1 Genetic Counseling: Preconception, Prenatal and Perinatal

Aubrey Milunsky and Jeff M. Milunsky Center for Human Genetics, Boston University School of Medicine, Boston, MA, USA

Advances in molecular genetics and fetal imaging or avoidance of genetic or acquired defects. In have enriched our ability to secure early prenatal context, women at risk for having progeny with diagnosis of a rapidly enlarging spectrum of genetic defects expect to be informed about their odds and and developmental disorders. Pari passu, a newly options, preferably during preconception coun- added layer of diagnostic uncertainty has dawned seling. Their concerns are serious, given the signifi - created by an extant lack of knowledge about poly- cant contribution of genetic disorders to morbidity morphisms and developmental structural and and mortality in children and adults. functional variations. Cognizance of “ normal ” has always been important and is especially critical in The i ncidence, p revalence and the evolution of fetal health. Analyses via chromo- burden of g enetic d isorders and somal microarrays and whole - genome sequencing c ongenital m alformations make mandatory the need to fi rst delineate normal variation, if erroneous decision making is to be Various measures refl ect the population burden of avoided. genetic disease and congenital anomalies. Common The widening scope of molecular diagnostics and assessments include the incidence or prevalence of fetal imaging has increased opportunities for pre- the disorder/defect, the associated morbidity and dictive, preconception, preimplantation and pre- mortality, the degree of disability and suffering, life natal diagnosis. Consequently, genetic counseling expectancy and economic burden. Indeed, many for prenatal diagnosis can be expected increasingly factors infl uence efforts to accurately determine the to involve newly recognized microdeletion and incidence or prevalence of congenital anomalies or microduplication syndromes (see Chapter 10 ), genetic disorders. Box 1.1 encompasses the major- early adult- onset malignancies,COPYRIGHTED neurodegenerative, ity ofMATERIAL known etiologic categories, discussed below, cardiovascular and other fatal genetic disorders, as which help explain sometimes striking differences well as those with signifi cant morbidity. among major studies. It is almost impossible to Against this background, physicians in all spe- account for all these potentially confounding factors cialties are expected to be cognizant of new devel- in a study and rarely has any one study come close. opments in genetics that facilitate the prevention Incidence and p revalence Estimates of aneuploidy in oocytes and sperm 1 Genetic Disorders and the Fetus, 6th edition. Edited by reach 18– 19 percent and 3– 4 percent, respectively. A. Milunsky & J. Milunsky. © 2010 Blackwell Publishing. Not surprisingly, then, about one in 13 concep- ISBN: 978-1-4051-9087-9 tions results in a chromosomally abnormal

1 2 Genetic Disorders and the Fetus

Box 1.1 Factors that infl uence estimates of the incidence or prevalence in the newborn of a congenital malformation (CM ) or genetic disorder

Availability and use of expertise in prenatal Maternal fever or use of hot tub in the fi rst 6 diagnostic ultrasound weeks of pregnancy Case selection, bias and ascertainment Maternal grandmother ’ s age Consanguinity Maternal obesity Defi nitions of major and minor congenital Maternal use of medication anomalies Multiple pregnancy rate Economic level in developed or developing world Paternal age Family history Previous affected child Frequency, inclusion and exclusion of stillbirths, Previous maternal immunization/vaccination fetal deaths and elective pregnancy termination Season of the year Frequency of certain infectious diseases Training and expertise in examination of History of recurrent spontaneous abortion newborns In vitro fertilization Use of chromosomal microarray Incidence and severity of prematurity Use of death certifi cates Intracytoplasmic sperm injection Use of folic acid supplementation Later manifestation or onset of disorder Use of maternal serum screening for Down Maternal age syndrome Maternal alcohol abuse Use of maternal serum screening for neural Maternal diabetes and gestational diabetes tube defects Maternal diet Use of prenatal necropsy Maternal epilepsy, lupus erythematosus and Use of registry data other illnesses

conceptus,2 while about 50 percent of fi rst- trimes- More than 12,000 monogenic disorders and ter spontaneous abortions are associated with traits have been catalogued.10 Estimates based on 1 chromosomal anomalies.3 Clinically signifi cant million consecutive livebirths in Canada suggested chromosomal defects occur in 0.65 percent of all a monogenic disease in 3.6 in 1,000, consisting of births; an additional 0.2 percent of babies are born autosomal dominant (1.4 in 1,000), autosomal with balanced structural chromosome rearrange- recessive (1.7 in 1,000) and X- linked - recessive ments (see Chapter 6 ) that have implications for disorders (0.5 in 1,000).11 Polygenic disorders reproduction later in life. Between 5.6 and 11.5 occurred at a rate of 46.4 in 1,000 (Table 1.1 ). percent of stillbirths and neonatal deaths have At least 3– 4 percent of all births are associated chromosomal defects.4 with a major congenital defect, mental retardation Congenital malformations with obvious struc- or a genetic disorder, a rate that doubles by 7 – 8 tural defects are found in about 2 percent of all years of age, given later- appearing and/or later- births.5 This was the fi gure in Spain among 710,815 diagnosed genetic disorders.12,13 If all congenital livebirths,6 with 2.25 percent in Liberia, 7 2.03 percent defects are considered, Baird et al. 11 estimated that in India,8 and 2.53 percent among newborn males 7.9 percent of liveborn individuals have some type in Norway.8a The Mainz Birth Defects Registry in of genetic disorder by about 25 years of age. These Germany in the 1990– 1998 period reported a 6.9 estimates are likely to be very low given, for percent frequency of major malformations among example, the frequency of undetected defects such 30,940 livebirths, stillbirths and abortions. 9 Factors as bicuspid aortic valves that occur in 1 – 2 percent that had an impact on the incidence/prevalence of of the population. 14 The bicuspid aortic valve is the congenital malformations are discussed below. most common congenital cardiac malformation CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 3

Table 1.1 The frequencies of genetic disorders in prenatal diagnosis over a 21 - year period (1979 – 1,169,873 births, 1952– 1983 11 1999) in a well- defi ned population showed a drop of 80 percent in the birth prevalence of DS. 21 A later Category Rate per million Percentage of report from the Paris Registry of Congenital livebirths total births Anomalies (2001 – 2005) noted a “ fairly stable prev- A alence of DS (7.1 per 10,000 livebirths) over Dominant 1,395.4 0.14 time. ” 22 A study from Newcastle, England, based Recessive 1,665.3 0.17 on ascertainment of all cases of NTDs revealed a X - linked 532.4 0.05 twofold reduction in the birth prevalence between Chromosomal 1,845.4 0.18 1984– 1990 and 1991– 1996. 23 A Scottish study Multifactorial 46,582.6 4.64 aimed at assessing the impact of prenatal diagnosis Genetic unknown 1,164.2 0.12 on the prevalence of DS from 1980 to 1996. Both Total 53,175.3 5.32a births and pregnancy terminations were included. B Pregnancy terminations for DS rose from 29 All congenital 52,808.2 5.28 percent to about 60 percent.24 In contrast, the anomalies prevalence of DS noted by the Dutch Paediatric 740 – 759b Surveillance Unit in 2003 was 16 per 10,000 live- Congenital 26,584.2 2.66 anomalies with births, exceeding earlier reports and thought to 25 genetic etiology refl ect an older maternal age cohort. In the US, a (included in DS prevalence rate of 13 per 10,000 was found in 26 section A) metropolitan Atlanta (1979– 2003). The effect of folic acid supplementation, via C tablet or food fortifi cation, on the prevalence of Disorders in 79,399.3 7.94 section A plus NTDs, now well known to reduce the frequency of 27,28 those congenital NTDs by up to 70 percent, (see Chapter 23 ) has anomalies not only recently been assessed in this context. A Cana- already included dian study focused on the effect of supplementa- tion on the prevalence of open NTDs among a Sum is not exact owing to rounding. 336,963 women. The authors reported that the b International Classifi cation of Disease numbers. prevalence of open NTDs declined from 1.13 in 1,000 pregnancies before fortifi cation to 0.58 in 1,000 pregnancies thereafter (see Chapter 23 ).29 and in the fi nal analysis may cause higher mortality In a population - based cohort study by the Met- and morbidity rates than all other congenital ropolitan Atlanta Congenital Defects Program, the cardiac defects.15 A metropolitan Atlanta study risk of congenital malformations was assessed (1998– 2005) showed an overall prevalence of 81.4 among 264,392 infants with known gestational per 10,000 for congenital heart disease among ages born between 1989 and 1995. Premature 398,140 livebirths.16 These numbers lead to a infants (< 37 weeks of gestation) were found to be signifi cant genetic disease burden and have more than twice as likely to have been born with accounted for 28 – 40 percent of hospital admis- congenital malformations than infants at term.30 sions in North America, Canada and England.17,18 Twins have long been known to have an increased Notwithstanding their frequency, the causes of rate of congenital anomalies. A UK study of 2,329 over 60 percent of congenital malformations twin pregnancies (4,658 twins) and 147,655 single- remain obscure.19,20 tons revealed an anomaly rate of 405.8 per 10,000 The availability of prenatal diagnosis and mater- twins versus 238.2 per 10,000 singletons (relative nal serum screening for neural tube defects (NTDs) risk (RR) 1.7). 31 The prevalence rate of anomalies and Down syndrome (DS) has also affected the among known monochorionic twins (633.6 per birth frequency of these two most common con- 10,000) was nearly twice that found in dichorionic genital defects. One French study of the impact of twins (343.7 per 10,000)(RR 1.8). 4 Genetic Disorders and the Fetus

