Delineation Of Syndromes Research Articles

PRENATAL DEATH IN FRASER SYNDROME

Cryptophthalmos may be partial or complete, unilateral or bilateral, apparently nonsyndromal or syndromal. A recent study of 2 stillborn infants at the University of Utah prompted an analysis of the developmental aspects of the syndromal form (Fraser syndrome). We conclude that, per se, cryptophthalmos is a developmental field defect on the basis of heterogeneity (autosomal dominant and recessive forms) and phylogeneity (occurrence also in the pheasant, rabbit, pigeon, dog, and mouse). In humans this autosomal recessive disorder maps to 4q21, is homologous to the bleb (bl/bl) mouse, and is due to mutations in the FRAS1 gene that codes for a 4007 amino acid protein 85% identical to the Fras1 gene of the bleb mouse. Commonest anomalies in humans are cryptophthalmos, cutaneous syndactyly of digits, abnormal ears and genitalia, renal agenesis, and congenital heart defects. Almost half of affected infants are stillborn or die in infancy, and mental retardation is common. The pathogenesis evidently involves abnormal epithelial integrity during prenatal life. Older (mostly German) publications, some dating to the 19th century, provide a fascinating historical insight into the process of syndrome delineation.

Book reviews

Book reviews

Challenging pancreatic cancer-prone pedigrees: a nosologic dilemma

OBJECTIVES: Our objective is to describe 11 pancreatic cancer (PC)-prone families, none of which are consonant with known hereditary cancer syndromes, in an attempt to portray familial aggregations of this disease that might be encountered in a clinical practice setting. METHODS: We selected 11 families containing two or more first- and/or second-degree relatives affected with PC from a registry of 200 PC-prone kindreds. Each proband and/or key relative(s) was interviewed and completed a detailed family history questionnaire (after providing informed consent) that allowed us to extend the pedigree as far as possible with retrieval of primary medical and pathology documents, whenever available. RESULTS: All of the 11 families show PC features that merit clinical attention and raise questions as to whether this familial clustering could be due to “chance” alone, exposure to certain common environmental factors, such as cigarette smoking, and/or polygenic, multifactorial, or Mendelian inherited factors. CONCLUSIONS: It is estimated that about 5% of PC may have a primary hereditary etiology. Because of early death, reduced penetrance, and often profuse phenotypic and genotypic heterogeneity, particularly with respect to variable age of onset and association with diverse patterns of cancer at different anatomic sites, the pedigrees require extension for ultimate diagnosis. Physician knowledge about PC’s natural history and syndrome delineation should ultimately foster earlier diagnoses and possibly prevention of this disease. These high-risk patients may provide a source of DNA for formal linkage analysis in the search for culprit cancer-prone susceptibility loci.

Challenging Pancreatic Cancer-Prone Pedigrees: A Nosologic Dilemma

Our objective is to describe 11 pancreatic cancer (PC)-prone families, none of which are consonant with known hereditary cancer syndromes, in an attempt to portray familial aggregations of this disease that might be encountered in a clinical practice setting. We selected 11 families containing two or more first- and/or second-degree relatives affected with PC from a registry of 200 PC-prone kindreds. Each proband and/or key relative(s) was interviewed and completed a detailed family history questionnaire (after providing informed consent) that allowed us to extend the pedigree as far as possible with retrieval of primary medical and pathology documents, whenever available. All of the 11 families show PC features that merit clinical attention and raise questions as to whether this familial clustering could be due to "chance" alone, exposure to certain common environmental factors, such as cigarette smoking, and/or polygenic, multifactorial, or Mendelian inherited factors. It is estimated that about 5% of PC may have a primary hereditary etiology. Because of early death, reduced penetrance, and often profuse phenotypic and genotypic heterogeneity, particularly with respect to variable age of onset and association with diverse patterns of cancer at different anatomic sites, the pedigrees require extension for ultimate diagnosis. Physician knowledge about PC's natural history and syndrome delineation should ultimately foster earlier diagnoses and possibly prevention of this disease. These high-risk patients may provide a source of DNA for formal linkage analysis in the search for culprit cancer-prone susceptibility loci.

