Symposium on Medical Genetics

Hereditary Considerations in Common Disorders Carol E. Anderson, M.D.,* Jerome 1. Rotter, M.D.,t and Jonathan Zonana, M.D.:f.

Tremendous advances have been made in the diagnosis, treatment, and prevention of human genetic disease. As described elsewhere in this symposium, the greatest advances have been in the delineation of single gene disorders, biochemical defects, and cytogenetic abnormalities. The frequency ofthese disorders, however, is still much less than that ofthe common malformations and chronic diseases the pediatrician most often encounters. Progress being made in the delineation of the genetic basis of these common disorders will have significant implications, not only for genetic counseling, but ultimately for prevention and therapy. It is important, therefore, to describe the current approaches by which the genetic factors in common disorders are being delineated, and the implications of these studies for the counseling ofpatients and families with these disorders. Familial aggregation is observed in many common disorders; that is, these disorders occur more frequently in some families than in the rest of the population. It is therefore inferred that someone with a relative affected by one ofthese disorders is more likely to be affected than if that person had no affected relatives. Examples include many of the common malformations, such as neural tube defects, cardiac anomalies, cleft lip with or without cleft palate, club foot, congenitally dislocated hip, and pyloric stenosis. They also include many chronic diseases of childhood and later life, such as the atopic disorders, diabetes mellitus, peptic ulcer, the hyperlipidemias, and schizophrenia. However, the exact genetic and environmental contribution to these disorders remain unknown, since both genetic and/or environmental etiologies could be expected to affect multiple family members.

'Fellow, Division of Medical Genetics, UCLA School of Medicine, Harbor General Hospital, Torrance, California tFeliow, Division of Medical Genetics, UCLA School of Medicine, Harbor General Hospital, Torrance, California tAssistant Professor of Pediatrics, Departments of Pediatrics and Emergency Medicine, UCLA School of Medicine, Harbor General Hospital, Torrance, California Supported in part by U. S. Public Health Service Grant AM 17328. Dr. Rotter is the recipient of NIAMDD Postdoctoral Research Fellowship Award AM 050602.

Pediatric Clinics of North America-Vol. 25, No.3, August 1978

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The difficulties in understanding the genetics of common disorders include separating the effects of environment from genetics, understanding their heterogeneity, and ignorance of the basic defect(s) involved. It is not possible to discuss all of the common disorders,3. 6, 39 so two examples, a common malformation, cleft lip, with or without palate, and a common chronic disease, diabetes mellitus, are presented. We will describe how the geneticist attempts to unravel the genetic and environmental contributions to these disorders. After considering the difficulties in assessing the genetics of these disorders and briefly reviewing what is known about them, we will discuss an approach to counseling. The interested reader is referred to other review articles for more comprehensive discussion of the genetics of these disorders. 11, 18, 52,56,68 Nature Versus Nurture The etiology of a given trait was originally conceived as being determined by either genetic (nature) or environmental (nurture) factors (Fig. 1). The prototype of a genetic disorder was a simple inborn error of metabolism such as phenylketonuria, while that of an environmental disorder was an infectious disease such as pneumococcal pneumonia or malaria. However, it became clear that the complete separation of etiology into either genetic or environmental was too arbitrary. Even in the disorders just mentioned, there was overlap between the effects of heredity and environment. The mental retardation of phenylketonuria can be prevented by restricting phenylalanine in the diet. Alternatively, with different genetic backgrounds, susceptibility to the infectious diseases mentioned vary: individuals with sickle cell anemia are more susceptible to pneumococcal pneumonia and more resistant to malaria. Thus, environment can influence the expression of what appears to be primarily a genetic disorder, and the genetic background influences the susceptibility to environmentally caused disease. While some disorders can be modified by environmental or genetic influences, others are apparent only when the proper combination of genetic and environmental factors occurs. One example is glucose-6phosphate dehydrogenase deficiency, where the enzyme deficiency predisposes to hemolysis of red blood cells only upon exposure to environmental agents such as fava beans or antimalarial drugs.

Figure 1.

Genetic or environmental factors determine the etiology of a given trait.

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There is increasing appreciation of the interaction between environment and genetics in many disorders, particularly in the common disorders under consideration. The goal of genetic studies of disorders such as diabetes or cleft lip with or without cleft palate is to identify those individuals who because of their genetic predisposition have a greater likelihood of developing the disorder. At the same time, there is an attempt to identify what environmental factors interact with a given genetic predisposition to produce clinical disease. "Indeed, it is very probable that one of the most important social and medical applications of genetic research will lie in the control of the environment, since the more it becomes possible to characterize the genetic constitution of someone precisely, the more likely are we to learn how to modify the environment according to his or her needs."27