A key study of homozygosity in consanguineous have an increased risk of bearing a child with gas- patients with an autosomal recessive disease showed troschisis, those between 12 and 15 years of age that on average, 11 percent of their genomes were having a more than fourfold increased risk. 38a homozygous.32 Each affected individual had 20 The frequency of congenital hypothyroidism, homozygous segments exceeding 3 cM. now known to be associated with up to a fourfold Incidence/prevalence rates of congenital defects increased risk of additional congenital malforma- are directly infl uenced by when and how diagnoses tions, represents yet another factor that may infl u- are made. Highlighting the importance of how ence incidence/prevalence rates of congenital early a diagnosis is made after birth, the use of anomalies. A French study of 129 infants with con- echocardiography and the stratifi cation of severity genital hypothyroidism noted that 15.5 percent of congenital heart defects, Hoffman and Kaplan 33 had associated congenital anomalies.39 Nine of the clarifi ed how different studies reported the inci- infants had congenital heart defects (6.9 percent). dence of congenital heart defects varying from 4 in Women with epilepsy who are taking anticon- 1,000 to 50 in 1,000 livebirths. They reported an vulsant medications have an increased risk of incidence of moderate and severe forms of con- having offspring with congenital malformations, genital heart disease in about 6 in 1,000 livebirths, noted in one study as 2.7 - fold greater than those a fi gure that would rise to at least 19 in 1,000 live- without epilepsy.40 The possible reduction of other births if the potentially serious bicuspid aortic congenital malformations as a result of folic acid valve is included. They noted that if all forms of supplementation remains to be proved. 41 congenital heart disease (including tiny muscular ventricular septal defects) are considered, the inci- Congenital m alformations and dence increases to 75 in 1,000 livebirths. i nfant m orbidity and m ortality The frequency of congenital defects is also infl u- enced by the presence or absence of such defects in The leading cause of infant death in the United at least one parent. A Norwegian Medical Birth States in 2005 was congenital malformations, Registry population- based cohort study of 486,207 deformations and chromosomal abnormalities, males recorded that 12,292 (2.53 percent) had been accounting for 19.5 percent of all infant deaths. 42 born with a congenital defect.8a Among the off- Survival is clearly dependent on the severity or spring of these affected males, 5.1 percent had a lethality of the congenital defect. The Centers for congenital defect, compared with 2.1 percent of Disease Control and Prevention assessed mortality offspring of males without such defects (RR 2.4). rates for infants born with trisomy 13 and trisomy Maternal obesity also has the potential for 18. Using death certifi cates and other source data, increasing the prevalence of congenital anomalies. 33a the authors identifi ed 5,515 infants born with In a population- based case– control study exclud- trisomy 13 and 8,750 born with trisomy 18. The ing women with pre- existing diabetes, Watkins median age at death for both trisomy 13 and et al. 34 compared the risks of selected congenital trisomy 18 was 10 days. Survival to at least 1 year defects among obese women with those of average- occurred in 5.6 percent of those born with trisomy weight women. They noted signifi cant odds ratios 13 or trisomy 18.43 A regional study in The Neth- for spina bifi da (3.5), omphalocele (3.3), heart erlands noted lethal congenital malformations in defects (2.0) and multiple anomalies (2.0). Others 35 51 percent of stillbirths and 70 percent among found a 2.2- fold increased risk of spina bifi da in those who died during the neonatal period. 44 A the offspring of obese women. Our own studies 36,37 Scottish study focused on the survival of infants have pointed in the direction of a prediabetic state with congenital anomalies up to the age of 5 years. or gestational diabetes as the biologic mechanism They used a population- based and systematically accounting for the increased rate of congenital validated registry of congenital anomalies contain- anomalies in the offspring of obese women. In ing 6,153 anomalous livebirths. Survival rates for contrast, markedly underweight women reportedly these infants to the age of 5 were: chromosomal have a 3.2 - fold increased risk of having offspring anomalies (48 percent), neural tube defects with gastroschisis. 38 Young nulliparous women (72 percent), respiratory system anomalies (74 CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 5 percent), congenital heart disease (75 percent), births in British Columbia from 1908 to 1981. They nervous system anomalies (77 percent) and DS (84 constructed survival curves (Figure 1.1 ) and a life percent).45 The survival rate among males with table (Table 1.2 ) for DS and for the general popula- congenital defects was 84 percent, compared with tion.53 Their estimates show that 44.4 percent and 97 percent in those born unaffected. 8a Liu et al.46 13.6 percent of liveborn individuals with DS will examined temporal changes in fetal and infant survive to 60 and 68 years, respectively, compared deaths caused by congenital malformations in with 86.4 percent and 78.4 percent of the general Canada, England, Wales and the United States. population. In another report,54 these authors have They concluded that the major factor responsible analyzed the causes of death in DS, highlighting for the accelerated decline in infant deaths was pre- congenital defects and cardiovascular and respira- natal diagnosis and elective abortion of fetuses tory illnesses as the most important. with abnormalities. Given the frequency of DS, a Additional studies of mortality rates in individu- more detailed discussion follows. NTDs are dis- als with DS revealed that those up to about 35 years cussed in Chapter 24 . of age were little different from others who were mentally retarded. Subsequently, however, mor- Down s yndrome tality rates in DS doubled every 6.4 years, com- The special problems and associated defects in DS pared with 9.6 years for other mentally retarded are well known, as is the increasing life expectancy. individuals. 54 Life tables constructed by these Studies from Japan,47 Denmark,48 England,49 Aus- authors indicated a life expectancy of 55 years for tralia,50 and Canada51,52 highlight the increased a 1 - year - old patient with DS and mild/moderate life expectancy with DS. Baird and Sadovnick51 retardation and a life expectancy of 43 years for a reported a large study of 1,610 individuals with DS 1 - year - old patient with DS and profound mental identifi ed in more than 1,500,000 consecutive live- retardation.

Figure 1.1 Survival curves for Down syndrome and for the general population of British Columbia. (Reproduced with permission from Baird and Sadovnik, 1987. 51 ) 6 Genetic Disorders and the Fetus

Table 1.2 Life expectancy with Down syndrome, to age 68 years 51

Age Total Deaths Withdrawals Survival at start of age interval (%)

0 1,337 164 0 100.00 1 1,173 51 0 87.73 2 1,122 23 0 83.92 3 1,099 10 29 82.20 4 1,060 5 35 81.44 5 1,020 10 33 81.05 6 977 5 37 80.24 7 935 6 20 79.82 8 909 3 30 79.31 9 876 7 28 79.04 10 841 2 27 78.40 11 812 4 28 78.21 12 780 2 34 77.82 13 744 3 21 77.61 14 720 6 35 77.30 15 679 3 41 76.64 16 635 1 34 76.29 17 600 1 26 76.16 18 573 4 36 76.03 19 533 1 35 75.48 20 497 1 46 75.34 21 450 1 26 75.18 22 423 5 40 75.01 23 378 0 38 74.08 24 340 2 50 74.08 25 288 0 46 73.61 26 242 3 38 73.61 27 201 0 36 72.62 28 165 1 36 72.62 29 128 0 37 72.12 30 91 0 35 72.12 31 56 0 30 72.12 32 26 0 26 72.12 33 255 1 19 72.12 34 235 0 27 71.83 35 208 1 7 71.83 36 200 0 12 71.48 37 188 2 21 71.48 38 165 2 12 70.67 39 151 0 15 69.78 40 136 1 8 69.78 41 127 0 11 69.25 42 116 1 17 69.25 43 98 1 5 68.61 44 92 0 6 67.89 45 86 3 4 67.89 46 79 0 5 65.47 47 74 3 4 65.47 48 67 0 4 62.74 49 63 2 4 62.74 CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 7

Table 1.2 Continued

Age Total Deaths Withdrawals Survival at start of age interval (%)

50 57 0 1 60.68 51 56 1 7 60.68 52 48 2 5 59.53 53 41 1 2 56.91 54 38 1 6 55.49 55 31 0 2 53.96 56 29 1 3 53.90 57 25 1 4 51.94 58 20 1 1 49.68 59 18 1 1 47.14 60 16 2 1 44.44 61 13 3 2 38.71 62 8 0 0 29.03 63 8 0 1 29.03 64 7 1 0 29.03 65 6 1 1 24.88 66 4 1 2 20.36 67 1 0 0 13.57 68 1 0 1 13.57

Source: Baird and Sadovnick, 1989. 53

A study from the Centers for Disease Control population of Australia, now approximating 76 and Prevention focused on the death certifi cates of years for males and 81.7 years for females. Another 17,897 individuals with DS born between 1983 and more recent Australian study found an overall sur- 1997.55 These authors reported that the median age vival fi gure for DS of 90 percent to at least 5 years at death for those with DS increased from 25 years of age. 60 The known co - morbidity of DS and earlier in 1983 to 49 years in 1997 (Figure 1.2 ). They also onset Alzheimer ’ s61 disease casts a longer shadow. observed that the median age at death was signifi - Over 50 percent of DS patients over 50 years cantly lower among blacks and people of other develop Alzheimer’ s disease and up to 84 percent races when compared with whites with DS. The of those with dementia develop seizures.62 authors acknowledge the limitations of their study Table 1.3 refl ects the common associated defects given the known problems with the epidemiologic that occur in DS and the more common complica- use of death certifi cates. tions that can be anticipated, monitored, prevented An Australian cohort study of 1,332 people with and treated. DS who had registered for intellectual disability services between 1953 and 2000 calculated a life The g oal and p urpose of p renatal expectancy of 58.6 years, with 25 percent expected d iagnosis to live to 62.9 years. The oldest person with DS was alive at 73 years of age. Their calculations con- The fundamental philosophy of prenatal genetic cluded that 75 percent of people with DS would diagnosis is to provide reassurance to couples at survive to 50 years, 50 percent to 58.6 and 25 risk so that they may selectively have unaffected percent to 62.9.59 The authors cautioned that this children even if their procreative risk for having study was not a birth cohort and also omitted some defective offspring is unacceptably high. 63 Fetal deaths that occurred in infancy or early childhood. defects serious enough to warrant parental election Nevertheless, they found that life expectancy of of abortion are generally found in less than 5 those with DS is approaching that of the general percent of all cases studied, based on current indi- 8 Genetic Disorders and the Fetus

Figure 1.2 Median age at death of people with Down syndrome by sex (upper ), by racial group ( middle ) and with or without congenital heart defects (CHD) by racial group (lower ). (Reproduced with permission from Yang et al., 2002. 55 )

cations for prenatal diagnosis. When couples are at sible for such high- risk couples to have children risk for having a seriously abnormal child, common that they would otherwise never have conceived. experience shows that those with risks between 10 As a consequence, the number of children born and 25 percent or even greater most often avoid because of prenatal diagnosis is much higher than pregnancies unless prenatal diagnosis is available. the very small number of pregnancies terminated The advent of prenatal diagnosis has made it pos- because of the detection of grave fetal defects. Pre- CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 9

Table 1.3 Defects and complications associated with multiple- specialty clinical, counseling and labora- Down syndrome tory teams. For the more common indications for prenatal diagnosis (such as advanced maternal Percentage age), the well- informed obstetrician should be able Defect to provide the necessary information. However, a Congenital heart disease ± 50 salutary observation in one study revealed that 43.3 Mitral valve prolapse 46 percent of patients referred for amniocentesis Aortic valve regurgitation 17 exclusively for advanced maternal age had addi- Hearing impairment 38 – 78 tional genetic risks or signifi cant concerns regard- a Eye disorders 80 ing one or more genetic or congenital disorders.64 Complication Neither a questionnaire in the physician’ s offi ce Obesity Majority nor limited consultation time is likely to reveal Periodontal disease ± all many of these disorders. This group required more Orthodontic problems ± all extensive genetic counseling. In a Hungarian study Hypothyroidism 15 98 percent and 92 percent of counsellees expected Celiac disease 4.6 – 7.1 detailed information and the possibility of control Juvenile rheumatoid- like 1.2 over decision making, respectively. 65 arthritis Atlantoaxial subluxation 6.7 Diabetes mellitus 1.4 – 10.6 Prerequisites for g enetic Leukemia > 20 - fold excess c ounseling Obstructive sleep apnea Frequency greater than in general population Genetic counseling is a communication process Epilepsy 13.6 concerning the occurrence and the risk of recur- Testicular cancer Standardized incidence rence of genetic disorders within a family. The aim ratio 4.8 of such counseling is to provide the counselee(s) > Alzheimer disease and 50 with as complete an understanding of the disorder dementia and/or problem as possible and of all the options