Heart development and the genetic aspects of cardiovascular malformations.

American Journal of Medical GeneticsVolume 97, Issue 4 p. 235-237 Introduction Heart development and the genetic aspects of cardiovascular malformations Angela E. Lin, Corresponding Author Angela E. Lin [email protected] Teratology Program, The Brigham and Women's Hospital, Old PBBH-B501, 75 Francis Street, Boston, MA 02115. Dr. Angela Lin (M.D.) completed training in pediatric cardiology and clinical genetics. She is on staff at Massachusetts General Hospital and the Brigham and Women's Hospital in Boston, Massachusetts. Dr. Lin's interests include dysmorphology and syndrome delineation, cardiovascular malformations in genetic syndromes, counseling for families of children with a cardiovascular malformation, and the epidemiology of cardiovascular malformations.Teratology Program, The Brigham and Women's Hospital, Old PBBH-B501, 75 Francis Street, Boston, MA 02115.Search for more papers by this authorMary Ella M. Pierpont, Mary Ella M. Pierpont Dr. Mary Ella Pierpont (M.D., Ph.D.) is Associate Professor of Pediatrics at the University of Minnesota, Minneapolis, and Director of the Ray and Hattie Anderson Center for the Study of Hereditary Cardiac Disease. She is a pediatric cardiologist and clinical geneticist and Director of Medical Genetics at the Children's Hospital, St. Paul. Dr. Pierpont has a longtime research interest in genetic aspects of cardiovascular malformations and syndromes. She edited The Genetics of Cardiovascular Disease in 1987, one of the first books to emphasize the importance of genetic aspects of cardiovascular malformations.Search for more papers by this author Angela E. Lin, Corresponding Author Angela E. Lin [email protected] Teratology Program, The Brigham and Women's Hospital, Old PBBH-B501, 75 Francis Street, Boston, MA 02115. Dr. Angela Lin (M.D.) completed training in pediatric cardiology and clinical genetics. She is on staff at Massachusetts General Hospital and the Brigham and Women's Hospital in Boston, Massachusetts. Dr. Lin's interests include dysmorphology and syndrome delineation, cardiovascular malformations in genetic syndromes, counseling for families of children with a cardiovascular malformation, and the epidemiology of cardiovascular malformations.Teratology Program, The Brigham and Women's Hospital, Old PBBH-B501, 75 Francis Street, Boston, MA 02115.Search for more papers by this authorMary Ella M. Pierpont, Mary Ella M. Pierpont Dr. Mary Ella Pierpont (M.D., Ph.D.) is Associate Professor of Pediatrics at the University of Minnesota, Minneapolis, and Director of the Ray and Hattie Anderson Center for the Study of Hereditary Cardiac Disease. She is a pediatric cardiologist and clinical geneticist and Director of Medical Genetics at the Children's Hospital, St. Paul. Dr. Pierpont has a longtime research interest in genetic aspects of cardiovascular malformations and syndromes. She edited The Genetics of Cardiovascular Disease in 1987, one of the first books to emphasize the importance of genetic aspects of cardiovascular malformations.Search for more papers by this author First published: 23 October 2002 https://doi.org/10.1002/1096-8628(200024)97:4<235::AID-AJMG1273>3.0.CO;2-SCitations: 4 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume97, Issue4Special Issue: Heart Developments and the Genetics Aspects of Cardiovascular MalformationsWinter 2000Pages 235-237 RelatedInformation

On the classification and diagnosis of pathological grief

It has been suggested that pathological grief should become either a separate category of mental disorder or be integrated within existing, extended classifications in systems such as the Diagnostic and Statistical Manual of Mental Disorders. Despite strong arguments for inclusion, and advancements by scientists toward development of diagnostic classification, there has been a lack of critical evaluation. Several issues need further scrutiny and clarification. These concern the definition of pathological grief, the distinction of pathological from normal grief, its relationship with other disorders, and the lack of agreement among scientists about criteria for pathological grief. Further research needs to focus on delineation of syndromes that comprise “pathological grief,” and on derivation of acceptable, valid, diagnostic criteria. Evaluation of the ramifications—both positive and potentially negative—associated with the revision of the diagnostic status of pathological grief needs also to be undertaken.