Difficulties in Genetic Analysis Twin studies represent one approach to resolving the question of the influence of genetics and environment. The frequency of concordance (both members of the twin pair affected) of monozygotic (identical) twins is compared with that of dizygotic (fraternal) twins. Monozygotic twins share all genes, and thus theoretically should be concordant for disorders with pure genetic etiology. Dizygotic twins share only half their genes and are no more alike genetically than any pair of siblings. If the characteristic being studied is genetically determined with no environmental influence, then one expects 100 per cent concordance in monozygotic twins, and less in dizygotic twins. If the disorder is entirely environmental, one should see equal concordance between monozygotic and dizygotic twins. If there is an interaction between a genetic predisposition and an environmental agent necessary for clinical expression, one would expect to see a higher concordance among monozygotic than dizygotic twins, but not 100 per cent. In diabetes and cleft lip, the rate of concordance of monozygotic twins is greater than that of dizygotic twins, butitis not 100 per cent. In cleft lip with or without cleft palate the overall reported concordance (combining 20 twin studies and case reports) is approximately 35 per cent for monozygous twins and 6.2 per cent for dizygous twins. 56 In diabetes, a 45 to 96 per cent concordance of clinical diabetes or glucose intolerance has been reported in monozygotic twins, in contrast to a 3 to 37 per cent concordance for dizygotic twinS. 33, 47 These studies indicate the presence of both genetic and environmental factors in these disorders. Once genetic factors have been determined to be important, the specific patterns of inheritance must be defined. However, major difficulties are encountered in the study of the common disorders. First, in disorders such as diabetes and schizophrenia, investigators cannot agree on a definition of what constitutes "affected." For example, in diabetes definitions range from an abnormal cortisone-primed glucose tolerance test to an individual with ketosis and vascular complications. For chronic diseases with late and variable age of onset, it is impossible at any single point in time to declare an individual unaffected. Longitudinal studies are required even to detect affected family members with clinical disease. If reliable subclinical markers for the detection of susceptible individuals were available, this problem would be partly overcome. Any test

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(biochemical, physiologic, or immunologic) which is related in some way to the underlying genotype, and thus helps to identify susceptible individuals, can serve as such a subclinical marker. All of the above difficulties are secondary to the central problem which is our ignorance concerning the basic defect(s) in each disorder. If we could identify the responsible gene products, we would have definite subclinical markers to identify members of the pedigree which are susceptible. In a disorder such as sickle cell anemia, we know that a change in the DNA base sequence at the gene level results in an altered gene product. The change in amino acid sequence in the hemoglobin molecule predictably affects its structure and function under hypoxic conditions. The abnormal gene product, hemoglobin S, can be identified in heterozygotes to whom exact genetic risks can be given. In the common disorders under consideration, no such understanding or biochemical marker exists. For example, we do not know what genes or gene products are involved in the complex embryologic processes leading to formation of cleft lip and palate between the 4th and 12th weeks of gestation. Most ofwhat is known is based on morphologic observations, often in animals: the primary palate is formed by penetration and obliteration of ectodermal grooves by three mesodermal masses between weeks 4 and 8; the secondary palate forms as bilateral palatine processes which fuse between 8 and 12 weeks. The biochemical basis for cellular adhesion and migration, programmed cell death, and epithelial-mesenchymal interactions is not understood, but it is likely that many pathways and metabolic intermediates are involved. 24 The concept of genetic heterogeneity has significantly altered the genetic analysis of these common disorders. Genetic heterogeneity simply means that what first appears to be one disease turns out to be many diseases, with different genetic and nongenetic etiologies. Therefore, differing genotypes and/or environmental causes may produce a single or similar phenotypes. For example, anemia and jaundice were each considered to be one disease. Today it is clear that anemia has many different causes. Hemolytic anemia can be due to pyruvate kinase deficiency, an autosomal recessively inherited enzyme deficiency, hereditary spherocytosis, with autosomal dominant transmission, or a drug. Similarly, many common disorders may really be composed of several different disorders, with distinct causes. Separating distinct genetic and nongenetic causes may reveal significant differences in the basic pathogenesis, natural history, and treatment which may have been previously blurred. This concept of heterogeneity will be further illustrated. Multifactorial Model and Empirical Risk In diabetes mellitus and cleft lip/palate the observed family data apparently does not fit any simple mendelian pattern of inheritance. For this reason, more complex models have been proposed to explain the familial aggregation. The most common model is that of "polygenic" or "multifactorial" inheritance,3, 4 which suggests that the hereditary component of a given disorder is due to many genes acting together, with or without environmental factors, to produce the disorder. The hereditary

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Figure 2. A sufficient number of genes, perhaps in combination with environmental factors, cause a disorder when the threshold level is exceeded.

