Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Syndrome delineation 1. Malformations and dysplasias Jürgen Herrmann & John M. Opitz To cite this article: Jürgen Herrmann & John M. Opitz (1979) Syndrome delineation 1. Malformations and dysplasias, Postgraduate Medicine, 65:1, 207-214, DOI: 10.1080/00325481.1979.11715035 To link to this article: https://doi.org/10.1080/00325481.1979.11715035
Published online: 07 Jul 2016.
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Citing articles: 1 View citing articles
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GENETICS A Series
Syndrome delineation 1. Malformations and dysplasias A practical classification of genetic disorders and birth defects divides them into five categories: malformations, dysplasias, inborn errors of metabolism, deformities, and variant familial developmental patterns. The first two categories are discussed here. The last three will be discussed next month in part 2.
Jiirgen Herrmann, MD John M. Opitz, MD
The pathogenetic mechanisms producing genetic disorders and birth defects are complex. Normal variations and abnormal developmental mechanisms produce a virtually endless number of different patterns of clinical manifestations. The manifestations are determined by the nature, time of action, and localization of the developmental mechanisms and by genetic constitution and environmental circumstances. When a physician becomes involved in a case of a genetic syndrome, even in a premature baby, it is late in the game; the pathogenetic mechanisms are active during embryonic and fetal development. Because of the radical change in environment from intrauterine to extrauterine life, birth is the most important milestone in the human developmental process. It is also the time when abnormalities become apparent. Often a congenital anomaly in a baby is readily recognizable as due to a particular event or cause; items in the obstetric or family history may be compelling. In other instances the manifestations may not indicate readily the full extent of the condition, its nature, its cause, or the implications.
During and in conjunction with evaluation of a genetic patient, I a phenotype analysis can lead to classification of manifestations into one or several of five broad categories: malformations, dysplasias, inborn errors of metabolism, deformities, and variant familial developmental patterns. This system of classification is based on the most impor-
One of a series of articles on genetics which began in October 1977
tant prenatal pathogenetic events that lead to and are associated with genetic disorders and birth defects. Generically, not all of these events differ from postnatal pathogenetic processes (degeneration, deterioration, chronic infection, disuse atrophy). However, the prenatal events produce manifestations that might not have been produced during later stages of development or might not
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
have been produced in the same manner. On the other hand, some of the typically prenatal pathogenetic processes may have a prominent postnatal component or a predominantly postnatal expression. In later life there is almost always a picture of intertwined prenatal and postnatal events that may be difficult to separate. In early life an analysis of phenotype with respect to pathogenesis often is possible and gives information that is helpful in the further evaluation, diagnosis, therapy, and counseling. Malformations Definitions-A malformation is a structural anomaly due to a primary defect in the differentiation of a certain part of the body, such as an organ, a rib or part of a rib, or a body wall. The term is used usually for the manifestation rather than for the pathogenetic mechanism and process. What constitutes a malformation and what does not is generally clear, but occasionally difficulties can arise in distinguishing among malformations, deformities, postnatal structural changes, and degenerative anomalies. Malformations are typically congenital, yet there are exceptions. Some malformations concern structures or organs that are not present at birth, such as the continued 207
GENETICS CONTINUED
Malformations are congenital structural defects with various genetic and nongenetic causes. The defects are localized and nonprogressive and usually unassociated with biochemical or histologic abnormalities.
teeth. Not all congenital structural anomalies are malformations; the largest number of congenital structural anomalies that are not malformations are the deformities. In an adult it can be difficult to distinguish true primary malformations from structural changes secondary to long-standing deformation or to chronic degeneration with disuse atrophy, contractures, osteoporosis, hypoperfusion, ulceration, or infection. Malformations can be due to any of a number of different causes: dominant and recessive autosomal mutations, X-linked mutations, chromosome aberrations, teratogens and prenatal infections, maternal illness during pregnancy, maternal exposure during pregnancy to fumes, chemicals, or radiation, and unknown or unidentified factors. Many malformations are known (eg, cleft palate) which are due in some cases to an autosomal dominant mutation, in others to an autosomal recessive or X-linked mutation, and in still others to maternal exposure to teratogens during pregnancy or unidentified factors. Thus, a malformation per se is, as a rule, etiologically nonspecific, but in conjunction with other data, other malformations, the clinical findings, and the historical information may suggest a specific diagnosis and a specific cause. Whether a patient has a single malformation or multiple malformations is therefore highly relevant, and it is in this context that the concept of the developmental field becomes important.