a Includes cataracts, strabismus, nystagmus, refractive and implications. The counseling process is also errors, keratoconus, glaucoma, and lens opacities. aimed at helping families cope with their problems Data from references 56, 57, 57a – d, 58 . and at assisting and supporting them in their deci- sion making. The personal right to found a family is consid- ered inviolable. Such reproductive autonomy is natal genetic studies are used in Western society enhanced by genetic counseling, a process that virtually exclusively for the detection of defects both emphasizes freedom of choice and reviews the generally characterized by irreparable mental available options in order to enrich the decision - retardation and/or irremediable, serious to fatal making process. All couples have a right to know genetic disease. Sadly, at present, the ideal goal of whether they have an increased risk of having chil- prevention or treatment rather than abortion dren with genetic disease and to know which after prenatal detection of a fetal defect is achieved options pertain to their particular situation. The only rarely, with the exception of NTDs (see physician and genetic counselor has a clear duty Chapter 23 ). Preimplantation genetic diagnosis and obligation to communicate this information, (see Chapter 29 ) does, however, provide another to offer specifi c tests or to refer couples for a second option that avoids abortion. or more expert opinion. In the United States, at All couples or individuals concerned about the least, the full force of law supports the prospective risks of genetic defects in their offspring should parents ’ right to know (see Chapter 33 ). seek genetic counseling before conceiving. Such As Kessler66 stated so succinctly, “ Because counseling is best provided in medical genetics genetic counselors work with people fi lled with departments of university medical centers with uncertainty, fear of the future, anguish and a sense 10 Genetic Disorders and the Fetus of personal failure, ” they have unusual challenges lacking in the necessary knowledge and communi- and opportunities “ to understand clients, give cation skills. 69– 72 them a sense of being understood and help them After the prenatal diagnosis of a serious genetic feel more hopeful, more valued and more capable disorder, the physician should be able to inform of dealing with their life problems. ” The physician the family fully about the anticipated burden and and genetic counselor providing genetic coun- to detail the effects of this burden on an affected seling should have a clear perception of the neces- child, the family, other siblings, the family eco- sary prerequisites, guiding principles and potential nomics and marital relations, along with any other problems. pros and cons of continuing pregnancy. The reality of early Alzheimer disease in DS and the care Knowledge of d isease requirements that may devolve on the siblings The need for a counselor to have extensive factual should not be omitted from the discussion. Exact knowledge about disease in general, as well as details should also be known about the risks of about the disease for which counseling is being elective abortion (see Chapter 28 ). provided, hardly needs emphasis. Such knowledge should include how the diagnosis is made and con- Expertise in g enetic c ounseling fi rmed, the test accuracy and limitations, the Genetic counseling is best provided by board- cer- important co- morbidities, the recurrence risks, the tifi ed clinical geneticists and genetic counselors. In mode of inheritance, the tests available to detect a countries with this specialization, such service is carrier (and their detection rates), the heterogene- provided by a team composed of clinical geneticists ity and pleiotropic nature of the disease, the quality (physicians) and genetic counselors, working in of life associated with survival, prognosis and the concert with clinical cytogeneticists, biochemical causes of death. When relevant, it is necessary to and molecular geneticists. It is, however, impracti- know about treatment and its effi cacy. cal and not cost effective to provide such formal The physician or genetic counselor who initiates counseling for every woman before prenatal diag- genetic counseling for an apparently straightfor- nosis for advanced maternal age. It is necessary for ward indication (e.g. advanced maternal age) may the obstetrician to be fully informed about the fi nd one or more other familial conditions with indications for amniocentesis and to explain the which he or she has little or no familiarity. Such techniques and requirements for obtaining the circumstances dictate referral for specialist consul- fl uid, the limitations of the studies, the risks of tation. A National Confi dential Enquiry into coun- chromosomal abnormality in the offspring of the seling for genetic disorders by nongeneticists in the patient being counseled, the risks of the procedure United Kingdom revealed that less than half of and, when pertinent, all matters concerned with those with known high genetic risks were referred elective abortion of an abnormal fetus. to medical geneticists. 67 This study focused on a Gordis et al.73 concluded that the way in which review of 12,093 “ genetic events” involving poten- an obstetrician managed patients at risk regarding tially avoidable cases of DS, NTDs, cystic fi brosis, referral for genetic screening was closely related to β- thalassemia and multiple endocrine neoplasia. that obstetrician’ s attitudes and education. Physi- Medical record reviews were frustrated by the poor cians in practice should be aware of the nuances quality of clinical notes, which lacked evidence of and needs in the genetic counseling process, counseling. An urgent call was made for genetic including the key psychologic aspects. 74 Perhaps management to be at least as well documented as most important is the requirement that they rec- surgical operations, drug records and informed ognize limitations in their knowledge of uncom- consent. A Dutch study evaluated the levels of mon or rare genetic disorders and be alert to knowledge, practical skills and clinical genetic situations requiring referral. Obstetricians or practices of 643 cardiologists. They noted low family practitioners are not expected to have an levels of self - reported knowledge and that only 38 extensive knowledge of all diseases but they should percent had referred patients to clinical geneti- be able to recognize that a condition could be cists.68 Other physicians too have been found genetic. Concern about litigation should not act as CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 11 a constant reminder to physicians of the need to the sole option. Even in situations in which a par- consult or refer75 – 77 (see Chapter 33 ). ticular disease is diagnosable prenatally, it is impor- tant to be certain that other avenues are explored. Ability to c ommunicate Prospective parents who are known, for example, Many physicians are not born communicators and to be carriers of an autosomal recessive disorder most have not had formal teaching and training to may be unaware of the possibility of sperm or ovum hone their communication skills. Recognizing donation or may be unwilling to raise the question. these defi ciencies, the American Academy of Pedi- This option may be viewed more favorably than atrics has provided valuable guidance and made prenatal diagnosis and elective abortion. Physicians specifi c recommendations for the development should be certain that their patients are familiar and teaching of communication skills, 78 as have with all the aforementioned important options, as others.79a,79b well as with adoption, vasectomy, tubal ligation, Simple language, an adequate allocation of time, treatments of the mother and/or fetus during preg- and care and sensitivity are keys to successful nancy and other methods of assisted reproduction genetic counseling. Technical jargon, used with (e.g. intracytoplasmic sperm injection, 85 epididy- distressing frequency,80 is avoided only through mal sperm aspiration, 86 and preimplantation conscious effort. How an issue requiring a decision genetic diagnosis) (see Chapters 7 and 29 ). is framed, 81 and the nature of the language used, 82 may infl uence the patient’ s choice.83 Counseling is Empathy facilitated when three key questions are asked: Empathy embodies the ability to not only under- “ Why did you come?” “ What exactly do you hope stand the perspectives and emotions of others to learn? ” and “ Have I answered all your questions but to communicate that understanding.87 Much and concerns? ” more than the communication of risk fi gures for Although the explanation of exact statistical a particular disorder is required in the genetic risks is important, patients often pay more atten- counseling process. Warmth, care, sympathy, tion to the actual burden or severity of the disease understanding and insight into the human condi- in question. How risks are explained and expressed tion are necessary for effective communication. is a skill to be mastered. Key to the exposition is The diffi culty of assimilating information and the patients’ educational level, cultural background making rational decisions in the face of anxiety 88 and the requirement of an interpreter (who may should be recognized and vocalized. Empathy and even bedevil a superb counselor). The use of sensitivity enable the counselor to anticipate and numeric probabililties, relative risk, risk reduction respond to unspoken fears and questions and are or simple numbers of chance (1 in 100) or words qualities that make the counseling experience most (almost never, sometimes, more often than not)84 benefi cial and valuable to the counselees. are choices a counselor must make. Clearly, the For example, a couple may have been trying to simpler, the better and the more likely the infor- conceive for 10 years and, having fi nally succeeded, mation is understood. Patients’ perceptions of risk may be confronted by a callous physician who is not infrequently differ markedly from those of the impatient about their concerns regarding amnio- counselor, a realization that should elicit no centesis and elective abortion. Another couple may comment. An essential ingredient of the coun- have lost their only child to a metabolic genetic seling process is time. The busy practitioner can disease and may be seeking counseling to explore hardly expect to offer genetic counseling during a the possibilities for prenatal diagnosis in a subse- brief consultation. Distress and misunderstanding quent pregnancy or even treatment following pre- are invariable sequelae of such hastily delivered natal diagnosis, as in the case of galactosemia. They counseling. may have in mind past problems encountered in prenatal diagnosis or may be aware of the uncer- Knowledge of a ncillary n eeds tain outcome of treatment. For the couple at high risk of having a child with a Sensitivity and awareness of the plight of pro- serious genetic disorder, prenatal diagnosis is not spective parents are critical prerequisites and 12 Genetic Disorders and the Fetus include the need to recognize and address the Sensitivity to p arental g uilt usually unspoken fears and anxieties. They may Feelings of guilt invariably invade the genetic con- have had a previous affected child with physical/ sultation; they should be anticipated, recognized mental defi cits and experienced stigmatizing and dealt with directly. Assurance frequently does encounters, including intrusive inquiries, staring not suffi ce; witness the implacable guilt of the and pointing, devaluing remarks and social obligate maternal carrier of a serious X - linked withdrawal.89 disease.90a Explanations that we all carry harmful Beyond the qualifi cations and factual knowledge genes often helps. Mostly, however, encourage- of the counselor is the person, who is key to suc- ment to move anguish into action is important. cessful and effective counseling. Attitude, body This might also help in assuaging any blame by the language, warmth, manners, dress, tone of voice husband in such cases. 91 and personality are facets that seriously infl uence Guilt is not only the preserve of the obligate the credibility and acceptance of the counseling carrier. Affected parents inevitably also experience offered. Curiously, counselors rarely realize during guilt on transmitting their defective genes.92,93 Fre- their counseling session that they are simultane- quently, a parent expresses guilt about an occupa- ously being assessed. Patients assess the apparent tion, medication or illegal drug that they feel has knowledge and credibility of the counselor, seek caused or contributed to their child ’ s problem. and are encouraged by evidence of experience and Kessler et al.93 advised that assuaging a parent’ s consider the information provided in light of the guilt may diminish their power of effective preven- counselor’ s attitude, body language and other non- tion, in that guilt may serve as a defense from being verbal characteristics. powerless. Quintessential prerequisites for the empathetic Guilt is often felt by healthy siblings of an affected genetic counselor include the following. child, who feel relatively neglected by their parents 1. Acknowledge the burden and empathize about and who also feel anger toward their parents and the sadness or loss (e.g. a previous child; recurrent affected sibling. What is termed “ survivor guilt ” is miscarriage; a deceased affected parent; a patient increasingly recognized, as the new DNA technolo- who has experienced mastectomy and chemother- gies are exploited. Experience with Huntington apy for breast cancer with daughters at risk). disease and adult polycystic kidney disease 94– 100 2. Vocalize the realization of the psychologic pain confi rm not only survivor guilt with a new reality and distress the person or couple has experienced (a future) but also problems in relationships with (e.g. recurrent pregnancy loss followed by multiple close family members. Huggins et al.97 found that IVF efforts and subsequently a successful preg- about 10 percent of individuals receiving low - risk nancy with a fetal defect). results experienced psychologic diffi culties. 3. Compliment the coping that has been neces- sary, including the stress a couple might have to Principles in g enetic c ounseling endure, despite sometimes confl icting feelings. 4. Recognize (and explain) psychologic diffi culties Eleven key principles are discussed that guide in decision making when faced with a prenatal genetic counseling in the preconception, prenatal diagnosis of the same disorder affecting one parent and perinatal periods. This section is in concert (discussion of self- extinction, self- image and issues with consensus statements concerning ethical of guilt and survival). principles for genetics professionals 101,102 and sur- 5. F u l fi ll the patient’ s need for hope and support veyed international guidelines. 103 and actively avoid any thoughtless comments66 that may erode these fundamental prerequisites. Well - Accurate d iagnosis intentioned statements are not infrequently per- Clinical geneticists, obstetricians or pediatricians ceived in a very different way.78 are frequently confronted by patients seeking guid- It is self- evident that empathy would engender ance because of certain genetic diseases in their greater patient satisfaction and may well be cor- families. A previous child or a deceased sibling or related with clinical competence.90 parent may have had the disease in question. The CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 13 genetic counseling process cannot begin, however, consecutive, spontaneously aborted fetuses, almost without an accurate diagnosis. Information about one- third had malformations, most associated the exact previous diagnosis is important not only with increased risks in subsequent pregnancies.113 for the communication of subsequent risks but Myotonic muscular dystrophy type 1 (DM), the also for precise future prenatal diagnosis. Hence, it most common adult muscular dystrophy, with an is not suffi cient to know that the previous child had incidence of about 1 in 8,000,114 serves as the para- a mucopolysaccharidosis; exactly which type and digm for preconception, prenatal and perinatal even subtype must be determined because each genetic counseling. Recognition of the pleiomor- may have different enzymatic defi ciencies (see phism of this disorder will, for example, alert the Chapter 14 ). A history of limb girdle muscular dys- physician hearing a family history of one individ- trophy will also not facilitate prenatal diagnosis ual with DM, another with sudden death (cardiac because there are two dominant types (1A and 1B) conduction defect) and yet another relative with and at least six autosomal recessive types (2A – cataracts. Awareness of the autosomal dominant 2F). 104 Similarly, a history of epilepsy gives no clear nature of this disorder and its genetic basis due to indication of which of over 45 genes and suscepti- a dynamic mutation refl ected in the number of bility loci are involved. 105– 107 Birth of a previous trinucleotide (CTG) repeat units raises issues child with craniosynostosis requires precise deter- beyond the 50 percent risk of recurrence in the mination of the cause (where possible) before risk offspring of an affected parent. As the fi rst disorder counseling is provided. Mutations in seven genes characterized with expanding trinucleotide repeats, (FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2, the observation linking the degree of disease sever- RAB23) are clearly associated with monogenic syn- ity to the number of triplet repeats was not long in dromic forms of craniosynostosis. 108 Moreover, a coming. 114 In addition, the differences in severity chromosomal abnormality may be the cause. when the mutation was passed via a maternal Awareness of genetic heterogeneity and of intra - rather than a paternal gene focused attention on and interfamily phenotypic variation of a specifi c the fact that congenital DM was almost always a disorder (e.g. tuberous sclerosis)109 is also neces- sign of the greatest severity and originating through sary. The assumption of a particular predominant maternal transmission. However, at least one genotype as an explanation for a familial disorder exception has been noted. 115 There is about a 93– 94 is unwarranted. The common adult - dominant percent likelihood that the CTG repeat will expand polycystic kidney disease due to mutations in the on transmission. This process of genetic anticipa- ADPKD1 gene has an early infancy presentation in tion (increasing clinical severity over generations) 2– 5 percent of cases. 110 However, mutations in the is not inevitable. An estimated 6– 7 percent of cases ADPKD2 gene may result in polycystic kidney of DM are associated with a decrease in the number disease and perinatal death111 and, further, should of triplet repeats or no change in number. 116 Rare not be confused with the autosomal recessive type cases also exist in which complete reversal of the due to mutations in the ARPKD gene. mutation occurs with spontaneous correction to a Instead of simply accepting the patient’ s descrip- normal range of triplet repeats. 117– 120 tion of the disease – for example, muscular dystro- There are also reports of patients born with a phy or a mucopolysaccharidosis – the counselor decreased number of triplet repeats who neverthe- must obtain confi rmatory data. The unreliability less show no decrease in the severity of their of the maternal history, in this context, is remark- DM. 121– 123 It is unclear whether these cases in part able, a positive predictive value of 47 percent refl ect somatic or germline (either or both com- having been documented.112 Photographs of the bined) mosaicism. 116 Somatic mosaicism is cer- deceased, autopsy reports, hospital records, results tainly well documented in DM with, for example, of carrier detection or other tests performed else- larger expansions being observed in skeletal muscle where and other information may provide the than in peripheral blood. 124 Another problem that crucial confi rmation or negation of the diagnosis complicates molecular diagnosis is that < 2 percent made previously. Important data after miscarriage of individuals without expanded triplet repeats may also infl uence counseling. In a study of 91 nevertheless have DM. 116,125,126 Discussion about 14 Genetic Disorders and the Fetus