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component of a disease is conceptualized as being due to the contribution of many genes (i.e., polygenic), which together result in a continuum of genetic predisposition. Thus, clinical disease would exist when the presence of a sufficient number of genes, perhaps in combination with environmental factors (i.e., multifactorial), exceeds a threshhold level (Fig. 2). The relatives of the index patient share genes in common in direct proportion to the closeness of their relationship. The multifactorial model thus predicts that the relatives will share some of the disease-predisposing genes and hence will be shifted toward the threshhold for disease. The fall-offin frequency from first to second to third-degree relatives should be greater than that predicted on the basis of mendelian inheritance. The multifactorial model also predicts a risk of recurrence that depends upon the sex ratio of the disorder seen in the population; that is, the risk to relatives of the least often affected sex will be greater than the risk to relatives of the most often affected sex. In contrast to simple mendelian inheritance, the risk to subsequent offspring should increase with the number of affected relatives. Also, the risk to subsequent offspring should increase with the severity of the defect in the proband. Historically, this hypothesis is very important because it suggested that diseases did not have to satisfy simple mendelian models to be genetic. Also, this multifactorial hypothesis predicts risk figures for certain disorders that are close to those actually observed in population studies. However, alternative models have been proposed to explain the observed data. 30 . 40 At this time in man, these models are hypotheses that are not yet rooted in known biological mechanisms. One danger of such models is that they may be applied to situations where there are insufficient data to know whether the disorder satisfies the prerequisites of the model. Therefore, many disorders that do not show monogenic patterns of inheritance have been labeled "multifactorial," without demonstration that they satisfy all of the criteria for use' of that model. Regardless of the applicability of models, there exist for some of the common disorders data concerning the recurrence of the disorders in families. The risks derived from these observations are termed "empirical

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recurrence risks," and may be applied to counseling situations. 7 However, studies upon which these risks are based should take into account the heterogeneity of the condition. Genetics of Cleft Lip with or without Cleft Palate As summarized above, a problem in the development of the primary palate resulting in cleft lip, may interfere with later development of the secondary palate. Thus, cleft lip and palate may be associated, whereas a problem in the development of the palate may not interfere with the previously formed primary palate. Thus, teratogens given to mice during secondary palate formation cause isolated cleft palate. In addition to this embryologic distinction between cleft lip with or without cleft palate, there is epidemiologic distinction between the twO. IB , 56 Family studies by Fogh-Andersen showed that siblings of patients with cleft lip had increased frequency of cleft lip and cleft palate, but no increased frequency of cleft palate alone. 17 Siblings of patients with cleft palate had increased frequency of cleft palate, but not cleft left and cleft palate. The sex ratio for cleft lip and cleft palate was different from that for cleft palate. For cleft lip and cleft palate, more males are born with the defect than females; the reverse is true for cleft lip. Finally, the racial variation for cleft lip and cleft palate is much more marked than for cleft palate. 34 For cleft lip and cleft palate, the incidence is greatest in the mongoloid populations; their rate is greater than the incidence in the Caucasian populations, which is in turn greater than for the Negroid populations. In contrast, the racial differences for cleft palate are not significant. There is evidence for etiologic heterogeneity in both cleft lip with or without cleft palate and cleft palate. Although environmental influences are difficult to study in humans, there are some prototypes. Rubella in the first 8 weeks of gestation is associated with clefting, whereas some of the other congenital infections apparently are not. 56 Cleft lip with or without cleft palate is part ofthe "fetal hydantoin syndrome" related to the use of diphenylhydantoin, its analogues, and other anticonvulsants in epileptic mothers.26 The teratogenic effect of drugs in human beings is difficult to study, given the problems with retrospective design, the difficulty in finding suitable controls, and the need for large numbers. Thus, studies of new drug associations must be interpreted with caution. For example, although the association between diazepam and cleft lip with or without cleft palate has been reported by two independent groups, 53, 55 an etiologic role for diazepam has not been proven. Chromosome abnormalities, notably trisomy D and also less frequently trisomy E, may cause multiple malformations including cleft lip with or without cleft palate. There are multiple deletions and translocations where individual case reports included clefting. Single gene defects may give rise to mendelian patterns of inheritance, either of isolated cleft lip with or without cleft palate or in multiple malformations associated with cleft lip with or without cleft palate. An example is the x-linked submucous cleft described in the British Columbia_Indians. 3 :; Another is Van der Woude's syndrome where lip pits associated with cleft lip with or without cleft palate occur with autosomal dominant inheritance. 66