208
Developmental
field
complex
(DFC)-A developmental field is
that "part of an embryo which reacts as a temporally and spatially coordinated unit to normal, localized forces of organization and differentiation, and to surgical manipulations, gene and chromosome mutations and the effect of certain teratogens."2 The extent of a malformation must be viewed in the context of known developmentalgenetic, embryologic, teratologic, and clinical principles. A complex of developmentally closely related anomalies is a developmental field complex. Recognition of DFCs serves to distinguish individual manifestations and thus to separate patients Jiirgen Hernnann Dr Herrmann is associate professor of pediatrics and medical genetics. University of Wisconsin Center for Health Sciences and Medical School, Madison.
with single and multiple malformations. A developmental field defect is the force that exerts the temporally and spatially coordinated changes in the field, and the D FC is the group of localized primary disturbances that result. All primary abnormalities within the field therefore represent the DFC and, hence, a single malformation. For example, ocular hypotelorism, midline cleft lip and cleft palate, hypoplasia of the nose with a single nostril, bilateral coloboma iridis, and alobar holoprosencephaly all constitute components of a single malformation, the holoprosenceph-
aly DFC. Primary malformations are always DFCs. An example might illustrate the etiologic nonspecificity of individual DFCs. We have observed the occurrence of the holoprosencephaly DFC with autosomal dominant transmission and variable expressivity. The propositus was lethally affected, his mother had a unilateral cleft lip and cleft palate, and the mother's brother had a single, midline upper central incisor as the sole manifestation of the trait. In other families the holoprosencephaly DFC can be seen to be an autosomal recessive trait. Furthermore, it can be observed as a component of certain syndromes, such as trisomy 13 syndrome. Most individual DFCs can occur in high-risk as well as in low-risk situations. Further examples come to mind readily: the cleft lip and palate DFC, the cloverleaf (Kleeblattschiidel) DFC, the various polydactyly DFCs, and many others. The majority of persons with a birth defect have a single malformation: cleft lip and palate, congenital heart defect, spina bifida with meningomyelocele, hypospadias, and so on. For each of these malformations, the DFC can be more or less extensive. At times a convenient characterization by degree is possible (eg, for hypospadias), but usually a description of the anatomic and physiologic manifestations is necessary. A cascade of morphologic and functional manifestations secondary
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
The cause of single malformations is frequently unrecognized. The cause of malformation syndrome can be established In many cases. All constitutional chromosome aberration syndromes are malfor· mation syndromes, but the reverse is not true.
to lumbar meningomyelocele, such as clubfoot, urinary bladder paralysis, hydrocephalus, and chronic kidney infection, does not mean that the patient does not have a single malformation. All malformations have secondary effects, be these morphologic, functional, psychologic, or a combination. The term "anomalad" has been suggested to describe a DFC plus the secondary morphologic manifestations.3 This is liable to create the impression that some birth defects are malformations and others are anomalads. We think that the term "anomalad" is superfluous, since naming the primary malformation and distinguishing it from secondary morphologic changes are sufficient and more accurate. All the secondary changes are, of course, etiologically nonspecific, as are individual primary malformations. Recognition of one single malformation leads to a search for others. Particularly important in this regard is examination of developmentally complex structures such as eyes, face, auricles, hands, feet, and genitalia. This examination is combined with evaluation of internal organs that are particularly important biologically, such as kidneys, heart, and brain. All patients with a single malformation need a careful, complete physical examination, and in each instance the physician should consider also obtaining an ECG, chest x-ray films, brain scan, and intravenous pyelogram (IVP). Whether the latter tests are needed depends on the nature of the
presenting primary malformation. A defect in the form of a single umbilical artery should prompt the physician to obtain an IVP, since major genitourinary tract malformations are associated (or are component manifestations in the same developmental field) in a high proportion of cases. Absence of thumbs or aplasia of radial bone should prompt a detailed cardiac evaluation to rule out the presence of HoltOram syndrome. Demonstration of two primary malformations in a patient, ie, demonstration of involvement of two developmental fields, should prompt more aggressive evaluation of other organs when there is even a slight indication that these may be abnormal. For instance, all patients with a documented vertebral segmentation defect and (even mild) aplasia of radial bone should be evaluated with respect to congenital heart defects, tracheoesophageal fistulas, and renal malformations. Similarly, persons with microphthalmia and dermatoglyphic or any other abnormality should have a thorough evaluation with respect to CNS syndromes. The DFCs in many malformation syndromes would seem unique and almost coincidental from a developmental standpoint were it not for consistency of occurrence in particular syndromes. The occurrence of the thumb/toe abnormalities (developmental field 1) and the characteristic facial appearance (field 2) in the Rubinstein-Taybi syndrome is such an example. However, the associa-
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
tion of the same two D FCs can be observed in different conditions. This indicates that such an association is etiologically nonspecific and suggests that in some instances the two separate DFCs may in fact represent a dis-located single malformation. The term "polytopic John M. Opitz
Dr Opitz is professor of medical genetics and pediatrics, University of Wisconsin Center for Health Sciences and Medical School, and director, Wisconsin Clinical Genetics Center.
