelocele/genetics , Mutation, Missense , Repressor Proteins/genetics , Trans-Activators/genetics , Transcription Factors/genetics , Vascular Endothelial Growth Factor A/genetics , Abnormalities, Multiple/classification , Abnormalities, Multiple/ethnology , Abnormalities, Multiple/pathology , Amino Acid Sequence , Animals , Asian Continental Ancestry Group , Cell Line , Child , Conserved Sequence , Gene Expression Regulation, Developmental , Heart Defects, Congenital/classification , Heart Defects, Congenital/ethnology , Heart Defects, Congenital/pathology , Homeodomain Proteins/metabolism , Humans , Hydrogen Bonding , Meningomyelocele/classification , Meningomyelocele/ethnology , Meningomyelocele/pathology , Mice , Models, Molecular , Myoblasts/cytology , Myoblasts/metabolism , Open Reading Frames , Protein Conformation , Protein Stability , Repressor Proteins/chemistry , Repressor Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Trans-Activators/chemistry , Trans-Activators/metabolism , Transcription Factors/metabolism , Vascular Endothelial Growth Factor A/metabolism
JAMA Otolaryngol Head Neck Surg ; 143(2): 168-177, 2017 02 01.
Article En | MEDLINE | ID: mdl-27832265

Importance: CHARGE syndrome refers to a syndrome involving coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary disorders, and ear anomalies. However, Verloes revised the characteristics of CHARGE syndrome in 2005 to define this syndrome more broadly. Deficiency of the semicircular canals is now a major criterion for CHARGE syndrome. Objective: To characterize patients with CHARGE syndrome at our center using Verloes' criteria and to reevaluate the nomenclature for this condition. Design, Setting, and Participants: We performed a medical chart review of patients with CHARGE syndrome and reviewed their temporal bone imaging studies at a tertiary care children's hospital affiliated with Washington University in St Louis. Two authors independently reviewed each imaging study (A.W. and K.H.). Radiologic studies, physical findings, genetic tests, and other diagnostic tests were included. Patients with no temporal bone imaging studies were excluded. Results: Eighteen children were included in this study; 13 children (72%) were male, and the mean (median; range) age of patients at the time of inner ear imaging studies was 2 years (4.5 years; 8 months to 8 years). Coloboma was present in 13 patients (72%) and choanal atresia in 5 (28%); semicircular canal anomalies were present in all patients. Additionally, 13 patients (72%) were diagnosed as having hindbrain anomalies, 17 (94%) as having endocrine disorders, 17 (94%) as having mediastinal organ malformations, and all as having middle or external ear abnormalities and development delay. Cleft lip and cleft palate were found in 6 of 14 patients (43%) who did not have choanal atresia. We tested 16 patients for mutations in the CHD7 gene; 10 were positive (63%) for mutations, 4 (25%) were negative, and 2 (13%) were inconclusive. Conclusions and Relevance: Semicircular canal anomalies were the most consistent finding in our patients with CHARGE syndrome. Given the high prevalence of semicircular canal hypoplasia and importance of imaging for diagnosing CHARGE syndrome, we propose changing the term CHARGE syndrome to 3C syndrome to emphasize the importance of the semicircular canals and to recall the 3 major criteria for diagnosis: coloboma, choanal atresia, and semicircular canal anomaly. The nomenclature would also reference the 3 semicircular canals in each ear. This new name for CHARGE syndrome would provide a mnemonic and focus the disease on the most important clinical criteria for diagnosis.

Abnormalities, Multiple/diagnosis , CHARGE Syndrome/diagnosis , Craniofacial Abnormalities/diagnosis , Dandy-Walker Syndrome/diagnosis , Heart Septal Defects, Atrial/diagnosis , Semicircular Canals/abnormalities , Abnormalities, Multiple/classification , Abnormalities, Multiple/genetics , CHARGE Syndrome/classification , CHARGE Syndrome/genetics , Child , Child, Preschool , Craniofacial Abnormalities/classification , Craniofacial Abnormalities/genetics , Dandy-Walker Syndrome/classification , Dandy-Walker Syndrome/genetics , Female , Heart Septal Defects, Atrial/classification , Heart Septal Defects, Atrial/genetics , Humans , Infant , Male , Prevalence , Retrospective Studies , Terminology as Topic
J Oral Maxillofac Surg ; 74(9): 1849.e1-1849.e10, 2016 Sep.
Article En | MEDLINE | ID: mdl-27321409