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Associated abnormalities may suggest a syndrome with monogenic inheritance. For example, the ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) includes lobster claw deformities of the hands and feet, sparse blond hair, and cleft lip with or without cleft palate. 43 This syndrome has been described as autosomal dominant with reduced penetrance; but some pedigrees may be consistent with autosomal recessive inheritance. Isolated cleft palate is a part of more syndromes than cleft lip with or without cleft palate, as shown in Table 1. Examples include the Stickler, Treacher Collins, and Apert's syndrome, all with autosomal dominant inheritance. 9 Pierre Robin anomalad is associated with a distinct set of syndromes, for example, the syndrome of persistent left superior vena cava, atrial septal defect, and talipes equinovarus, which is inherited by X-linked recessive inheritance. 22 The number of syndrome-related cases may be relatively small: less than 3 per cent of all cases of cleft lip with or without cleft palate were suggested in one report and 8 per cent of all cases of cleft palate in a reanalysis of Fogh-Anderson's Danish data. 41 The overwhelming majority of cases are not associated with syndromes. A portion of these may demonstrate vertical transmission from generation to generation: 26.3 per cent of cases of cleft lip with or without cleft palate and 13 percent of cases of cleft palate in the Danish data. The largest portion occur without any previous family history. These cases present a challenge to try to separate genetic from environmental stimuli, to define their interaction, and to predict recurrence. It may not be possible in the individual case to define an exact etiology. The question is whether or not other population studies have recognized the etiologic heterogeneity that is certainly present, with a variety of environmental and genetic factors. Carter interpreted the data from Fogh-Andersen's study on cleft lip and palate in Denmark as being consistent with what might be expected according to the multifactorial model. 3 Of first-degree relatives, the siblings of index cases, 4.9 per cent also had cleft lip with or without cleft palate. This is approximately 40 times the incidence in the general population, roughly 1 in 1000. Of the second-degree relatives (aunts and uncles), 0.8 per cent were affected. This rate is approximately 7 times that of the general population. Of third degree relatives (first cousins), 0.3 per cent were affected. This rate is approximately 3 times that of the general population. In contrast to the situation with only one member affected in the family, Carter suggested that when two affected children were born to normal parents, the risk of recurrence increased to about 14 per cent. The risk would be the same when an affected parent has one affected child. Recent review of the Danish data, with a view to defining heterogeneity, showed that some of the predictions of the multifactorial model were not true for cleft lip with or without cleft palate. 40 For example, the risk to first-degree and second-degree relatives was independent of the sex of the proband. This does not invalidate use of the data as empirical risk data; . but it does raise questions about the use of the multifactorial model as a theoretical framework for the investigation of such malformations. It would be helpful in the analysis of family studies to have a measurement indicating degrees of susceptibility. Although there are no sub. clinical markers for cleft lip and cleft palate in human beings, one animal

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Table 1. Syndromes Associated with Clefting':' CLEFT LIP WITH OR WITHOUT CLEFT PALATE

Monogenic syndromes Appelt syndrome Bixler syndrome Bowen-Armstrong syndrome Clefting/ankyloblepharon syndrome Clefting/enlarged parietal foramina syndrome Cryptophthalmos syndrome Ectrodactyly-ectodennal dysplasia-defting syndrome Freire-Maia syndrome Fetal face syndrome Gorlin syndrome Hemifacial microsomia (Goldenhar syndrome) Environmentally induced syndromes Amniotic band syndrome Fetal hydantoin syndrome Fetal trimethadione syndrome Unknown genesis syndromes Clefting/ectropion syndrome Hernnann syndrome II

Hypertelorism-hypospadias syndrome Juberg-Hayward syndrome Meckel syndrome Oculodentoosseous dysplasia Popliteal pterygium syndrome Pseudothalidomide syndrome Rapp-Hodgkin syndrome W syndrome van der Woude syndrome Waardenberg syndrome

Pilotto syndrome Wildervanck-Smith syndrome

CLEFT PALATE ALONE

Monogenic syndromes Aase-Smith syndrome Apert syndrome Braun-Bayer syndrome Campomelic syndrome Cerebrocosto-mandibular syndrome de la Chapelle syndrome Chondrodysplasia punctata (rhizomelic type) Christian syndrome I Cleft palate/brachial plexus neuritis syndrome Cleft palate/connective tissue dysplasia syndrome Cleft palate/lateral synechiae syndrome Cleft palate/stapes fixation syndrome Cleidocranial dysplasia Diastrophic dwarfism Dubowitz syndrome Ectrodactyly-deft palate syndrome Fontaine syndrome Gareis-Smith syndrome Gordon syndrome Katcher-Hall syndrome

Environmentally induced syndromes Aminopterin syndrome Fetal alcohol syndrome

Larsen syndrome Lowry-Miller syndrome Marden-Walker syndrome Marfan syndrome Megepiphyseal dwarfism Micrognathic dwarfism Multiple pterygia syndrome Nance-Sweeney chondrodysplasia Nager acrofacial dysostosis Orofaciodigital syndrome I Orofaciodigital syndrome II Otopalatodigital syndrome Palant syndrome Persistent left superior vena cava syndrome Phillips-Griffiths syndrome Pseudodiastrophic dwarfism Rudiger syndrome Saethre-Chotzen syndrome Say syndrome Smith-Lemli-Opitz syndrome Spondyloepiphyseal dysplasia congenita Stickler syndrome Treacher Collins syndrome Wildervanck syndrome

Thalidomide syndrome

*Modifiedfrom Cohen, M. M., Jr., in Stewart, R. E., and Prescott, G. H., eds.: Oral Facial Genetics. St. Louis, C. V. Mosby Co., 1976, p. 100.