on such instructions to improve their health status. Box 1.2 Myotonic muscular Such directive approaches are not consonant dystrophy: potential pregnancy, with the overwhelming consensus of opinion that neonatal and other complications 127 governs genetic counseling. Nondirective genetic Potential abortion counseling has been endorsed by medical geneti- 106,132 – 135 Fetal death cists, as well as by the World Health Organ- 136 Polyhydramnios ization Expert Committee on Genetic Counseling Prolonged labor and in a multinational study focused on the atti- 137,138 Fetal distress tudes of genetic counselors. In an analysis of 139 Uterine atony nondirective genetic counseling, Kessler prof- Postpartum hemorrhage fered this defi nition: “ Nondirectiveness describes Cardiac arrhythmias procedures aimed at promoting the autonomy and Increased sensitivity to anesthetic and relaxant self - directedness of the client. ” The role of the phy- agents sician and genetic counselor is to provide the most Postoperative respiratory depression complete information available, remaining impar- Neonatal death tial and objective in this communication process Arthrogryposis while recognizing a tenet of medicine as being to Mental retardation prevent disease. This might not be an easy task. Hsia140 validly observed that optimistic counselors may tell anxious individuals not to worry, whereas pessimistic ones might unwittingly exaggerate the potential complications of pregnancy (Box 1.2 ) in signifi cance of even small risks. Not unexpectedly, the prospective affected mother is crucial. 127 signifi cant differences in counseling techniques The lack of CAG triplet expansion among indi- mirror the divergent views of counselors on the viduals presenting with Huntington disease - like goals, content and process of genetic counseling. 14 symptoms and a family history of neurodegenera- On the other hand, Kessler139 believes that the dif- tive disease has focused attention on phenocopies fi culties counselors have with answering direct of Huntington disease. 128 Estimates of such pheno- questions and being nondirective reveal a lack of copies range between 1 and 2.4 percent of patients skill and an incompetence, which he lays at the manifesting Huntington disease- like signs with a door of inadequate training. In calling for correc- family history of a neurodegenerative disorder. 129 tion of the major inadequacies in counseling, train- Among the reported phenocopies found thus far ing and skill, he emphasized that nondirectiveness are a familial prion disease 128 and a triplet expan- is an “ active strategy ” aimed at “ evoking the cli- sion (CAG/CTG) in the junctophilin- 3 gene on ent’ s competence and ability for self- direction. ” chromosome 16 in patients presenting with Hunt- The expansion of genetic counseling training and ington disease- like manifestations.130 degree programs (at least in the USA) has amelio- The guiding role to explain a clinical diagnosis rated many of these issues. as due to a single cause will not always apply. Michie et al. 142 studied nondirectiveness in Careful attention to the clinical presentation, genetic counseling. They defi ned directiveness as including the family history, will enable recogni- advice and expressed views about or selective rein- tion of more than a single disorder. Two examples forcement of counselees’ behavior, thoughts or include a personal case of hypohidrotic ectodermal emotions. Not unexpectedly, they concluded that dysplasia and the Loeys – Dietz syndrome and a genetic counseling as currently practiced was not reported case of concomitant spinal muscular characterized, either by counselors, counselees or atrophy and Rett syndrome. 131 a standardized rating scale they used, as uniformly nondirective. Nondirective c ounseling Clarke143 remarkably argued that nondirective Physicians are accustomed to issuing therapeutic genetic counseling in the context of prenatal diag- directives and indeed, patients invariably depend nosis is “ inevitably a sham, ” largely because of the CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 15