anomaly" has been used to describe this phenomenon. 4 The best example is the association of acral (hand, foot) and renal malformations, the acrorenal "syndrome," which occurs in some 20 different conditions. In some cases a condition may be recognized as representing a malformation syndrome on the basis of one major plus one or two minor malformations. For example, absence of a kidney plus a highly abnormal dermatoglyphic pattern (in itself harmless) would identify a malformation syndrome (or a polytopic single malformation). Recurrence risks-In the majority of patients with a birth defect, the malformation apparently is caused by a number of different factors acting in concert; the cause is multifactorial, involving environmental as well as genetic factors, most of them unidentified. An analogy is the occurrence of a car accident due to the combination of a slippery road, twilight, heavy traffic, worn brakes, and a sleepy driver. No continued 209
GENETICS CONTINUED
Clinically significant major dysplasia& are rare, although a large number are known.
Dysplasia& are developmental abnormalities of tissues. Common minor dysplasia& are nevi, freckles, and hemangiomas. single factor would have been sufficient to cause the accident. In the analysis of most single malformations, identification of a single causal factor usually is not possible. This does not mean that single factors, such as an autosomal dominant mutation, cannot be important in causing single malformations; in fact, examples of such causation are known for most of the common single malformations,s but in the majority of patients with a single malformation this is not the case. It does mean that a constellation of the individual factors sufficient to reach the threshold again is unlikely during a future pregnancy. Thus, the empirical risk is small that parents of a child with a single malformation would have another affected child in the future. For most parents, the actual risk in this regard is apparently very small, but some parents, at least those who subsequently do have another affected child, are at a higher actual risk. The empirical risk, which for many single malformations is about 5%, is the combined average of the risk for two (or more) groups of parents. Recognition of multiple DFCs in a patient increases the chance that a single important causal factor can be identified. These single factors include single mutant genes, prenatally effective viruses, teratogens, and, as a special class, the chromosome aberrations. All constitutional chromosome aberrations give rise to multiple malformation syndromes. Chromosome aberration syn-
210
dromes--Constitutional chromosome aberrations are those that are present in the fertilized egg, including aberrations transmitted from one parent and arising de novo in egg or sperm. Less frequent is the occurrence of a multiple malformation syndrome with a mosaic chromosome aberration that occurred early during development and persisted in a sizable number of cells or tissues. Chromosome analysis of single or multiple tissues is therefore an important tool in the evaluation of multiple malformation syndromes, but this is not true of single malformations or, for that matter, of inborn errors of metabolism, dysplasias, or deformity syndromes. Many specific chromosome aberrations are associated with charactenstlc multiple malformations, namely, the particular "chromosome syndrome." This holds true even when only parts of particular chromosomes are involved, eg, the deficiency of portions of the short arm of chromosome 5 that causes the eat's cry syndrome. Abnormalities concerning the X and the Y chromosome have less severe effect than those concerning any of the autosomes. Another general rule is that addition of (normal) chromosome material is frequently less harmful than is its deletion. Some malformation syndromes, eg, the caudal regression syndrome (due to maternal diabetes mellitus), consist of multiple major DFCs with entirely normal development of most other areas. In contrast, chromosome aberrations produce multi-
pie major malformations and in addition subtle minor malformations in most if not all other areas. The categorization of manifestations as malformations is frequently of great importance for prognosis. Malformations are nonprogressive, their extent is definable, and their secondary manifestations are foreseeable in general terms. Many malformations can be functionally and cosmetically corrected surgically. The general features and the timetable of such efforts can be explained to parents soon after an affected infant is born. Dysplasias
A dysplasia is a developmental abnormality of tissue. The term describes manifestations resulting from a process rather than the process itself; there is no adequate term available to describe the process that leads to dysplasia. Dysplasias may be small (eg, nevi), extensive (the hemangiomas in K.lippel-Trenaunay syndrome), multiple (cafe au lait spots), or generalized (hypertrichosis), and they may involve tissues from one germ layer (eg, ectodermal dysplasia) or from several (nevoid basal cell carcinoma syndrome, Gardner syndrome). Minor or major dysplasias may be present at birth or may develop afterward. Every person, presumably, has several small, circumscribed dysplasias: freckles, nevi, hemangiomas, and nonvisible equivalent lesions in tissues other than skin; these are of no concern. Among continued
VOL 65/NO 1/JANUAAY 1979/POSTGAADUATE MEDICINE
Tablets
GENETICS CONTINUED
PERCOCET-5 ([ Brief Summary of Prescribing Information
Monodysplasias are confined, while polydysplasias occur at several sites. Unidysplasias involve tissue(s) from one germ layer, and multidysplasias tissue(s) from two or more.