Familial patent ductus arteriosus and bicuspid aortic valve with hand anomalies: A novel heart-hand syndrome

The association between cardiac and limb defects, particularly those affecting the hand, has been well documented by the delineation of several heart-hand syndromes. Based on observations with a three-generation family with seven affected individuals, we describe a novel heart-hand syndrome comprising patent ductus arteriosus, bicuspid aortic valve, 5th metacarpal hypoplasia, and brachydactyly. The inheritance pattern was consistent with autosomal dominance, although X-linked dominance could not be excluded. Penetrance appeared to be complete, but there was variability of the cardiac and hand phenotypes. Because this new syndrome closely resembled Char syndrome (patent ductus arteriosus, 5th finger middle phalangeal hypoplasia, and minor facial anomalies), multipoint linkage analysis was performed using polymorphic DNA markers spanning the recently identified Char syndrome critical region at chromosomal bands 6p12-p21.1. This analysis formally excluded this 3-cM region, documenting that the two traits are not allelic. In sum, a novel heart-hand syndrome involving left ventricular outflow and aortic arch as well as an ulnar ray derivative has been identified. Because the hand anomalies can be subtle, thorough evaluation is suggested for families inheriting these cardiac defects as a mendelian trait.

Familial patent ductus arteriosus and bicuspid aortic valve with hand anomalies: A novel heart‐hand syndrome

The association between cardiac and limb defects, particularly those affecting the hand, has been well documented by the delineation of several heart-hand syndromes. Based on observations with a three-generation family with seven affected individuals, we describe a novel heart-hand syndrome comprising patent ductus arteriosus, bicuspid aortic valve, 5th metacarpal hypoplasia, and brachydactyly. The inheritance pattern was consistent with autosomal dominance, although X-linked dominance could not be excluded. Penetrance appeared to be complete, but there was variability of the cardiac and hand phenotypes. Because this new syndrome closely resembled Char syndrome (patent ductus arteriosus, 5th finger middle phalangeal hypoplasia, and minor facial anomalies), multipoint linkage analysis was performed using polymorphic DNA markers spanning the recently identified Char syndrome critical region at chromosomal bands 6p12-p21.1. This analysis formally excluded this 3-cM region, documenting that the two traits are not allelic. In sum, a novel heart-hand syndrome involving left ventricular outflow and aortic arch as well as an ulnar ray derivative has been identified. Because the hand anomalies can be subtle, thorough evaluation is suggested for families inheriting these cardiac defects as a mendelian trait.

The Emanuel Miller Memorial Lecture 1998: Autism: Two‐way Interplay between Research and Clinical Work

The two-way interplay between research and clinical practice in relation to autism is reviewed with respect to: (1) diagnosis and syndrome delineation; (2) the nature of the disorder: (3) intervention studies; and (4) aetiology, as manifest during four time periods; (a) the 1950s and 1960s; (b) the 1970s into the mid 1980s; (c) the late 1980s and early 1990s; and (d) the late 1990s. It is concluded that clinical practice has changed out of all recognition during the last 50 years and that research findings have been crucial in bringing about that change. It has not, however, been a one-way traffic. Many key advances were prompted by astute clinical observations and some extravagant research claims were given a more balanced perspective through the light of clinical experience. Crucial research and clinical tasks remain but the means to meet them are there if the opportunities are taken and attention is paid to the lessons of the past.

Autism: Two-way Interplay between Research and Clinical Work

The two-way interplay between research and clinical practice in relation to autism is reviewed with respect to: (1) diagnosis and syndrome delineation; (2) the nature of the disorder; (3) intervention studies; and (4) aetiology, as manifest during four time periods; (a) the 1950s and 1960s; (b) the 1970s into the mid 1980s; (c) the late 1980s and early 1990s; and (d) the late 1990s. It is concluded that clinical practice has changed out of all recognition during the last 50 years and that research findings have been crucial in bringing about that change. It has not, however, been a one-way traffic. Many key advances were prompted by astute clinical observations and some extravagant research claims were given a more balanced perspective through the light of clinical experience. Crucial research and clinical tasks remain but the means to meet them are there if the opportunities are taken and attention is paid to the lessons of the past.