“ structure of the encounter between counselor and are known to have specifi cally not offered or client. ” He further contended “ that an offer of pre- referred patients for prenatal genetic studies natal diagnosis implies a recommendation to because of their antiabortion views and have accept that offer, which in turn entails a tacit rec- unconscionably exaggerated the specifi c risks of ommendation to terminate a pregnancy” if the amniocentesis in order to discourage prenatal fetus is abnormal. Forty years ago,144 it was empha- genetic studies. A Mexican study showed that phy- sized that the offer of prenatal diagnosis was not sicians in specialties other than clinical genetics associated with any explicit or implicit commit- tend to counsel directively. 153 ment to abort. Clarke 143 further opined that “ non- The duty of the physician and genetic counselor directive counseling was unattainable, despite the is to communicate all the available information counselor’ s motives, since the offer and acceptance and then to assist a counselee to recognize his or of genetic counseling has already set up a likely her major priorities, beliefs, fears and other con- chain of events in everyone ’ s mind. ” Experienced cerns in order to make possible the counselee ’ s clinical geneticists were taken aback by his rational decision making. To remain impartial is views,145 – 147 and rightly so. He regarded reproduc- diffi cult and takes valuable time and conscious tive choice as part of the “ 1980s consumerism effort but it is largely attainable. Time - pressed model of clinical genetics.” 148 The personal values nongeneticists providing genetic counseling may of geneticists/counselors may infl uence behavior in easily experience slippage between choice and clinical practice and individual vigilance is neces- coercion. 154 The diffi culty lies mainly in trying to sary to abide by the nondirective principle. This remain impartial while aiming to prevent the may be less challenging than imagined given the occurrence of genetic disease. The insinuation of reported highly valued benevolence, self- direction the physician’ s prejudices into the decision- mak- and pattern of concern for the welfare of others. 149 ing process of the counselee constitutes a moral Clarke ignored a fundamental tenet of genetic affront to individual privacy and reproductive counseling founded in a free society, where choice autonomy.151 is not a fad but a right. His ideas suggest contempt In rare instances, family circumstances may for the views (and hence choices) of the public, challenge the need to adhere to personal autonomy maintaining that respect for the handicapped is not and nondirective counseling. The right of one achievable in a society that “ makes judgements monozygous twin at 50 percent risk for Hunting- about what types of people are worthy of life. ” 148 ton disease not to know information after predic- Others have reported that people’ s decision- mak- tive testing should be respected. If there is possible ing processes are more rational than they might harm to the co- twin, Chapman suggested that appear to be. 149 Simms150 noted that with hindsight, testing should “ be denied in the absence of mutual 80 percent of parents with handicapped children consent. ”155 She further argued that in the interest would have aborted their pregnancies. Later, in of benefi cence, directive counseling is acceptable taking Clarke to task, she concluded that it was “ his for individuals at 50 percent risk of Huntington professional duty to advise parents to the best of disease, who suffer from depression, lack social his ability, not to make decisions for them. They support and have a history of attempted suicide. will have to live with the consequences: he will For these patients, psychiatric evaluation and not.” 151 counseling, rather than predictive testing, have The intrinsic danger of using a directive been recommended. In a study of counseling fol- approach is the opportunity (even subconscious or lowing prenatal diagnosis of Klinefelter syndrome, inadvertent) for the physician/counselor to insinu- Marteau et al. 156 found that pregnancy was almost ate his or her own religious, racial, eugenic or other two and a half times more likely to continue when beliefs or dictates of conscience into the counseling counseling was provided by a geneticist. that is offered. 107 A breach of this principle, sup- ported by some,152 invites the provider to visit Concern for the i ndividual upon the patient unwarranted conscious or sub- Many issues should be raised by the physician or liminal prejudices. Some obstetricians, for example, genetic counselor during counseling. Communica- 16 Genetic Disorders and the Fetus tion should not depend on questions posed by the note in the patient ’ s record. A brief letter to the patient, who may not be cognizant of the subject’ s patient noting the indication for prenatal study dimensions or the available options. For example, and that such study was declined is also helpful. in the case of a couple who are at risk of having a Litigation has ensued in which patients have main- profoundly retarded child, the physician should tained that no amniocentesis had been offered, explore the consequences for the inter - relation- while obstetricians (without notes in the records) ships of the couple, the effects on their other chil- have taken an opposite view. dren, the suffering of the affected child, the possible social stigma 89 and the economic and other societal Truth in c ounseling implications, as well as the need for contraception. Since the time of Hippocrates, physicians have Many feel that the economic burden of a defective often withheld the truth from their patients and, as offspring on society should at least be mentioned Katz157 emphasized in The silent world of doctor and as part of a comprehensive view of all issues being patient, defended the morality of this position. considered. Although this may not be unreasona- Sparing the patient emotional distress, removing ble, the major emphasis should focus on the hope and/or diminishing the physician’ s personal concern for the individual, whose priorities, needs esteem may have been some of the quintessential and choices remain paramount. In the physician/ reasons for the lack of truth telling. While recog- counselor– patient relationship, concern for the nizing the modern change in moral sentiment, individual should always over - ride consideration Lantos158 acknowledged that truth telling has of the needs of society. Many avenues exist for become “ morally obligatory.” Notwithstanding his society to infl uence the actions of its citizens. In preference that he “ would not want a doctor genetic counseling, the role of the physician/coun- judging the morality of my decision, ” he remained selor is not that of an advocate for society. uncertain about the value of the “ comforting lie. ” A couple may elect to have an amniocentesis In a number of situations in genetic counseling, that is indeed indicated without making a commit- it is possible that the facts may be deliberately dis- ment to pregnancy termination if the fetus is found torted, de- emphasized or even hidden. Obstetri- to be abnormal. Some may deny such couples the cians opposed to prenatal genetic studies and opportunity for prenatal genetic studies. All abortion of an abnormal fetus have been known to couples have a right to have information about deny the genetic origin of a disorder, to describe it their fetus and prenatal diagnosis is a fundamen- as a fl uke occurrence or to provide incorrect (much tally reassuring technique.130 More than 95 percent lower) recurrence fi gures. of such couples do not need to consider elective The physician may be unable to establish an abortion. The few who are initially ambivalent exact diagnosis, to be certain of the carrier status almost invariably move to terminate the pregnancy of an individual or to predict accurately the after the detection of a serious fetal defect. Never- outcome of pregnancy when faced with a very theless, abortion may be declined after the prenatal unusual fetal karyotype. Painful as it may be to diagnosis of disorders such as trisomy 21, anen- both parties, the physician must ensure that cephaly or trisomy 13. Concern for the individual patients understand the limitations completely. includes providing ambivalent couples with the The unexpected fi nding, for example, of an XYY opportunity for reassurance or the choice to fetus should not be withheld from the parents, decline abortion with preparation for the conse- despite the inability to predict with certainty the quences. Moreover, opportunities to save their ultimate development of an individual so affected offspring ’ s life, or at least to improve the outcome, (see Chapter 7 ). now exist in specifi c circumstances (e.g. for In the course of a prenatal diagnostic study, omphalocele). The availability of adoption should blood samples from both parents may be called for be emphasized. to elucidate a potential diagnostic dilemma. On Quite often, a patient declines an otherwise occasion, such studies unexpectedly reveal nonpa- clearly indicated amniocentesis. Today, the stand- ternity. Not sharing this information with the ard of care dictates the need for an explanatory patient’ s husband may subsequently have legal CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 17 implications. The management and resolution of sacrosanct. The American Medical Association has such a problem will most often rest on the nature affi rmed the importance of keeping genetic infor- of the dilemma (for example, translocation, dele- mation confi dential.162 Established precedent for tion) to be solved. Advising the mother of these breaking this confi dentiality relates to recognition fi ndings, as well as the paternity issue, is necessary, by the physician of danger to a third party. Threats as is documentation in the physician ’ s notes. to kill a former girlfriend shared with a psychiatrist The expanding indications for prenatal diagno- were recognized by the courts as knowledge that sis and the use of molecular techniques for carrier should have been communicated.163,164 Certainly, detection and prenatal diagnosis are likely to the clinical notes and letters should refl ect the increase the frequency of detected nonpaternity. geneticist’ s recommendation that the patient The warning that the rate of infi delity is higher promptly contact the indicated close relatives who than the rate of inborn errors of metabolism should are at risk for a specifi c genetic disorder. not be reserved for medical students only. Manage- However, faced with an intractable patient, ment is invariably tricky and medical, ethical and some guidance about disclosure is refl ected in a legal issues abound. An important guiding princi- statement issued by the American Society of ple is that the noncarrier male partner should not Human Genetics in 1998. 165 When serious and be misled. foreseeable harm to at - risk relatives can be antici- pated, when the disorder is preventable or treatable Confi dentiality and t rust or when reduction of risk through monitoring is Action by the physician after the diagnosis of the achievable, disclosure is seen to be permissible. carrier state for an X - linked disease demands more “ The harm that may result from failure to disclose than simply offering prenatal studies in all subse- should outweigh the harm that may result from quent pregnancies. There is an obligation to convey disclosure. ” In practice, few geneticists appear to this information to the sisters of any such carrier have warned at - risk relatives without patient female. The patient may, however, expressly forbid consent. The vast majority of medical geneticists the physician to communicate this information, who decided not to warn such relatives were con- even to her sisters at risk, despite the international cerned by patient confi dentiality issues and legal consensus that individuals have a moral obligation liability.166 to communicate genetic information to their family members.159 Certain legal pitfalls involving Timing of g enetic c ounseling the transmission of privileged communications Today, more than ever before, counseling before and breach of medical ethics 159 need to be consid- conception or marriage167 may provide opportuni- ered by the conscientious physician faced with this ties for carrier detection, prenatal diagnosis or the rare but not unheard of situation. A view rein- presentation of other important options noted forced by the courts posits that there is a duty to earlier. Therefore, the optimal time to initiate warn the relative at risk as a standard of expected counseling is not during pregnancy. Counselees care despite the absence of a physician/counselor whose fi rst antenatal visits occur after the second relationship,152,160 regardless of privacy laws! Prior missed menstrual period miss the critical period of consent to contact relatives (given frequent disaf- organogenesis and patients referred well after con- fection in families) is another option. 161 The need ception have lost almost all their options except for for caution is clear when one realizes that in some selective abortion. Given the 70 percent protection states in the United States, the physician may lose afforded by periconceptional folic acid supplemen- his or her license to practice medicine after a tation against the occurrence of an NTD 27,28 (see breach of confi dentiality. Chapter 23 ), there is a need to advise women about Disclosure to third parties, other than relatives, the importance of preconception care. also includes employers, insurance companies and Confronted by a fatally malformed newborn, the schools. It is hoped that the confi dentiality of the physician may attempt to counsel a couple on the physician – patient relationship and the patients ’ very day of the birth of such a child or before the right to privacy and personal autonomy remain mother ’ s discharge from the hospital. Although 18 Genetic Disorders and the Fetus communication and support are both vital during that were independently and signifi cantly associ- those fateful days, the physician needs to recognize ated with problems experienced by 43 percent of the great diffi culty that anguished patients would counseled couples. These included no postcoun- have in assimilating or comprehending even the seling support, recognition of high risk, disap- essence of any counseling. 151,168,169 The physician/ proval by relatives, the presence of an affected child counselor should share with the couple his or her and decisions not to have a (or another) child. Due awareness that it is diffi cult to remember all the diligence is necessary for the partners of genetic important information in the face of emotional disease carriers who clearly experience signfi cant upset and that it would be normal and expected for psychologic distress. 171 them to raise all the same questions some weeks later, when the entire subject could be fully covered. Counselee e ducation Support for the parents should continue to be Hsia et al. 169 emphasized that genetic counseling is available for many months. an educational process in which the counselee acquires a set of facts and options. Fraser’ s 129 essen- Parental c ounseling tial message was that genetic counseling does not Physicians/counselors have a duty to convey infor- involve telling families what they should do but mation about the known options, risks, benefi ts rather what they can do. We maintain that members and foreseeable consequences 75– 77 to couples with of the health professions should adopt as a guiding increased risks of having children with genetic principle the critical imperative that the concept of defects. Such a duty may be diffi cult, if not impos- genetic counseling be introduced in high school sible, to fulfi ll if only one member of the couple and in continuing public education 140,171– 173 about attends genetic counseling. The issues are usually genetic disease. Children sensitized in school about complex and are frequently compounded by feel- the importance of the family history, elements of ings of guilt and by ignorance, family prejudices, heredity, concepts of individual susceptibility and religious obstacles, fear and serious differences of risk and opportunities for anticipatory prevention opinion between partners. Hence, when possible of unnecessary catastrophes are likely to better (at the time the appointment is made would seem comprehend pregnancy risks and options. to be best), the necessity that the couple attend Genetic counseling and prenatal diagnostic serv- together should be emphasized. Physicians/coun- ices are of little avail if many women attend for selors have often seen an extremely anxious parent their fi rst antenatal visit after 16 weeks of gestation. attend counseling alone and then have learned Currently, this is the case in many urban hospitals later of the counselee ’ s incorrect interpretation to in the Western world, where between 20 and 40 the partner, lack of appreciation of the true risk percent of obstetric patients arrive at this late stage. fi gures and unnecessary emotional chaos. Not even Education beginning in high school and continued letters written to couples after the counseling ses- by public health authorities working in the public sion77a (a recommended procedure, to summarize sector could effectively communicate the critical the essence of the counseling provided) can safely importance of preconception and prenatal care. substitute for face- to - face discussions with both, allowing for questions and interchange about the Duty to r econtact issues and an opportunity to examine the partner. The remarkable and rapid advances in medical Genetic counselors should be cognizant of the genetics have introduced a “ new ” responsibility complex interactive factors involved in parental related to the well - established requirement to dis- reproductive decision making. Frets 170 confi rmed close risk information that materially bears on a the importance of the burden of the disease in patient’ s decision making. 174,175 Pelias175 focused question and found that the interpretation of risk attention on the geneticist’ s continuing obligation (high or low) and the wish to have children were to recontact patients when new information devel- paramount factors. The absence of personal expe- ops that would prove material to them, so far as rience of the disease was also found to be a signifi - personal health and child bearing are concerned cant infl uence. Frets identifi ed a number of factors (see Chapter 33 ). The implications raise serious CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 19 ethical, legal and policy issues. 