dysplasias that are extensive, multiple, or generalized, a distinction between monodysplasias with a single site of dysplastic tissue and polydysplasias with two or more sites seems useful, as well as characterization of dysplasias according to number of tissues and germ layers involved. Unidysplasias involve tissue(s) from only one germ layer, whereas multidysplasias involve tissue(s) from two or more germ layers. The multidysplasias include the ectoendodermal, mesectodermal, mesendodermal, and mesectoendodermal dysplasias. A dysplasia is not as easy to recognize as is a malformation. Also, the distinction between malformation and dysplasia sometimes is not made clear. The examples that follow may be helpful in this regard. Achondroplasia is a unidysplasia of bone. Wherever a certain bone tissue or unknown component thereof normally occurs, the same characteristic dysplastic changes are present. These changes (limited to bone tissue unless there is secondary involvement) are systemic, generalized, symmetric, congenital, and basically nonprogressive (although striking changes occur during development and with age). Other dysplasias have different characteristics but many are systemic, generalized, and symmetric. In contrast, bilateral aplasia of the radial bone is not a dysplasia but a malformation, since the manifestation is not systemic or generalized. Not all bone dysplasias are as extensive as achondroplasia. The
212
different epiphyseal dysplasias or the metaphyseal dysplasias apparently involve only certain components of bone tissue. Similar observations have been made for dysplasias of connective tissue, vasculature, nervous tissue, and ectoderm. For instance, some ectodermal dysplasias involve only the hair, and others involve hair, teeth, nails, and skin. The skin involvement in different ectodermal dysplasias may extend to different components, to different changes of the same components, or the same changes produced in different ways. Clinically identical or nearly identical forms of epidermolysis bullosa, ectodermal dysplasia, epiphyseal dysplasia, and other conditions are found to be caused by different mutant genes and thus to have different causes. The process leading to dysplasia starts before birth in many instances. It may "arrest" or may progress slowly (sometimes) or rapidly (rarely) after birth. The course is often characteristic for a certain disorder. On the basis of the clinical manifestations, histologic characteristics, autosomal dominant inheritance, and an essentially stable course (at times marked by episodes of tissue deterioration), a large number of dysplasias can be assumed to be due to "faulty construction" of tissue by incorporation of abnormal protein or of other tissue constituents. Other groups of dysplasias may be due to "faulty maintenance" of tissues. The processes involved apcontinued
DESCRIPTION Each tablet of PERCOCET®-5 contains 5mg oxycodone hydrochloride (WARNING: May be habit forming), 325 mg acetaminophen (APAP). INDICATIONS For the relief of moderate to moderately severe pain. CONTRAINDICATIONS Hypersensitivity to oxycodone or acetaminophen. WARNINGS Drug Dependence Oxycodone can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of PERCOCET®-5, and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic-containing medications. Like other narcotic-containing medications, PERCOCET®-5 is subject to the Federal Controlled Substances Act. Usage in ambulatory patients Oxycodone may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using PERCOCEP:-5 should be cautioned accordingly. Interaction with other central nervous system depressants Patients receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCOCEP-5 may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Usage in pregnancy Safe use in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, PERCOCET®-5 should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Usage in children PERCOCET®-5 should not be administered to children. PRECAUTIONS Head injury and increased intracranial pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Acute abdominal conditions The administration of PERCOCET®-5 or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Special risk patients PERCOCET®-5 should be given with caution to certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, and prostatic hypertrophy or urethral stricture. ADVERSE REACTIONS The most frequently observed adverse reactions include light-headedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation, skin rash and pruritus. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. lt may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of narcotics. PERCOCET®-5 is given orally. The usual adult dose is one tablet every 6 hours as needed for pain. DRUG INTERACTIONS The CNS depressant effects of PERCOCET®-5 may be additive with that of other CNS depressants. See WARNINGS. 6085 BS DEA Order Form Required.