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Table 1. Syndromes Associated with Clefting (Continued) Unknown genesis syndromes Beckwith-Wiedemann syndrome Charlie M. syndrome Cleft palate/acanthosis nigricans syndrome Coffin-Siris syndrome Femoral hypoplasia-unusual facies syndrome Glossopalatine ankylosis syndrome

Ho syndrome Klippel-Fell syndrome Kniest syndrome de Lange syndrome Walden syndrome

CHROMOSOMAL SYNDROMES ASSOCIATED WITH CLEFTING

1q+, 3p+, (3p-, q+), 4p+, 4p-, 4q+, 5p+, 5p-, 7p-, 7q+, 8+, 9+, 9p+, lOp+, 10q+, IIp+, llq+, 13+, 13q+P, 13q+d, 13q-, 14q+, 18+, 18p-, 18q-, 21+, 21q-, 22+, 22q+, 22q-, XO, XXXXY, Triploidy

model in inbred strains of mice is the cortisol induction of cleft palate. Correlation was reported between H-2 genotype (analogous to HLA in man) and the level of cortisol receptors in cytoplasm of developing palatal tissues.21 This does not fully explain how the cortisol might affect tissue developmen t during the critical period of palate formation; and, of course, cortisone is not known to be teratogenic in human beings. But this sort of approach in animals, utilizing biochemical markers, may provide clues to understanding the interaction between environmental factors and genetically programmed organogenesis, revealing underlying defect(s). Perhaps in the future subclinical markers may be available for use in human beings. Genetics of Diabetes Mellitus The concept central to understanding the genetics of diabetes today is genetic heterogeneityY' 45, 52, 68 It is now apparent that diabetes and glucose intolerance are not diagnostic terms but, like anemia, are simply symptom complexes or laboratory abnormalities respectively, which can result from a number of distinct causes. Diabetes presently can be divided into several different entities-diabetes associated with genetic syndromes, juvenile-onset diabetes, maturity-onset diabetes, and maturityonset diabetes of the young. And, as will be discussed, there is preliminary evidence that these entities can be even further subdivided. Although twin studies indicated a significant genetic component in diabetes, there has been little agreement as to the specific nature of the genetic factors involved. All possible modes of inheritance have been proposed. Nevertheless, an autosomal recessive hypothesis was prevalent for many years as an explanation for the genetics of diabetes. This implied that if two affected individuals marry, all of their children would be affected, and all monozygotic twins would be concordant. Although there is an increased risk of diabetes in these two groups, it does not begin to approach the 100 per cent predicted with simple autosomal recessive inheritance. For example, in most of the published studies, less than 50 per cent of the offspring of conjugal diabetics (diabetic parents) have

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abnonnal glucose tolerance and less than 10 per cent of them have clinical diabetes. 64 Thus, simple monogenic patterns of inheritance do not fit the observed family data. Gradually, the methodologic problem was appreciated to be a lumping of heterogeneous disorders together. The evidence for heterogeneity in diabetes is based on numerous lines of evidence. Indirect evidence originally consisted of the recognition that there are over 30 distinct disorders associated with glucose intolerance, as shown in Table 2, and in some cases clinical diabetes. 48,49 Although individually rare, these syndromes demonstrate that mutations at different loci can produce glucose intolerance. Furthermore, they illustrate the wide variety of pathogenetic mechanisms which can result in glucose in tolerance, ranging from absolute insulin deficiency to inhibition ofinsulin secretion and insulin resistance. These rare syndromes suggest that similar heterogeneity, both genetically and pathogenetic ally, may exist in idiopathic diabetes mellitus. Their existence stresses the need to include, in approaches to the genetics of any common disorder, the search for other associated abnonnalities that may suggest an inherited syndrome. Distinction between juvenile and maturity-onset diabetes has been considered for years because of the clear clinical and physiological differences between the thin, ketosis-prone, insulin-dependent juvenile-onset diabetic and the obese, nonketotic, insulin-independent maturity-onset diabetic. The insulinopenia of juvenile onset diabetics in contrast to the hyperinsulinemia of maturity onset diabetics parallels the therapeutic observation of the absolute insulin requirement of the ju venile (insulindependent) as compared to the ability to manage most adult onset cases with oral hypoglycemics and/or diet (insulin-independent). A number of family studies supported the concept that juvenile and adult onset diabetics appear to be separate disorders genetically; 52, 59 that is, they breed true within families. Recently monozygotic twin studies by Pyke et al. have provided further strong evidence for the separation of juvenile and maturity-onset diabetes. 44 ,63 Among the twin pairs with maturity-onset type of insulin independent diabetes, concordance approached 100 per cent, whereas in those twin pairs with insulin dependent juvenile onset diabetes, concordance was only about 50 per cent. This would suggest that there is a large group of individuals with genetic predisposition for juvenile onset diabetes, but for whom nongenetic factors are important. Further advances have come from the development of subclinical markers. The discovery of antibodies to the islet cells of the pancreas provided evidence supporting an autoimmune pathogenesis for at least some fonns of diabetes. 28 , 29 Islet cell antibody studies supported the differentiation of insulin-dependent from insulin-independent diabetes since antibodies were present in 30 to 40 per cent of the former as opposed to 5 to 8 per cent of the latter. An additional marker has been the observation that HLA (major histocompatibility) antigens B8 and BW15 are found in association with juvenile-onset insulin-dependent, but not maturity-onset insulin-independent diabetes. 13, 41, 60 The most popular hypothesis for the B8 and BW15 association is that the antigens serve as markers for closeby but as yet untypable diabetogenic genes in the HLA complex. 37, 38 Thus, the family, twin, pancreatic islet cell antibody, and HLA studies clearly indi-