165,176,177 Certainly, escalating number of neurodegenerative disorders following genetic research and new meaningful (e.g. Huntington disease; some of the spinocere- results, an ethical duty to inform the patient has bellar ataxias) and certain serious disorders incld- become apparent. 156a Medical genetics consulta- ing multiple endocrine neoplasia type 2B and tions frequently involve only one encounter and breast, colon and other malignancies. Published the requirement to contact that patient years later recommendations and guidelines180 urge rigorous may be regarded as both irrational and unreason- pretest and post- test genetic counseling and rec- able. Pelias pointed to a 1971 case178 in which the ommendations that testing of children younger University of Chicago failed to notify women who than 18 years of age be proscribed, except in life - had been given diethylstilbestrol. The University threatening disorders (e.g. multiple endocrine had apparently become aware of the dangers of this neoplasia type 2B). The inherent harm that could drug but had delayed notifi cation for 4– 5 years. In potentially be done by presymptomatic testing is yet another case, after a single visit to her gynecolo- the potential for demoralization and depression gist for insertion of an intrauterine device (a with possible suicidal consequences. Extreme Dalkon Shield), a woman sued this physician for caution is recommended in considering predictive failing to notify her of the subsequently recognized testing for a disorder without curative, let alone risks of this device. 179 In that case, as Pelias noted, meaningful, palliative treatment. Although for the court allowed the case to proceed because of certain dominant disorders some 50 percent of the continuing status of the physician– patient rela- individuals at risk may receive good news, the tionship and because the physician had a “ separate other 50 percent face, effectively, a death sentence. duty to act.” 179 Given the remarkable pace of advances in human In cases in which reasonable expectations for genetics, it may well be possible in the foreseeable signifi cant advances exist (e.g. tests for carrier future to develop a therapy that enhances the detection or prenatal diagnosis), the authors rec- extant biologic mechanism already in place that ommend that the patient be in contact annually delays the manifestations of later- onset disease for and/or before planned child bearing. Pelias 175 decades after birth. No life should be ruined by opined that this recommendation should be severe depression or suicide only to discover later recorded in clinical notes and echoed in letters to that a critical palliative remedy has emerged. referring physicians and patients alike. Ultimately, Clearly, there are extraordinarily diffi cult cir- the responsibility to return for further counseling cumstances related to planned child bearing in the in the light of new advances must be vested with face of 50 percent risks for a neurodegenerative the patient’ s primary care physician and shared disorder coupled with a wish not to know. In these with the patient. To a variable extent, the patient ’ s special circumstances, predictive testing can be physician can be expected to remain cognizant of regarded as acceptable only if performed with genetic risks family members may have and refer extreme care, concern and professionalism. them for specifi c genetic counseling or testing Preconception care should begin during visits to when appropriate. However, given that tens of the family physician after menarche. Reiterated millions change their addresses annually and fre- and expanding discussions on personal health quently seek other medical care, the patients habits that will affect both the adolescent herself themselves, once informed of potential advances and a future child provide a basis for promoting and the need to remain in contact with a clinical good health behavior, while a solid grounding in geneticist, take on personal responsibility. knowledge about the hazards of smoking, drugs, alcohol, sexually transmitted diseases and nutri- Do n o h arm tion is provided. Early adolescence is also a vital The classic exhortation primum non nocere (fi rst, period during which to inculcate the importance do no harm) is as pertinent to clinical genetics as of genes and the wisdom of assimilating and updat- it is to medicine in all specialties. Attention to this ing information on family history. Linkage of principle arises particularly in the context of pre- family history to the common experience of physi- dictive genetic diagnosis, possible for a rapidly cal and mental handicap, outlined in the context 20 Genetic Disorders and the Fetus of personal risk in child bearing, provides a com- harbored 151 presymptomatic carriers! The loss of pelling and cogent framework on which physi- chance doctrine makes it incumbent upon geneti- cians, teachers and parents can build. cists/counselors to impress on their patients the This preparatory background may help educate need to warn blood relatives, if a serious genetic all women about the importance of planning preg- threat is determined. This counsel should be in nancy. Over 50 percent of pregnancies in the writing and documented in the medical record. United States are not planned and are often unin- Litigated examples include failure to warn of the tended. 181 Physicians also need to reorient their risk of medullary thyroid cancer, familial adeno- practices so that women of child - bearing age matous polyposis with colon cancer and the fragile understand that to optimize the chance of having X syndrome (see Chapter 33 ). a healthy child,171 prenatal care is best initiated before conception and not after the second missed Preconception g enetic c ounseling menstrual period, as is still anachronistically prac- ticed so widely. It is an anachronism that preconception care in The discovery or realization of nonpaternity at the 21st century, despite being recognized as the time of prenatal diagnosis is fraught with important, is not widely practiced. 185,186 Expecta- potentially serious personal, medical, social and tions at the fi rst preconception visit include legal problems. The counseling provider has to be routine documentation of the medical, obstetric extremely adept in managing these cases. Warning and family history, the latter regarded arguably as about the potential discovery of nonpaternity as the most important “ genetic test” . 187 This activity part of informed consent prior to testing 182,183 may includes a review of medical records, photographs lead a pregnant woman to decline an indicated (e.g. previous stillbirths) and pertinent autopsy chorionic villus sample (CVS) or amniocentesis. reports, radiographs, brain scans and chromosome Nondisclosure is ill advised when nonpaternity is or other special laboratory reports. Physical exam- discovered. In the effort to do no harm, we have ination and necessary special tests also focus on requested a counseling session with the prospective acquired and genetic disorders that could, during mother alone. Her decision, taken in confi dence, pregnancy, threaten maternal and/or fetal welfare. would govern further action. If, however, testing of Previously undiagnosed/undetected disorders may the misattributed partner has genetic implications, be determined for the fi rst time at this visit and nondisclosure becomes legally untenable. may be important for planned child bearing and the selection of future prenatal diagnostic tests. Duty to w arn There is a need to insist that the male partner Physicians and counselors traditionally owe no attend the preconception visit (or absolutely the duty to individuals with whom they have never fi rst prenatal visit), providing an opportunity to met or entered into any treatment relationship. detect at least obvious genetic disorders and solid- However, following the decision of the California ify information possibly provided earlier about Supreme Court (in Tarasoff v. Regents of the Uni- his family history. The senior author recalls, over versity of California),129 it has become clear that many years during prenatal diagnosis counseling when a serious risk to the health or life of a third for other issues, diagnosing various disorders in party is recognized, a duty of reasonable care male partners who were wholly unaware of their evolves that demands protective action. Examples conditions, including osteogenesis imperfecta, include contact with blood relatives at risk in situ- Treacher – Collins syndrome, tuberous sclerosis, ations of threatened violence, exposure to infection neurofi bromatosis, Charcot – Marie – Tooth (type (HIV - AIDS) and now harmful genes (e.g. in famil- 1A) disease, limb girdle muscular dystrophy, facio- ial adenomatous polyposis). A salutary lesson is scapulohumeral muscular dystrophy, blepharo- provided in the study of 43 families with at least phimosis, mitral valve prolapse, the XYY male and one sudden unexplained death.184 Identifi cation of spinocerebellar ataxia. the genetic cardiac disorder (e.g. long QT syn- The fi rst preconception visit also serves to drome) was made in 40 percent of the families who instruct about the need for folic acid supplemen- CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 21 tation for the avoidance of NTDs (see Chapter 23 ) A p revious f etus or c hild with a g enetic and about diabetic control, management of d isorder obesity, cessation of illicit drugs, medications and A genetic evaluation and counseling are usually alcohol. Referral to other specialists (e.g. neurolo- indicated when a previous fetus or child has or had gists), for tailoring medication requirements to a genetic disorder, unless the matter is straightfor- safer and possibly less teratogenic agents, is also ward (e.g. previous trisomy 21) and the obstetri- recommended. This is also the time for specialists cian is well informed. Careful inquiry should be caring for the same patient to confer about the made about the health status of a previous child. planned care of their patient through pregnancy Failure or delay in the diagnosis of a monogenic and for documentation of that exchange to be disorder leaves the parents without the option of made. prenatal diagnosis in a subsequent pregnancy. Failure to make an early diagnosis of a genetic dis- Indications for p reconception g enetic order during the fi rst 5 years of life is not unusual. c ounseling For example, the Rotterdam Clinical Genetics The indications for preconception genetic coun- Group reported that 50 percent of children affected seling should be determined at the fi rst visit and by neurofi bromatosis had been treated for related can be considered in a few clear categories. symptoms before a specifi c diagnosis had been made.189 Such delay has become problematic given Advanced m aternal a ge that the NF - 1 gene and genes for many other An arbitrary age of 35 years has functioned in the monogenic disorders are routinely sequenced for a United States as an expected standard of care, precise dagnosis. which requires that a prospective mother be Not infrequently, distressed parents will select a informed of her risks of having a child with a chro- different physician for a subsequent pregnancy and mosome defect, informed of the recommendation a new or more recent insight may shed light on the for prenatal diagnosis and given an explanation of cause of the previous defect. For example, confi ned the risks of CVS or amniocentesis, with the associ- placental mosaicism (see Chapter 6 ) may now ated details related to any problems, pitfalls or res- serve to explain the discrepancy between reported ervations. In some countries, largely for economic chromosomal fi ndings at the time of CVS and fetal reasons, older ages have been used as an indication tissues obtained at elective abortion. Confi ned pla- for prenatal study. Amniocentesis risks lower than cental mosaicism may also be associated with 0.5 percent for fetal loss in some US centers prompt intrauterine growth restriction 190 requiring serial the offer of such studies earlier than 35 years of age ultrasounds during the pregnancy. (see Chapter 2 ). Given the heterogeneous nature of genetic While maternal age risk counseling is still neces- disease, being alert to alternative mechanisms of sary, risks derived from multianalyte maternal causation will on occasion be rewarding. For serum screening for DS (see Chapter 24 ) largely example, during a consultation with a patient who dominate decisions about amniocentesis. had previously delivered a child with cystic fi brosis Excluding infants with chromosome abnormali- (CF), preparatory discussions about establishing ties, a prospective analysis of 102,728 pregnancies the specifi c mutation from each parent could (including abortions, stillbirths and livebirths) in reveal that the father is not a carrier of the mutated Texas found that the incidence of congenital mal- CF gene. Although nonpaternity is more likely, a formations increased signifi cantly and progres- judicious approach would also include considera- sively in women after 25 years of age.188 The authors tion of uniparental disomy. 191 This mode of inher- found that an additional age - related risk of non- itance, in which an offspring can inherit two copies, chromosome malformations was approximately 1 part or all of a chromosome from one parent and percent in women 35 years of age or older. The no copy from the other parent, has been seen in a odds ratio for cardiac defects was 3.95 in infants of number of disorders, including Prader – Willi syn- women 40 years of age or older when compared drome192 and Angelman syndrome.193,194 About 30 with women aged 20– 24 years. percent of cases of Prader– Willi syndrome are 22 Genetic Disorders and the Fetus caused by maternal uniparental disomy. 192 These disorder affecting one parent, and the concern vis- disorders, then, represent situations in which one à - vis prenatal diagnosis and pregnancy termina- parent is the source of both gene mutations tion is about personal existence and self - extinction. for a recessively inherited condition. Disorders This dilemma was exemplifi ed by a young father involving chromosomes 11, 14 and 15 have been with CADASIL (cerebral autosomal dominant notable.195 Uniparental disomy is caused primarily arteriopathy with subcortical infarcts and leukoen- by meiotic nondisjunction events and followed by cephalopathy) who, faced with our prenatal diag- trisomy or monosomy “ rescue. ”196 Most cases nosis of this disorder, by mutation analysis of the described have been associated with advanced Notch3 gene, with his wife, elected termination. 199 maternal age and have been detected primarily in Mutation analysis in a subsequent pregnancy the process of prenatal genetic studies. 196 assured an unaffected fetus.200 Recognition of the molecular basis of a disorder These consultations may invoke deep personal from which a previous child died may provide a emotional confl ict, especially when pleiomorphic couple with an opportunity for prenatal diagnosis genes are concerned. For example, a parent with in a subsequent planned pregnancy. A caveat tuberous sclerosis and normal intelligence could would be the availability of analyzable tissue from not be certain that an affected child would not be the deceased child. In the recent past this was mentally retarded. This was especially evident in mostly not done but with the escalation of new our series of 50 couples having prenatal diagnosis discoveries in genetics, tissues are now being frozen for tuberous sclerosis.198 Discovery of fetal cardiac for potential future DNA analysis. The establish- rhabdomyoma led to sequencing of both the TSC1 ment of the molecular basis of recognized syn- and TSC2 genes in the fetus and diagnosis in one dromes, previously undetectable prenatally, now of the asymptomatic parents. Parental decisions provides new opportunities for couples seeking are neither simple nor predictable. In a UK study 201 prenatal diagnosis. Examples abound (see Chapter of 644 deaf individuals and 143 with hearing 10 ) and include some of the craniosynostosis syn- impairment, 2 percent opined that they would dromes, certain skeletal dysplasias and many other prefer to have deaf children and would consider an disorders. elective abortion if the fetus was found to be In one of our cases, a father with metaphyseal hearing. dysplasia of Schmid, troubled by the indignities Certain genetic disorders may (1) threaten and hurts of growing up with severe short stature, maternal health in pregnancy, (2) threaten fetal elected prenatal diagnosis at a preconception visit. health and survival or (3) be aggravated by Subsequent mutation analysis of conceived twins pregnancy. yielded a normal prenatal diagnosis result con- fi rmed postnatally. 197 Genetic d isorders that t hreaten m aternal h ealth Heterogeneity and pleiotropism also require Dramatic advances in medical care have resulted consideration in the context of a previous child ’ s in more women affected by genetic disorders sur- disorder and anticipation of future prenatal diag- viving to child- bearing age and becoming preg- nosis. For example, a previous child with tuberous nant. There are several genetic disorders affecting sclerosis or a fetus with cardiac rhabdomyomas the mother that can be aggravated and worsened would prompt molecular analysis of the TSC1 during pregnancy. Awareness of these disorders and 2 genes for more precise future prenatal facilitates better preconception anticipatory guid- diagnosis.198 ance and expectant management during preg- nancy. Metabolic disorders that may worsen A p arent with a g enetic d isorder include ornithine transcarbamylase defi ciency, Given the pace of advances in human genetics, homocystinuria, acute intermittent porphyria and physicians are advised to determine whether pre- lysinuric protein intolerance. Hyperammonemia natal diagnosis has become available for the spe- during pregnancy/delivery or postpartum coma cifi c genetic disorder under discussion. Increasingly, may be the presenting signs of a female heterozy- these discussions may focus on a dominant genetic gote with ornithine transcarbamylase defi ciency.202 CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 23