小児のてんかん症候群における最近の進歩

小児のてんかん症候群における最近の進歩

Study of behavioral phenotypes: goals and methodological considerations.

The study of behavioral phenotypes associated with genetic syndromes has gained increasing momentum over the past two decades. In this paper, the definition of behavioral phenotypes is presented and the complexities and obstacles to progress in this field are summarized. Also described are the goals of such investigations, including the need for syndrome delineation, provision of guidance for clinical management, contributions to understanding brain-behavior relations, advancements in developmental theory, and gaining understanding of the genetic bases of behavior. Methodological issues addressed in relation to such goals include the need for cross-disciplinary collaboration, concerns regarding sampling methods and comparison group selection, and developmental considerations. The complexity of cognitive abilities, the limitations of existing tests and measures, and ways of approaching the study of behavior are discussed. A final comment concerns the potential risks of research in behavioral phenotypes.

Literature Review

This work by the American Academies of Orthopaedic Surgeons and Pediatrics offers primary care practitioners a useful overview for the diagnosis and treatment of many musculoskeletal conditions and provides guidelines for referral. The initial discussion of general orthopedics is followed by sections on each anatomical region (eg, knee and lower leg), concluding with a section on pediatric orthopedics. A brief overview with a pictorial summary of physical tests prefaces each section. The discussions of the foot and ankle and of pediatric orthopedics are most impressive. The standardized format (definition, symptoms, tests, outcomes, etc) presents a large body of material concisely and informatively—it is easily accessible to the busy clinician. Other useful chapters include general principles of fractures, splinting, regionalized exercise programs, and podiatric orthotics. Appropriate injection techniques are outlined and diagrammed beautifully.Other parts of the book are more limited. The section on general orthopedics is superficial and the discussions of rheumatoid arthritis (two pages) and magnetic resonance imaging (six sentences) are perfunctory. Although it is difficult to discuss controversial subjects such as the complexities associated with thoracic outlet syndrome in a basic text, such controversies could be better identified. Furthermore, although psychosocial issues frequently complicate musculoskeletal pain problems, there is no consideration of this issue beyond nonorganic physical findings (such as Waddell findings) and worn stereotypes. Finally, the diagram of carpal tunnel syndrome on page 196 does not reflect its caption; this was corrected in the second printing of the book.The book would benefit from further discussion of evaluation. The section on radiculopathy omits the pronator teres and hamstring reflexes in the delineation of C6 and L5 syndromes. Also, each region needs a summary of specialized radiological views. Electrodiagnosis receives little more than a few sentences in the entire book, several of which are oversimplifications. Treatment recommendations could also be improved. The recommendations for prophylaxis of deep venous thrombosis would spark considerable debate. There are no references within the book, but it is well indexed.Overall, Essentials of Musculoskeletal Care has made a good start with room for improvement in the second edition.

Perspectives on craniofacial syndromes

This article reviews syndrome classification; types of anomalies and their interrelations; syndrome delineation; birth prevalence; nomenclature; molecular delineation; and phenotype/genotype correlations.

Mosaic trisomy 22: A case presentation and literature review of trisomy 22 phenotypes

In a case of mosaic trisomy 22 the trisomic cells were detected primarily in fibroblasts. Results of initial lymphocyte chromosome analysis were normal. However, mosaicism was suspected because the patient had hypomelanosis of Ito, hemiatrophy, failure to thrive, and mental retardation. Mosaicism was confirmed in cultured fibroblasts. Repeat cytogenetic analysis of peripheral blood demonstrated a low level of trisomic metaphase cells, which was confirmed by interphase fluorescent in situ hybridization (FISH) analysis. Molecular studies supported maternal disomy in the child's disomic cells. The phenotype of this condition overlaps that of non-mosaic trisomy 22 chromosome mosaicism in general and to some extent the Ullrich-Turner syndrome phenotype. Improved cytogenetic and molecular techniques now allow better delineation of aneuploidy syndromes. Molecular and FISH studies added information about this case (mosaicism and uniparental disomy) not appreciated by routine cytogenetic analysis of lymphocytes. The detection of low-level mosaicism and/or uniparental disomy in such cases may change the clinical classification and our understanding of pathogenesis and recurrence risk of these disorders.