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Table 2. Genetic Syndromes Associated with Glucose Intolerance or Clinical Diabetes* Syndromes associated with pancreatic degeneration Hereditary relapsing pancreatitis Cystic fibrosis Polyendocrine deficiency disease Hemochromatosis Alpha,-antitrypsin deficiency'" 54 Hereditary endocrine disorders with glucose intolerance Isolated growth hormone deficiency Hereditary panhypopituitary dwarfism Pheochromocytoma Multiple endocrine adenomatosis I Multiple endocrine adenomatosis II Glucagonoma' Inborn errors of metabolism with glucose intolerance Glycogen storage disease type I Acute intermittent porphyria Hyperlipidemias Hyperglycerolemia5() Syndromes with nonketotic, insulin resistant early-onset diabetes Ataxia telangiectasia Myotonic dystrophy Lipoatrophic diabetes syndromes Hereditary neuromuscular disorders with glucose intolerance Muscular dystrophies Late-onset proximal myopathy Huntington's chorea Machado's disease Herrmann syndrome Optic atrophy-diabetes mellitus syndrome Friedreich's ataxia Alstrom syndrome Laurence-Moon-Biedl syndrome Retinopathy-hypogonadism-mental retardation-nerve deafuess syndrome'· Pseudo-Refsum syndrome Progeroid syndromes with glucose intolerance Cockayne syndrome Werner syndrome Syndromes with glucose intolerance secondary to obesity Prader-Willi syndrome Achondroplasia Miscellaneous syndromes with glucose intolerance Steroid-induced ocular hypertension Mendenhall syndrome Epiphyseal dysplasia and infantile-onset diabetes Cytogenetic disorders with glucose intolerance Trisomy 21 Klinefelter syndrome Turner syndrome *Modified from Rimoin, D. L., in Creutzfeldt, W., et al. (eds.): The Genetics of Diabetes Mellitus. New York, Springer Verlag, 1976, pp. 43-63.

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cated that juvenile-onset insulin-dependent and maturity-onset insulinindependent diabetes are genetically distinct. 52 Besides juvenile-onset insulin-dependent, and maturity-onset insulin-independent diabetes, another distinct form of diabetes has been described by Tattersall and Fajans, and they have called it "maturity onset diabetes of the young."62 This group of patients have the onset of glucose intolerance in childhood or adolescence, but have few symptoms, no ketonuria, are insulin independent, and have little progression of severityin carbohydrate intolerance over the years. These patients are clearly different from those with classical juvenile-onset diabetes. Individual pedigree studies have provided further evidence that they are separate entities. Among the propositi of patients with maturity-onset diabetes of the young, 85 per cent had a diabetic parent usually with a similar phenotype, 53 per cent of the siblings tested had diabetes, and 46 per cent of the families showed three generations of direct vertical transmission of the trait. In contrast, only 11 percent of the parents of patients with juvenileonset diabetes were diabetic, 8 of 74 of the siblings were diabetic, 6 with similar phenotypes, and only 6 per cent of the families showed three generation transmission. Thus, patients with maturity-onset diabetes of the young clearly have a distinct, dominantly inherited syndrome. If these patients had been classified by either age of onset or diabetic phenotype alone, they would have been lumped together with the classic juvenileonset diabetics or maturity-onset diabetics respectively, and their distinct pattern of inheritance would have been obscured. The recognition of this entity emphasizes the importance of the analysis of individual families, lacking in many studies of chronic disorders. Thus, there is clear evidence that juvenile and maturity-onset diabetes are separate genetic disorders, and it is likely that further heterogeneity exists within these broad groups. On the basis of analysis ofrecently published immunologic and metabolic studies, it has been suggested that further heterogeneity exists within juvenile-onset diabetes. It has been postulated that the HLA B8 and BW15 associated forms of juvenile-onset diabetes are distinct diseases. 51 The B8 form appears to be characterized by autoimmunity, pancreatic autoantibodies, and microangiopathy. The BW15 form is associated with antibodies to exogenous insulin. In addition, there is evidence for heterogeneity within juvenile-onset diabetes on a pathogenetic basis. There is now evidence that at least some types are due to autoimmunity against the pancreas islet. This evidence includes the finding of cell-mediated immunity against pancreatic islet cells, humoral immunity against these tissues, and the increased frequency of diabetes with other autoimmune endocrine diseases and endocrine antibodies. 28, 36 At the same time, a body of evidence has accumulated suggesting that viral infections may playa role in the etiology of some forms of juvenile diabetes. A number of animal models of vir ally induced diabetes have been described. 10 Epidemiologic evidence has suggested the onset of juvenile diabetes can have seasonal incidence and can be correlated with the outbreak of various viral infections. 12 Thus, it has also been proposed that juvenile diabetes can be subdivided into autoimmune and virus-induced forms. 28