Thrombophlebitis and other thromboembolic 8. Prophylactic antibiotics should be used because events have been reported during pregnancy and of the likely associated presence of mitral valve operative delivery in women with homocystinu- prolapse. ria.203 Ehlers – Danlos syndrome IV, Marfan syn- Additional advice would be to avoid contact sports, drome and Loeys – Dietz syndrome may have physical exhaustion and isometric exercises (push- associated aortic/vascular rupture and uterine ups, pull- ups) or weight lifting. Encouraged by rupture during pregnancy and delivery.204 – 206 Diag- promising therapeutic response to an angiotensin nostic gene sequencing for all three disorders is II receptor blocker in a mouse model of Marfan available. In a study of 12 women with Loeys– Dietz syndrome and a limited clinical study,211 a rand- syndrome with 21 pregnancies, six had one of these omized trial comparing β - blocker therapy is in major complications. 207 progress. 212 Sophisticated care and counseling are necessary First - trimester spontaneous abortion and gas- for women with Marfan syndrome who are con- trointestinal bleeding during pregnancy have been sidering pregnancy. A Dutch study of 63 affected described in women with pseudoxanthoma elasti- women who had 142 pregnancies revealed that cum.213 Worsening of the mother’ s pulmonary in 40 percent of completed pregnancies, there status is seen with cystic fi brosis. 213a An increase in was an obstetric and/or neonatal complication. the size and number of neurofi bromata during Prematurity, preterm premature rupture of mem- pregnancy in women affected with neurofi broma- branes, cervical incompetence and increased tosis type 1 may occur (in 60 percent of 105 cases (7.1 percent) fetal and neonatal mortality were in one study214 ) and has resulted in both cosmetic reported. 208 Among the guidelines for Marfan changes as well as signifi cant morbidity (paraplegia syndrome recommended by Lipscomb et al.204 are with rapid growth of intraspinal tumors). 215 Hyper- the following. tension may be a problem for the pregnant patient 1. Women with Marfan syndrome who are plan- with either neurofi bromatosis type 1 or autosomal ning to have children should be encouraged to do dominant polycystic kidney disease. As well as so in their early 20s, given that the mean age for causing potentially life- threatening events for aortic dissection is 32 years.209 both the fetus and mother affected by myotonic 2. Women should be counseled that there is a sig- muscular dystrophy, 112,216 the condition itself may nifi cant likelihood of aortic dissection if the aortic worsen during a pregnancy.216 Hematologic disor- root dimension exceeds 4.0 cm or if there has been ders may complicate pregnancy by altering normal a steady increase in this dimension over preceding physiology. visits. Carriers of hemophilia A are best cared for by a 3. Monthly echocardiography during pregnancy high- risk perinatal obstetric group. Prenatal sex should begin as early as 6 weeks of gestation. determination (whether or not prenatal diagnosis Lipscomb et al. emphasize that aortic catastrophes by mutation analysis is chosen) is important for are not confi ned to late pregnancy, labor and the the management of labor and delivery, with special postnatal period. reference to the possible need for cesarean section. 4. Vaginal deliveries with epidural anesthesia are In addition, vacuum - assisted delivery with an recommended for women with stable aortic meas- affected male could result in a massive cephalohe- urements < 4 cm during pregnancy. matoma requiring blood transfusion.217 Moreover, 5. Elective cesarean section with epidural anesthe- a high incidence of primary and secondary post- sia is recommended for women with changes in partum hemorrhage in carriers of hemophilia A aortic root dimensions during pregnancy and for (22 percent) and hemophilia B (11 percent)217 those with measurements exceeding 4 cm. should further inform anticipatory care. 6. Hypertension must be treated aggressively and ideally with β - blockers.210 Maternal g enetic d isorders that m ay t hreaten f etal 7. Routine β - blocker treatment slows the rate of h ealth and s urvival aortic dilation and should be used at least after the Among the more common examples in this cate- fi rst trimester. gory are diabetes, sickle cell disease, epilepsy,218 and 24 Genetic Disorders and the Fetus lupus erythematosus. Fetal loss, stillbirth and mal- was known for 75 patients noted a prematurity rate formations are the primary concerns. Lupus is of 18 percent and one maternal death during preg- associated with a signifi cant frequency of congeni- nancy.226 Later, some 12 deaths were recorded after tal heart block in seropositive mothers219 and elec- pregnancy, with three in the year following the tronic fetal monitoring in the third trimester and pregnancy. Four affected children were diagnosed during labor is important. However, caution after birth. Clearly, partners should be tested for should attend plans for immunosuppressive treat- their CF carrier status before the initiation of preg- ment. In a Brazilian study, 32 (78 percent) of 41 nancy in a woman with CF (see Chapter 17 ). A fetuses with normal cardiac anatomy and seroposi- Norwegian study of pregnancy with CF noted tive mothers received no treatment, with livebirth preterm delivery in 24 percent of cases and the and 1 - year survival rates of 97 percent and 93 development of gestational diabetes in four of 23 percent respectively. 220 As many as 60 percent of patients.227 Similar observations were made in a mothers of offspring with congenital heart block Swedish study, except that these authors noted an have lupus or other connective tissue disorders. overall mortality rate of 19 percent among 48 Maternal myotonic muscular dystrophy, which patients.228 If pregnancy is pursued regardless of may be presymptomatic, is a key example in which counseling, special care and attention will be nec- both the life and health of the mother and fetus/ essary and hospitalization is commonly needed at child may be threatened. 221,222 In addition to the some time during the third trimester (see Chapter earlier discussion, serious- to - fatal fetal/neonatal 17 ). Women with severe sickle cell disease may also complications can be anticipated.221,222 One study become sicker during pregnancy and should be showed that 12 percent of the offspring of affected counseled accordingly. In some women, epilepsy is women are stillborn or die as neonates, 9 percent aggravated by pregnancy and could threaten the survive although severely affected and 29 percent life of both mother and fetus. Given the potential are affected later. 223 Awareness of the obstetric - teratogenic risks of anticonvulsants (in the 7– 10 related risks facilitates optimal pregnancy care but percent range),229 change to the least teratogenic does require in - depth preconception discussion. medication should be achieved in the preconcep- Untreated maternal phenylketonuria (PKU) tion period and should be done under the direct represents a potentially unmitigated disaster for guidance of a neurologist. the fetus and child. Besides pregnancy loss, there is Prospective mothers with insulin - dependent a 90 percent likelihood of mental retardation, diabetes mellitus (IDDM) could fi nd their disorder cardiac or other defects in the offspring of mothers harder to control during pregnancy. Diabetes who undertake pregnancy without being on strict should be well controlled before pregnancy. The preconception dietary therapy.224 Caution needs to better the control, the lower the risk of having a be exercised in counseling women with PKU, espe- child with congenital defects.230,231 An Australian cially if adherence to diet has been an issue. Com- study noted that with good preconception care of prehension and decision making may be less than type 1 IDDM, the major congenital malformation adequate given the increased realization of residual rate decreased from a high of 14 percent to 2.2 behavioral and intellectual defi cits.225 Similar cau- percent.232 Notwithstanding extant knowledge tions are obvious for other disorders (e.g. fragile X about IDDM and pregnancy, a report of 273 syndrome; see Chapter 9 ) where similar limitations women noted rates of stillbirth (1.85 percent), peri- may be evident and complicate informed consent natal mortality (2.78 percent) and congenital and decision making generally. anomalies (6 percent).233 In our study maternal obesity clearly posed an increased risk of congenital Genetic d isorders that p regnancy m ay a ggravate malformations (as noted earlier), probably through Women who are severely affected by CF may jeop- a metabolic route involving prediabetes. 36 ardize their survival by becoming pregnant and Muscle weakness may increase during should be advised accordingly. Those with mild - pregnancy in women with limb girdle muscular to - moderate disease are likely to have a successful dystrophy, leading to the need for assistance after pregnancy. A French study in which the outcome delivery.231 In women with congenital myopathies, CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 25 including central core disease and cytoplasmic analysis. After analysis of 100 of the most common body myopathy, cesarean sections may be needed mutations, we found that only 35.9 percent of men more frequently and some deterioration in preg- with CBAVD had two identifi able mutations, 31.5 nancy and weakness after delivery may be experi- percent had only one mutation recognized and no enced.234 Anesthetic risks may be increased in CF mutation was found in the remainder.241 women with central core disease in whom malig- Sequencing of the CFTR gene should follow, espe- nant hyperthermia may be a complication.235 cially if the partner is a CF gene mutation carrier. The mutation detection rate is likely to exceed 92 A h istory of i nfertility percent including large gene rearrangements.242 Of About 10 percent of couples have infertility prob- interest is the observation of Traystman et al. 243 lems. A World Health Organization multicenter that CF carriers may be at higher risk for infertility study concluded that the problem appeared pre- than the population at large. dominantly in males in 20 percent of cases, pre- Some patients with CBAVD (21 percent in one dominantly in females in 38 percent and in both study244 ) also have renal malformations. These partners in 27 percent. In the remaining 15 percent patients may have a normal sweat test and thus far of cases, no defi nitive cause for the infertility was no recognizable mutations in the CF gene.244 Renal identifi ed. 236 Care should be exercised in the pre- ultrasound studies are recommended in all patients conception counseling of a couple with a history with CBAVD who have normal results on a sweat of infertility. In the absence of a recognizable cause, chloride test and no identifi ed mutations. karyotyping of both is recommended. Unrecog- The partner of a male with CBAVD should rou- nized spontaneous abortions may have occurred tinely be tested for the common CF mutations and without the patient ’ s awareness, caused by overt optimally by gene sequencing. Such couples fre- structural chromosome rearrangements or micro- quently consider epididymal sperm aspiration,245,246 deletions or duplications (see Chapter 10 ). Recog- with pregnancy induced by in vitro fertilization. nized habitual abortion due to the same causes Precise prenatal diagnosis can be achieved only if would also require cytogenetic analysis. Such specifi c mutations have been recognized. studies may reveal a parent (rarely both) with a Second, Y chromosome microdeletions occur in chromosomal rearrangement with signifi cant risks 10 – 20 percent of men with “ idiopathic ” azoosper- for bearing a child with mental retardation and/or mia or severe oligospermia.247,248 Genes, including malformations who could benefi t from prenatal DAZ ( “ deleted in azoospermia ” ), YRRM (Y chro- diagnosis. mosome RNA recognition motif) 248,249 and others Other disorders characteristically associated may be deleted singly or together in the region of with recurrent pregnancy loss include the X - linked Yq11.23. 250 Couples must be informed that male disorders, steroid sulfatase defi ciency,237 and offspring of men with these interstitial deletions in incontinentia pigmenti.238 Acceptance of throm- the Y chromosome will have the same structural bophilia as a cause awaits the results of randomized chromosome defect. The female partner of the controlled trials. 239 A recently recognized cause in male undergoing intracytoplasmic sperm injection about 8 percent of women experiencing recurrent (ICSI) needs explanations about procedures and abortion is mutations occurring in the SYCP3 medications for her that are not risk free. Patients gene,240 which encodes an essential component of should realize that ICSI followed by in vitro fertili- the synaptonemal complex, key to the interaction zation is likely to achieve pregnancy rates between between homologous chromosomes. 20 and 24 percent, 251 a success rate not very differ- Although the investigation to determine the ent from the approximately 30 percent rate in a cause of male or female infertility can be extensive, single cycle after natural intercourse at the time of three observations are pertinent here. First, we rec- ovulation.251 Pregnancy follow- up data from cases ognized that congenital bilateral absence of the vas culled from 35 different programs reported in a deferens (CBAVD),241 which occurs in 1 – 2 percent European survey252 and a major American study of of infertile males, is primarily a genital form of CF. 578 newborns showed no increased occurrence of Men with CBAVD should have CF gene mutation congenital malformations. 85 However, a statisti- 26 Genetic Disorders and the Fetus cally signifi cant increase in sex chromosome der or a previously affected offspring. In virtually defects has been observed253 (see Chapter 7 ). Pre- all ethnic groups, particular recessive disorders natal diagnosis is recommended in all pregnancies occur more frequently than in the population at following ICSI. large256 (Table 1.4 ). Increasingly, carrier tests will Third, even “ balanced ” reciprocal translocations become available for these various ethnic groups. in males may be associated with the arrest of sper- Carrier testing for cystic fi brosis (Caucasians), matogenesis and resultant azoospermia. 254 In one Tay– Sachs and Canavan diseases (Ashkenazi Jews), series of 150 infertile men with oligospermia or sickle cell disease (blacks), α - thalassemia (Asians) azoospermia, an abnormal karyotype was found in and β - thalassemia (peoples of Mediterranean 10.6 percent (16/180), 5.3 percent (8/150) had an descent) is regarded as standard and indicated AZF- c deletion and 9.3 percent (14/150) had at least simply on the basis of ethnicity. a single CF gene mutation.255 This study revealed a Individuals of French - Canadian ancestry living genetic abnormality in 36/150 (24 percent) of men in New England were reported to have a maximum with oligospermia or azoospermia. frequency of heterozygosity for Tay – Sachs disease or Sandhoff disease of 1 in 42.257 Enzymatic analy- Parental c arrier of a g enetic d isorder sis of hexosaminidase was confi rmed by mutation The fi rst preconception visit should be the time to analysis with exclusion of benign pseudodefi ciency establish the carrier state for a chromosomal rear- mutations. In contrast to these fi ndings, which rangement or a gene mutation in prospective could refl ect ascertainment bias, are the prior salu- parents. tary observations of Palomaki et al. 258 These Physicians should be alerted to the possibility of authors recorded no cases of Tay– Sachs disease in chromosomal rearrangements or gene mutations 41,000 births to couples who were both of French - that one or the other partner might carry relative Canadian ancestry. Further studies are necessary to a history of previous recurrent spontaneous before formal recommendations can be made for abortions, infertility or previous offspring with a carrier testing in this ethnic group. chromosomal or single gene defect or a positive Notwithstanding the screening guidelines for CF family history. Referral for genetic counseling in in Caucasians, a family history of CF is a direct these circumstances is appropriate given complex indication for mutation analysis.259 Moreover, questions relative to risk, prognosis in a future given the ability to detect over 90 percent of CF pregnancy and potential pitfalls/reservations con- carriers by routine testing of the most common cerning prenatal diagnosis (see Chapter 6 ). mutations (see Chapter 17 ), all Caucasian couples Determination of single gene mutations in car- should be offered these analyses at the preconcep- riers may be prompted by the patient’ s ethnic tion visit.260 Unfortunately, even after DNA muta- group, a family history of a specifi c genetic disor- tion analysis, couples may not be aware of the