PURPOSE: Numerous case reports have been published on lip pits in Van der Woude syndrome explaining the morphology and genetics in detail; however, thus far, no article has focused on the classification of lip pits as an aid in surgical management. Although the procedure for lip pits in Van der Woude syndrome appears straightforward, even in the best of hands, the excision can be very challenging with no guarantee of esthetically desirable results. Therefore, we have devised a classification based on a difficulty index in the management of lower lip pits to assist in predicting the treatment outcome before surgery, as well as to offer the choice of a particular technique in a specific situation. MATERIALS AND METHODS: We reviewed 19 cases of Van der Woude syndrome having lower lip pits that were operated on at our unit from May 2005 to June 2015 with a minimum follow-up of at least 6 months. The data analyzed included the patient's age and gender, location of the lip pits with regard to their proximity to the white skin roll, number of lip pits, presurgical depth of the lip pits, and discharge of mucous secretion from the pits, as well as timing of lip pit excision. Four techniques of excision were performed via routine excision, modified routine excision, vertical wedge excision, and inverted-T lip reduction. The data were tabulated and analyzed. On the basis of our experience in managing lip pits, a clinically relevant classification with a difficulty index was then proposed. RESULTS: Among the 12 patients having preoperative involvement of the white skin roll, 8 had distortion of the white skin roll when operated on by either routine excision (n = 2), modified routine excision (n = 3), or inverted-T lip reduction (n = 3). The remaining 4 patients had no distortion of the white skin roll after surgery when the vertical wedge excision technique was performed. The 7 patients who had no distortion of the white skin roll preoperatively presented with esthetic results when operated on by either the routine excision, modified routine excision, or inverted-T lip reduction technique. In 2 patients with a presurgical pit depth greater than 6 mm, mucocele formation was observed after surgery. Using the data obtained, we proposed a classification based on 2 parameters: involvement of the white skin roll and presurgical depth. A difficulty index also was proposed using these same variables. CONCLUSIONS: Classification and evaluation of the difficulty of lip pit excision are essential in planning the surgical treatment to give improved esthetic results. This proposed classification and difficulty index will provide the operating surgeon with a standardized scheme to evaluate the difficulty of the excision as well as to predict the overall outcome of the procedure before surgery.

Abnormalities, Multiple/classification , Abnormalities, Multiple/surgery , Cleft Lip/classification , Cleft Lip/surgery , Cleft Palate/classification , Cleft Palate/surgery , Cysts/classification , Cysts/surgery , Lip/abnormalities , Lip/surgery , Child , Child, Preschool , Esthetics , Female , Humans , Infant , Male , Treatment Outcome
Dan Med J ; 63(6)2016 Jun.
Article En | MEDLINE | ID: mdl-27264942

INTRODUCTION: The WHO has launched a common classification for disabilities in children, the International Classification of Functioning, Disability and Health, Child and Youth Version (ICF-CY). We wanted to determine whether cat-egories of the environmental (e) and the body functions (b) components of the classification could address environmental needs in children with different disorders and various disability severities. METHODS: A set of 16 e categories and 47 b categories were selected and worded to best enable parents to describe children's everyday support needs and environmental influences through interviews in their own homes. RESULTS: Of the 367 invited parents, 332 (90.5%) participated, providing data on children with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairments, hearing impairments, mental disability and disabilities following brain tumour treatment. The mean age of children across disabilities was 9.4 years (range: 1.0-15.9). The mean e code score was 35.7 (range: 4.0-64.0), and the mean b code score was 32.2 (range: 0.0-159.0). The most urgent needs as detected by qualifier 4 environmental categories scores were common among children with complex disorders and issues related to health professionals, legal services and health services. CONCLUSIONS: Parents understand the environmental and body function components in a meaningful manner and the codes seem to be valid. Special emphasis should be given to environmental issues for children with more complex disabilities. There was no correlation between the severity of a disability and environmental issues, indicating that each child's needs were basically met, irrespective of disability severity. FUNDING: partnership project § 16, 21, 31 administered by the Danish Health Authority. TRIAL REGISTRATION: not relevant.

Abnormalities, Multiple/classification , Disability Evaluation , Disabled Children/classification , Activities of Daily Living , Adolescent , Child , Child, Preschool , Developmental Disabilities/classification , Humans , Infant , International Classification of Functioning, Disability and Health , Interviews as Topic , Parents , Psychometrics , Social Environment