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Heterogeneity has also been described in maturity-onset diabetes. The frequency of affected diabetic siblings of obese diabetics is significantly less than siblings of nonobese probands. 3 1. 32 This suggests that maturity-onset diabetes in the obese and nonobese may be etiologically different entities. It also demonstrates the well known role of obesity and diet as environmental predispositions to maturity-onset diabetes. This has been well documented in certain populations such as the Yemenite Jews in Israel, where the prevalence of diabetes has markedly increased following their migration to Israel and subsequent change in diet. s This example illustrates that the interaction of genetics and environment is being delineated even among these common disorders. Finally it should be noted that all of the heterogeneity that has been described thus far is within the Caucasian, northern European racial-ethnic groups. There are clear ethnic differences in the prevalence of diabetes, many of which are explicable on the basis of diet and environment. Nevertheless, there are clear differences in the clinical phenotype of diabetes between different ethnic groups that do not appear to be totally the result of environmental differences. 46• 49 For example, there are different ethnic groups with the same diets, some of which have common vascular complications and rare ketosis, and other ethnic grau ps with similar diets in which ketosis is a usual presenting symptom, and vascular complications are rare. In addition to the clinical differences in the diabetic syndrome between ethnic groups, there can be marked differences in normal plasma glucose and insulin concentration between different populations. There are also racial differences in the HLA diabetes association. 52 This implies that the heterogeneity within diabetes may have to be defined for each ethnic group.

GENETIC COUNSELING Cleft Lip and Cleft Palate Given all the difficulties described in assessing the genetic components of common disorders, such as cleft lip/palate and diabetes mellitus, then how does one approach the family's concerns and questions about risk of recurrence? It will most likely be the primary care physician to whom a family will address such questions. A patient or his family who does not articulate those concerns may be assuming an unrealistically high risk of recurrence. Alternatively, unless a physician evaluates the complete family and pedigree, the family with 50 per cent risk of recurrence might be given a lower empirical risk figure. Questions may arise at different points during the course of these chronic conditions, such as when a sibling is preparing for marriage or when an affected family member dies. Information pertinent to the genetic counseling given for cleft lip with or without cleft palate, or for the different entity of cleft palate alone, can be gathered in the traditional way: history, physical examination, family history, and resultant assessment. In obtaining the prenatal history for the proband, it is important to ask about exposure to known teratogens,

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such as diphenylhydantoin (Dilantin), because of potential intervention and prevention. It is also important to ask about the family's concerns about what they think might have caused the malformation, since itmay be possible to reassure them about unnecessary concerns or misconceptions. Physical examination is done first to carefully define the problem in the proband and also to rule out associated abnormalities. It is important to distinguish between cleft lip with or without cleft palate, and cleft palate alone, for reasons previously outlined. The characteristics of the cleft may have diagnostic significance. For example, the cleft associated with Robin anomaly may be round as opposed to the V-shape of most palatal clefts. 25 The presence of other anomalies suggests syndromes with known mendelian or chromosomal patterns of inheritance. Since there are over 50 syndromes, including clefting, it is often necessary to refer to systematic lists and tables 9 , 23 as well as the original descriptions. Multiple abnormalities in the newborn infant may suggest the need for chromosome analysis. In stillborn infants, where careful postmortem examinations too often are not done, photography, x-rays, chromosome analysis, as well as careful examination should be carried out so that the information needed to make an accurate diagnosis is not lost. The x-rays, posteroanterior and lateral views, are particularly helpful in making the diagnosis of bone dysplasias, many of which may include clefts: diastrophic, Ellis van Creveld, Kniest, campomelic, chondrodysplasia punctata, and short-rib polydactyly syndromes. Family history of clefting, with or without associated abnormalities such as lip pits, is obviously important. Physical examination of both parents as well as available family members should be done with the purpose of discovering microforms. These incomplete expressions of clefting, for example bifid uvula or submucous cleft, may help complete a pedigree with a clear pattern of inheritance. It may be necessary to do x-ray examinations of family members in order to define bone abnormalities as part of inherited syndromes, such as Klippel-Feil or Goldenhar syndromes. If the family pedigree shows a pattern ofinheritance, either of isolated clefting or a syndrome of abnormalities , then the risks given to the family should be altered accordingly. If it is not possible on the basis of history, physical examination, and family history to define a situation with known recurrence risk, as will be true in the majority of cases, it is then necessary to rely on empirical risk figures in order to give the family the best possible estimate. In order to apply the empirical risks from family studies,3, 5,14,17 however, one must be careful to observe certain principles. 7, 67 The diagnosis must be comparable to that of the patients included in the study. Thus, other forms of facial clefting, such as median facial cleft or PierreRobin anomaly, must be treated separately. The ethnic group of the patient should ideally be comparable to the series reported. The sex of the patient, the severity of the defect, or possible exposure of the mother to a particular environmental agent must be taken into account in each situation. The polygenic model of inheritance has been used to derive computer programs and tables to be used in the estimation of risk of recurrence in situations where adequate family studies may not exist,2, 61 namely com-