Leprechaunism/Donohue syndrome/insulin receptor gene mutations: a syndrome delineation story from clinicopathological description to molecular understanding.

Leprechaunism/Donohue syndrome/insulin receptor gene mutations: a syndrome delineation story from clinicopathological description to molecular understanding.

Recent advances and some problems in the delineation of epileptic syndromes in children

The current International Classification of Epilepsies and Epileptic Syndromes has classified a number of age-related epileptic syndromes in children, but some of these entities have not been well delineated and many syndromes not included in the International Classification have been proposed. This article is intended to supplement some of the currently listed childhood epileptic syndromes, discuss certain problems with the classification system, and review some of the proposed pediatric syndromes.

Diagnosis of four chromosome abnormalities of unknown origin by chromosome microdissection and subsequent reverse and forward painting.

A molecular cytogenetic method consisting of chromosome microdissection and subsequent reverse/forward chromosome painting is a powerful tool to identify chromosome abnormalities of unknown origin. We present 4 cases of chromosome structural abnormalities whose origins were ascertained by this method. In one MCA/MR patient with an add(5q)chromosome, fluorescence in situ hybridization (FISH), using probes generated from a microdissected additional segment of the add(5q) chromosome and then from a distal region of normal chromosome 5, confirmed that the patient had a tandem duplication for a 5q35-qter segment. Similarly, we ascertained that an additional segment of an add(3p) chromosome in another MCA/MR patient had been derived from a 7q32-qter segment. In a woman with a history of successive spontaneous abortions and with a minute marker chromosome, painting using microdissected probes from the whole marker chromosome revealed that it was i(15)(p10) or psu dic(15;15)(q11;q11). Likewise, a marker observed in a fetus was a ring chromosome derived from the paracentromeric region of chromosome 19. We emphasize the value of the microdissection-based chromosome painting method in the identification of unknown chromosomes, especially for marker chromosomes. The method may contribute to a collection of data among patients with similar or identical chromosome abnormalities, which may lead to a better clinical syndrome delineation.

Hereditary Hearing Loss and its Syndromes

1: Robert J. Gorlin: Genetic hearing loss - a brief history. 2: M. Michael Cohen, Jr.: Syndrome delineation and heteroegeneity. 3: M. Michael Cohen, Jr. Robert J. Gorlin: Hearing loss - epidemiology, etiology, and genetic patterns. 4: Kathleen K. Sulik: Embryology of the ear. 5: Robert J. Gorlin: Genetic hearing loss with no associated abnormalities. 6: Judith Allanson: Genetic hearing loss associated with external ear abnormalities. 7: Robert J. Gorlin: Genetic hearing loss associated with eye disorders. 8: M. Michael Cohen, Jr.: Genetic hearing loss associated with musculo-skeletal disorders. 9: Robert J. Gorlin, Derin C. Webster, John C. Carey: Genetic hearing loss associated with renal disorders. 10: William B. Dobyns: Genetic hearing loss associated with nervous system disorders. 11: Robert J. Gorlin: Genetic hearing loss associated with endocrine and metabolic disorders. 12: Alberty Schinzel: Genetic hearing loss associated with chromosomal disorders. 13: Helga C. Toriello: Genetic hearing loss associated with integumentary disorders. 14: Robert J. Gorlin: Genetic hearing loss associated with oral and dental disorders. 15: Robert J. Gorlin: Genetic hearing loss associated with miscellaneous disorders

Auriculocephalic index: A new anthropometric index for syndrome delineation

We describe a new anthropometric index, the "auriculocephalic index." It results from the ratio between the length of auricle and the corresponding preauricular head height. The index is independent of sex and of age. Normally it ranges between 0.25 (-2s) and 0.33 (+2s). In syndrome delineation it may help to diagnose more precisely large or small auricles as phenogenetic variants.