PERCOCEP is a U.S. registered trademark of Endo Inc.
fndo Inc. Manat1. Puerto R1co0070t Subsid1ary of Endo laboratOI'Ies. Inc. Subsidiary of the Du Pant Company
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Syndrome delineation 1. Malformations and dysplasias Jürgen Herrmann & John M. Opitz To cite this article: Jürgen Herrmann & John M. Opitz (1979) Syndrome delineation 1. Malformations and dysplasias, Postgraduate Medicine, 65:1, 207-214, DOI: 10.1080/00325481.1979.11715035 To link to this article: https://doi.org/10.1080/00325481.1979.11715035
Published online: 07 Jul 2016.
Submit your article to this journal
Article views: 2
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20
GENETICS A Series
Syndrome delineation 1. Malformations and dysplasias A practical classification of genetic disorders and birth defects divides them into five categories: malformations, dysplasias, inborn errors of metabolism, deformities, and variant familial developmental patterns. The first two categories are discussed here. The last three will be discussed next month in part 2.
Jiirgen Herrmann, MD John M. Opitz, MD
The pathogenetic mechanisms producing genetic disorders and birth defects are complex. Normal variations and abnormal developmental mechanisms produce a virtually endless number of different patterns of clinical manifestations. The manifestations are determined by the nature, time of action, and localization of the developmental mechanisms and by genetic constitution and environmental circumstances. When a physician becomes involved in a case of a genetic syndrome, even in a premature baby, it is late in the game; the pathogenetic mechanisms are active during embryonic and fetal development. Because of the radical change in environment from intrauterine to extrauterine life, birth is the most important milestone in the human developmental process. It is also the time when abnormalities become apparent. Often a congenital anomaly in a baby is readily recognizable as due to a particular event or cause; items in the obstetric or family history may be compelling. In other instances the manifestations may not indicate readily the full extent of the condition, its nature, its cause, or the implications.
During and in conjunction with evaluation of a genetic patient, I a phenotype analysis can lead to classification of manifestations into one or several of five broad categories: malformations, dysplasias, inborn errors of metabolism, deformities, and variant familial developmental patterns. This system of classification is based on the most impor-
One of a series of articles on genetics which began in October 1977
tant prenatal pathogenetic events that lead to and are associated with genetic disorders and birth defects. Generically, not all of these events differ from postnatal pathogenetic processes (degeneration, deterioration, chronic infection, disuse atrophy). However, the prenatal events produce manifestations that might not have been produced during later stages of development or might not
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
have been produced in the same manner. On the other hand, some of the typically prenatal pathogenetic processes may have a prominent postnatal component or a predominantly postnatal expression. In later life there is almost always a picture of intertwined prenatal and postnatal events that may be difficult to separate. In early life an analysis of phenotype with respect to pathogenesis often is possible and gives information that is helpful in the further evaluation, diagnosis, therapy, and counseling. Malformations Definitions-A malformation is a structural anomaly due to a primary defect in the differentiation of a certain part of the body, such as an organ, a rib or part of a rib, or a body wall. The term is used usually for the manifestation rather than for the pathogenetic mechanism and process. What constitutes a malformation and what does not is generally clear, but occasionally difficulties can arise in distinguishing among malformations, deformities, postnatal structural changes, and degenerative anomalies. Malformations are typically congenital, yet there are exceptions. Some malformations concern structures or organs that are not present at birth, such as the continued 207
GENETICS CONTINUED
Malformations are congenital structural defects with various genetic and nongenetic causes. The defects are localized and nonprogressive and usually unassociated with biochemical or histologic abnormalities.
teeth. Not all congenital structural anomalies are malformations; the largest number of congenital structural anomalies that are not malformations are the deformities. In an adult it can be difficult to distinguish true primary malformations from structural changes secondary to long-standing deformation or to chronic degeneration with disuse atrophy, contractures, osteoporosis, hypoperfusion, ulceration, or infection. Malformations can be due to any of a number of different causes: dominant and recessive autosomal mutations, X-linked mutations, chromosome aberrations, teratogens and prenatal infections, maternal illness during pregnancy, maternal exposure during pregnancy to fumes, chemicals, or radiation, and unknown or unidentified factors. Many malformations are known (eg, cleft palate) which are due in some cases to an autosomal dominant mutation, in others to an autosomal recessive or X-linked mutation, and in still others to maternal exposure to teratogens during pregnancy or unidentified factors. Thus, a malformation per se is, as a rule, etiologically nonspecific, but in conjunction with other data, other malformations, the clinical findings, and the historical information may suggest a specific diagnosis and a specific cause. Whether a patient has a single malformation or multiple malformations is therefore highly relevant, and it is in this context that the concept of the developmental field becomes important.