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plicated pedigrees. After the birth of an infant with cleft lip with or without cleft palate, there is an immediate need to address the family's questions, usually about risks to their future offspring. With time, questions about more distantly related relatives and finally offspring of the proband may arise. This is another instance where programs and tables may be helpful to give an exact risk. The optimal follow -up of a child with cleft lip with or without cleft palate by a multidisciplinary team might include contact with someone particularly interested in the genetics of clefting. That person might address such questions as they arise, in addition to interpreting the risk and burden to concerned family members. Thus, genetic counseling may be useful on an on-going basis to enhance the family's adjustment to the occurrence of such a malformation. Diabetes Mellitus Although we now recognize heterogeneity, the question still arises: how will we provide genetic counseling at this time for our diabetic patients? First, as in all genetic counseling, an accurate diagnosis must be made. On clinical grounds one can distinguish between juvenile insulindependent diabetes, maturity-onset insulin-independent diabetes, and maturity-onset diabetes of the young. In distinguishing between these phenotypes, one already has information that can be relayed to the counselee. In a given family the increased risk for diabetes over the general population is only for that specific type of diabetes that has already occurred in the family, not for all diabetes. Associated abnormalities or diseases may suggest the rare genetic syndromes that include diabeteseach of which has its own risk of recurrence. Once we have accurately characterized the clinical phenotype of the patient, how do we then proceed? At this stage, we must fall back for the most part on observed empirical recurrence risks. Even with the reservation that these empirical risks can be safely applied only to the populations from which they were derived, the most reassuring aspect of the data is the overall low absolute risk for the development of clinical diabetes in first degree relatives. If a child has juvenile insulin-dependent diabetes, published studies report an average risk to his siblings of 5.5 to 11 per cent. 15 • 32. 37.58.62.65 If a parent has juvenile-onset diabetes, the risk for his offspring of overt diabetes during the first decades of life is generally reported to be 1 to 2 per cent or less. We should be alert to the possibility that these average risks were obtained by pooling families with a low risk with others with a higher risk. Thus, clinically, if there were a very prominent history of juvenile-onset diabetes, one cannot exclude the possibility that that family has a higher risk than the reported average, since there is tentative evidence for higher risk subgroups among patients with juvenile-onset diabetes. But though the numerical risk of recurrence is high in maturity-onset diabetes of the young, the burden of the type of diabetes must be made clear to the family. Maturity-onset diabetes of the young is mild, with fewer complications, so the burden is not as great as for other diabetic phenotypes. One might ask, can we not use the new markers, such as HLA typing or pancreatic islet cell antibodies, to define this risk, and to identify pre-

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diabetics? Efforts are being made in this direction. For the most part they currently remain in the realm of research, rather than providing useful clinical tools. Advances have been so rapid that it would not be surprising to be able to utilize some of these markers in the near future to aid in counseling diabetic patients and their families.

SUMMARY We have reviewed the approach of the modern clinical geneticist to the genetics of common diseases. The importance of considering genetic heterogeneity within these groups of disorders has been emphasized. The physician should recognize our present inability to deliver exact recurrence risks for most families with these common disorders. As our know ledge improves, we must constantly update our counseling. Until then, in most cases, we can only utilize the empirical risk data presently available and provide an idea of the magnitude of risk, which in many of these disorders appears low. However, continued utilization ofimprecise risk data must not impede recognition of potential and demonstrated heterogeneity within these disorders, or retard the development of new and improved risk data based on knowledge of the heterogeneity within common diseases.

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