208
Developmental
field
complex
(DFC)-A developmental field is
that "part of an embryo which reacts as a temporally and spatially coordinated unit to normal, localized forces of organization and differentiation, and to surgical manipulations, gene and chromosome mutations and the effect of certain teratogens."2 The extent of a malformation must be viewed in the context of known developmentalgenetic, embryologic, teratologic, and clinical principles. A complex of developmentally closely related anomalies is a developmental field complex. Recognition of DFCs serves to distinguish individual manifestations and thus to separate patients Jiirgen Hernnann Dr Herrmann is associate professor of pediatrics and medical genetics. University of Wisconsin Center for Health Sciences and Medical School, Madison.
with single and multiple malformations. A developmental field defect is the force that exerts the temporally and spatially coordinated changes in the field, and the D FC is the group of localized primary disturbances that result. All primary abnormalities within the field therefore represent the DFC and, hence, a single malformation. For example, ocular hypotelorism, midline cleft lip and cleft palate, hypoplasia of the nose with a single nostril, bilateral coloboma iridis, and alobar holoprosencephaly all constitute components of a single malformation, the holoprosenceph-
aly DFC. Primary malformations are always DFCs. An example might illustrate the etiologic nonspecificity of individual DFCs. We have observed the occurrence of the holoprosencephaly DFC with autosomal dominant transmission and variable expressivity. The propositus was lethally affected, his mother had a unilateral cleft lip and cleft palate, and the mother's brother had a single, midline upper central incisor as the sole manifestation of the trait. In other families the holoprosencephaly DFC can be seen to be an autosomal recessive trait. Furthermore, it can be observed as a component of certain syndromes, such as trisomy 13 syndrome. Most individual DFCs can occur in high-risk as well as in low-risk situations. Further examples come to mind readily: the cleft lip and palate DFC, the cloverleaf (Kleeblattschiidel) DFC, the various polydactyly DFCs, and many others. The majority of persons with a birth defect have a single malformation: cleft lip and palate, congenital heart defect, spina bifida with meningomyelocele, hypospadias, and so on. For each of these malformations, the DFC can be more or less extensive. At times a convenient characterization by degree is possible (eg, for hypospadias), but usually a description of the anatomic and physiologic manifestations is necessary. A cascade of morphologic and functional manifestations secondary
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
The cause of single malformations is frequently unrecognized. The cause of malformation syndrome can be established In many cases. All constitutional chromosome aberration syndromes are malfor· mation syndromes, but the reverse is not true.
to lumbar meningomyelocele, such as clubfoot, urinary bladder paralysis, hydrocephalus, and chronic kidney infection, does not mean that the patient does not have a single malformation. All malformations have secondary effects, be these morphologic, functional, psychologic, or a combination. The term "anomalad" has been suggested to describe a DFC plus the secondary morphologic manifestations.3 This is liable to create the impression that some birth defects are malformations and others are anomalads. We think that the term "anomalad" is superfluous, since naming the primary malformation and distinguishing it from secondary morphologic changes are sufficient and more accurate. All the secondary changes are, of course, etiologically nonspecific, as are individual primary malformations. Recognition of one single malformation leads to a search for others. Particularly important in this regard is examination of developmentally complex structures such as eyes, face, auricles, hands, feet, and genitalia. This examination is combined with evaluation of internal organs that are particularly important biologically, such as kidneys, heart, and brain. All patients with a single malformation need a careful, complete physical examination, and in each instance the physician should consider also obtaining an ECG, chest x-ray films, brain scan, and intravenous pyelogram (IVP). Whether the latter tests are needed depends on the nature of the
presenting primary malformation. A defect in the form of a single umbilical artery should prompt the physician to obtain an IVP, since major genitourinary tract malformations are associated (or are component manifestations in the same developmental field) in a high proportion of cases. Absence of thumbs or aplasia of radial bone should prompt a detailed cardiac evaluation to rule out the presence of HoltOram syndrome. Demonstration of two primary malformations in a patient, ie, demonstration of involvement of two developmental fields, should prompt more aggressive evaluation of other organs when there is even a slight indication that these may be abnormal. For instance, all patients with a documented vertebral segmentation defect and (even mild) aplasia of radial bone should be evaluated with respect to congenital heart defects, tracheoesophageal fistulas, and renal malformations. Similarly, persons with microphthalmia and dermatoglyphic or any other abnormality should have a thorough evaluation with respect to CNS syndromes. The DFCs in many malformation syndromes would seem unique and almost coincidental from a developmental standpoint were it not for consistency of occurrence in particular syndromes. The occurrence of the thumb/toe abnormalities (developmental field 1) and the characteristic facial appearance (field 2) in the Rubinstein-Taybi syndrome is such an example. However, the associa-
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
tion of the same two D FCs can be observed in different conditions. This indicates that such an association is etiologically nonspecific and suggests that in some instances the two separate DFCs may in fact represent a dis-located single malformation. The term "polytopic John M. Opitz
Dr Opitz is professor of medical genetics and pediatrics, University of Wisconsin Center for Health Sciences and Medical School, and director, Wisconsin Clinical Genetics Center.
anomaly" has been used to describe this phenomenon. 4 The best example is the association of acral (hand, foot) and renal malformations, the acrorenal "syndrome," which occurs in some 20 different conditions. In some cases a condition may be recognized as representing a malformation syndrome on the basis of one major plus one or two minor malformations. For example, absence of a kidney plus a highly abnormal dermatoglyphic pattern (in itself harmless) would identify a malformation syndrome (or a polytopic single malformation). Recurrence risks-In the majority of patients with a birth defect, the malformation apparently is caused by a number of different factors acting in concert; the cause is multifactorial, involving environmental as well as genetic factors, most of them unidentified. An analogy is the occurrence of a car accident due to the combination of a slippery road, twilight, heavy traffic, worn brakes, and a sleepy driver. No continued 209
GENETICS CONTINUED
Clinically significant major dysplasia& are rare, although a large number are known.
Dysplasia& are developmental abnormalities of tissues. Common minor dysplasia& are nevi, freckles, and hemangiomas. single factor would have been sufficient to cause the accident. In the analysis of most single malformations, identification of a single causal factor usually is not possible. This does not mean that single factors, such as an autosomal dominant mutation, cannot be important in causing single malformations; in fact, examples of such causation are known for most of the common single malformations,s but in the majority of patients with a single malformation this is not the case. It does mean that a constellation of the individual factors sufficient to reach the threshold again is unlikely during a future pregnancy. Thus, the empirical risk is small that parents of a child with a single malformation would have another affected child in the future. For most parents, the actual risk in this regard is apparently very small, but some parents, at least those who subsequently do have another affected child, are at a higher actual risk. The empirical risk, which for many single malformations is about 5%, is the combined average of the risk for two (or more) groups of parents. Recognition of multiple DFCs in a patient increases the chance that a single important causal factor can be identified. These single factors include single mutant genes, prenatally effective viruses, teratogens, and, as a special class, the chromosome aberrations. All constitutional chromosome aberrations give rise to multiple malformation syndromes. Chromosome aberration syn-
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dromes--Constitutional chromosome aberrations are those that are present in the fertilized egg, including aberrations transmitted from one parent and arising de novo in egg or sperm. Less frequent is the occurrence of a multiple malformation syndrome with a mosaic chromosome aberration that occurred early during development and persisted in a sizable number of cells or tissues. Chromosome analysis of single or multiple tissues is therefore an important tool in the evaluation of multiple malformation syndromes, but this is not true of single malformations or, for that matter, of inborn errors of metabolism, dysplasias, or deformity syndromes. Many specific chromosome aberrations are associated with charactenstlc multiple malformations, namely, the particular "chromosome syndrome." This holds true even when only parts of particular chromosomes are involved, eg, the deficiency of portions of the short arm of chromosome 5 that causes the eat's cry syndrome. Abnormalities concerning the X and the Y chromosome have less severe effect than those concerning any of the autosomes. Another general rule is that addition of (normal) chromosome material is frequently less harmful than is its deletion. Some malformation syndromes, eg, the caudal regression syndrome (due to maternal diabetes mellitus), consist of multiple major DFCs with entirely normal development of most other areas. In contrast, chromosome aberrations produce multi-
pie major malformations and in addition subtle minor malformations in most if not all other areas. The categorization of manifestations as malformations is frequently of great importance for prognosis. Malformations are nonprogressive, their extent is definable, and their secondary manifestations are foreseeable in general terms. Many malformations can be functionally and cosmetically corrected surgically. The general features and the timetable of such efforts can be explained to parents soon after an affected infant is born. Dysplasias
A dysplasia is a developmental abnormality of tissue. The term describes manifestations resulting from a process rather than the process itself; there is no adequate term available to describe the process that leads to dysplasia. Dysplasias may be small (eg, nevi), extensive (the hemangiomas in K.lippel-Trenaunay syndrome), multiple (cafe au lait spots), or generalized (hypertrichosis), and they may involve tissues from one germ layer (eg, ectodermal dysplasia) or from several (nevoid basal cell carcinoma syndrome, Gardner syndrome). Minor or major dysplasias may be present at birth or may develop afterward. Every person, presumably, has several small, circumscribed dysplasias: freckles, nevi, hemangiomas, and nonvisible equivalent lesions in tissues other than skin; these are of no concern. Among continued
VOL 65/NO 1/JANUAAY 1979/POSTGAADUATE MEDICINE
Tablets
GENETICS CONTINUED
PERCOCET-5 ([ Brief Summary of Prescribing Information
Monodysplasias are confined, while polydysplasias occur at several sites. Unidysplasias involve tissue(s) from one germ layer, and multidysplasias tissue(s) from two or more.
dysplasias that are extensive, multiple, or generalized, a distinction between monodysplasias with a single site of dysplastic tissue and polydysplasias with two or more sites seems useful, as well as characterization of dysplasias according to number of tissues and germ layers involved. Unidysplasias involve tissue(s) from only one germ layer, whereas multidysplasias involve tissue(s) from two or more germ layers. The multidysplasias include the ectoendodermal, mesectodermal, mesendodermal, and mesectoendodermal dysplasias. A dysplasia is not as easy to recognize as is a malformation. Also, the distinction between malformation and dysplasia sometimes is not made clear. The examples that follow may be helpful in this regard. Achondroplasia is a unidysplasia of bone. Wherever a certain bone tissue or unknown component thereof normally occurs, the same characteristic dysplastic changes are present. These changes (limited to bone tissue unless there is secondary involvement) are systemic, generalized, symmetric, congenital, and basically nonprogressive (although striking changes occur during development and with age). Other dysplasias have different characteristics but many are systemic, generalized, and symmetric. In contrast, bilateral aplasia of the radial bone is not a dysplasia but a malformation, since the manifestation is not systemic or generalized. Not all bone dysplasias are as extensive as achondroplasia. The
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different epiphyseal dysplasias or the metaphyseal dysplasias apparently involve only certain components of bone tissue. Similar observations have been made for dysplasias of connective tissue, vasculature, nervous tissue, and ectoderm. For instance, some ectodermal dysplasias involve only the hair, and others involve hair, teeth, nails, and skin. The skin involvement in different ectodermal dysplasias may extend to different components, to different changes of the same components, or the same changes produced in different ways. Clinically identical or nearly identical forms of epidermolysis bullosa, ectodermal dysplasia, epiphyseal dysplasia, and other conditions are found to be caused by different mutant genes and thus to have different causes. The process leading to dysplasia starts before birth in many instances. It may "arrest" or may progress slowly (sometimes) or rapidly (rarely) after birth. The course is often characteristic for a certain disorder. On the basis of the clinical manifestations, histologic characteristics, autosomal dominant inheritance, and an essentially stable course (at times marked by episodes of tissue deterioration), a large number of dysplasias can be assumed to be due to "faulty construction" of tissue by incorporation of abnormal protein or of other tissue constituents. Other groups of dysplasias may be due to "faulty maintenance" of tissues. The processes involved apcontinued
DESCRIPTION Each tablet of PERCOCET®-5 contains 5mg oxycodone hydrochloride (WARNING: May be habit forming), 325 mg acetaminophen (APAP). INDICATIONS For the relief of moderate to moderately severe pain. CONTRAINDICATIONS Hypersensitivity to oxycodone or acetaminophen. WARNINGS Drug Dependence Oxycodone can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of PERCOCET®-5, and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic-containing medications. Like other narcotic-containing medications, PERCOCET®-5 is subject to the Federal Controlled Substances Act. Usage in ambulatory patients Oxycodone may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using PERCOCEP:-5 should be cautioned accordingly. Interaction with other central nervous system depressants Patients receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCOCEP-5 may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Usage in pregnancy Safe use in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, PERCOCET®-5 should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Usage in children PERCOCET®-5 should not be administered to children. PRECAUTIONS Head injury and increased intracranial pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Acute abdominal conditions The administration of PERCOCET®-5 or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Special risk patients PERCOCET®-5 should be given with caution to certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, and prostatic hypertrophy or urethral stricture. ADVERSE REACTIONS The most frequently observed adverse reactions include light-headedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation, skin rash and pruritus. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. lt may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of narcotics. PERCOCET®-5 is given orally. The usual adult dose is one tablet every 6 hours as needed for pain. DRUG INTERACTIONS The CNS depressant effects of PERCOCET®-5 may be additive with that of other CNS depressants. See WARNINGS. 6085 BS DEA Order Form Required.
PERCOCEP is a U.S. registered trademark of Endo Inc.
fndo Inc. Manat1. Puerto R1co0070t Subsid1ary of Endo laboratOI'Ies. Inc. Subsidiary of the Du Pant Company