Table 1.4 Common genetic disorders in various ethnic groups

Ethnic group Genetic disorder

Africans (blacks) Sickle cell disease and other disorders of hemoglobin α - and β - thalassemia Glucose- 6 - phosphate dehydrogenase defi ciency Benign familial leukopenia High blood pressure (in females)

Afrikaaners (white South Africans) Variegate porphyria Fanconi anemia

American Indians (of British Columbia) Cleft lip or palate (or both)

Armenians Familial Mediterranean fever CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 27

Table 1.4 Continued

Ethnic group Genetic disorder

Ashkenazi Jews A - β - lipoproteinemia Bloom syndrome Breast cancer Canavan disease Colon cancer Congenital adrenal hyperplasia Dysferlinopathy (limb girdle muscular dystrophy 2B) Dystonia musculorum deformans Factor XI (PTA) defi ciency Familial dysautonomia Fanconi anemia (type C) Gaucher disease (adult form) Glycogen storage disease (type 1a) Iminoglycinuria Maple syrup urine disease Meckel syndrome Niemann – Pick disease Pentosuria Spongy degeneration of the brain Stub thumbs Tay – Sachs disease

Chinese Thalassemia ( α ) Glucose- 6 - phosphate dehydrogenase defi ciency (Chinese type) Adult lactase defi ciency

Eskimos E1 pseudocholinesterase defi ciency Congenital adrenal hyperplasia

Finns Aspartylglucosaminuria Congenital nephrosis

French - Canadians Neural tube defects Tay – Sachs disease

Irish Neural tube defects Phenylketonuria Schizophrenia

Italians (northern) Fucosidosis

Japanese and Koreans Acatalasia Dyschromatosis universalis hereditaria Oguchi disease

Maori (Polynesians) Clubfoot

Mediterranean peoples (Italians, Familial Mediterranean fever Greeks, Sephardic Jews, Armenians, Turks, Glucose- 6 - phosphate dehydrogenase defi ciency (Mediterranean type) Spaniards, Cypriots) Glycogen storage disease (type III) Thalassemia (mainly β )

Norwegians Cholestasis- lymphedema Phenylketonuria

Yugoslavs (of the Istrian Peninsula) Schizophrenia

Source: Modifi ed from Milunsky, 2001. 256 28 Genetic Disorders and the Fetus limitations of these results. In one study, over half zation that carrier females for Duchenne and of those having CF carrier tests were unaware of Becker muscular dystrophy have preclinical or their residual risk after having received a negative clinically evident myocardial involvement in 45– 84 test result,261 while in another report only 62 percent of cases. 277,312 A study of 197 females aged percent correctly understood their results 6 months 5 – 60 years who were carriers of either Duchenne after testing.262 or Becker muscular dystrophy revealed progressive Among the many items to be considered during dilated cardiomyopathy, myocardial hypertrophy the preconception visit are the potential physical and/or dysrhythmias. The American Academy of features indicative of sex- linked disorders that may Pediatrics recommended that female carriers be manifest in female carriers (Table 1.5 ). With or informed of their risks, have a full cardiac evalua- without a family history of the disorder in ques- tion in late adolescence or early adulthood and be tion, referral to a clinical geneticist would be re- evaluated at least every 5 years. 312a Unfortu- appropriate for fi nal evaluation of possible impli- nately, a majority of carriers have not been cations. Failure to recognize obvious features in a informed of their risks or had cardiac evaluations. 312b manifesting female may well result in a missed Dilemmas may also occasionally arise in coun- opportunity for prenatal genetic studies and an seling, for example, for a mildly retarded female outcome characterized by a seriously affected male with fragile X syndrome, compounded in one (or occasionally female) offspring. Of crucial addi- report in which the partner was also retarded. 313 tional importance in considering manifesting The involvement of close relatives is key to the female carriers of sex- linked disorders is the reali- counseling needs in this type of situation.

Table 1.5 Signs in females who are carriers of X - linked recessive disease

Selected disorders Key feature(s) that may occur Selected references

Achromatopsia Decreased visual acuity and myopia 263 Adrenoleukodystrophy Neurologic and adrenal dysfunction 264 , 265 α - thalassemia/mental retardation Rare hemoglobin H inclusions in red blood cells 266 Alport syndrome Microscopic hematuria and hearing impairment 267 Ameliogenesis imperfecta, Mottled enamel vertically arranged 268 hypomaturation type Arthrogryposis multiplex congenita Club foot, contractures, hyperkyphosis 269 Borjeson syndrome Tapered fi ngers, short, widely spaced, fl exed toes, 270 mild mental retardation Choroideremiaa Choreoretinal dystrophy 271 Chronic granulomatous disease Cutaneous and mucocutaneous lesions 272 , 273 Cleft palate Bifi d uvula 274 Conductive deafness with stapes fi xation Mild hearing loss 275 Congenital cataracts b Posterior suture cataracts 276 Duchenne muscular dystrophy Pseudohypertrophy, weakness, cardiomyopathy/ 277 – 279 conduction defects Dyskeratosis congenita Retinal pigmentation 280 Emery – Dreifuss muscular dystrophy Cardiomyopathy/conduction defects 281 Fabry disease Angiokeratomas, corneal dystrophy, “ burning” 282 hands and feet FG syndrome Anterior displaced anus, facial dysmorphism 283 Fragile X syndrome Mild - to - moderate mental retardation, behavioral 284 – 286 aberrations, schizoaffective disorder, premature ovarian failure G6PD defi ciency Hemolytic crises, neonatal hyperbilirubinemia 287 Hemophilia A and B Bleeding tendency 288 CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 29

Table 1.5 Continued

Selected disorders Key feature(s) that may occur Selected references

Hypohydrotic ectodermal dysplasia Sparse hair, decreased sweating 289 Lowe syndrome Lenticular cataracts 290 Menkes disease Patchy kinky hair, hypopigmentation 291 , 292 Myopia Mild myopia 293 Nance – Horan syndromeb Posterior Y - sutural cataracts and dental anomalies 294 Norrie disease Retinal malformations 295 Ocular albinism type 1 Retinal/fundal pigmentary changes 296 Oligodontia Hypodontia 297 Ornithine transcarbamylase defi ciency Hyperammonemia, psychiatric/neurologic 298 , 299 manifestations Retinoschisis Peripheral retinal changes 300 Retinitis pigmentosa Night blindness, concentric reduction of visual 301 fi eld, pigmentary fundal degeneration, extinction of electroretinogram Sideroblastic anemia Minor red cell abnormalities without anemia 302 Simpson – Golabi – Behmel syndrome Extra lumbar/thoracic vertebrae, accessory nipples, 303 facial dysmorphism Split - hand/split - foot anomaly Mild split - hand/split- foot anomaly 304 Spondyloepiphyseal dysplasia, late onset Arthritis 305 Ulnar hypoplasia with lobster- claw Slight hypoplasia of ulnar side of hand and mild 306 defi ciency of feet syndactyly of toes Wiskott – Aldrich syndromea Abnormal platelets and lymphocytes 307 , 308 X - linked mental retardation Short stature, hypertelorism 309 , 310 X - linked retinitis pigmentosa Retinal changes 311 a Uncertain. b May be same disorder.

A f amily h istory of a g enetic d isorder cystic kidney disease (APKD) may be the diagnosis, The explicit naming of a specifi c genetic disorder which will require further investigation by both when the family history is being discussed facili- ultrasound and DNA analysis.316 Moreover, two tates evaluation and any possible testing. Diffi cul- different genes for APKD have been cloned (about ties are introduced when neither family nor 85 percent of cases due to APKD1 and close to 15 previous physicians have recognized a genetic dis- percent due to APKD2)317 and a rare third locus is order within the family. Such a disorder may not known. In yet other families, a history of hearing be uncommon (e.g. factor V Leiden defi ciency) but impairment/deafness in some members and sudden nevertheless unrecognized. Clinical clues would death in others may translate to the autosomal include individuals in the family with deep vein recessive Jervell and Lange – Nielsen syndrome. 318 thrombosis, sudden death possibly due to a pulmo- This disorder is characterized by severe congenital nary embolus and yet other individuals with recur- deafness, a long QT interval and large T waves, rent pregnancy loss.314,315 For some families, together with a tendency for syncope and sudden individuals with quite different apparent clinical death due to ventricular fi brillation. Given that a features may in fact have the same disorder. For number of genetic cardiac conduction defects have example, there may be two or more deceased family been recognized, a history of an unexplained members who died from “ kidney failure” and sudden death in a family184 should lead to a routine another one or two who died from a cerebral aneu- electrocardiogram at the fi rst preconception visit rysm or a sudden brain hemorrhage. Adult poly- and possibly mutation analysis of at least fi ve long 30 Genetic Disorders and the Fetus

QT syndrome genes. Other disorders in which uted to consanguinity. An observational study of sudden death due to a conduction defect might 5,776 Indian newborns noted a prevalence of 11.4 have occurred, with or without a family history of per 1,000 births with a consanguinity rate of 44.74 cataract or muscle weakness, should raise the sus- percent.329 picion of myotonic muscular dystrophy. 114 The occurrence of rare, unusual or unique syn- Rare named disorders in a pedigree should auto- dromes invariably raises questions about potential matically raise the question of the need for genetic consanguinity and common ancestral origins. counseling. We have seen instances (e.g. pancrea- Clinical geneticists will frequently be cautious in titis) in which in view of its frequency, the disorder these situations, providing potential recurrence was simply ascribed to alcohol or idiopathic cate- risks of 25 percent. Consanguineous couples may gories. Hereditary pancreatitis, although rare, is an opt for the entire gamut of prenatal tests to dimin- autosomal dominant disorder for which several ish even their background risks, with special focus genes are known.319 – 321 on their ethnic- specifi c risks. 173 The pattern of inheritance of an unnamed dis- order may signal a specifi c monogenic form of Environmental e xposures that t hreaten inheritance. For example, unexplained mental f etal h ealth retardation on either side of the family calls for Concerns about normal fetal development after fragile X DNA carrier testing.322 Moreover, unex- exposure to medications, illicit drugs, chemical, pected segregation of a maternal premutation may infectious or physical agents and/or maternal have unpredicted consequences, including rever- illness are among the most common reasons for sion of the triplet repeat number to the normal genetic counseling during pregnancy. Many of range.323 Genetic counseling may be valuable, more these anxieties and frequently real risks could be especially because the phenomena of pleiotropism avoided through preconception care. Public health (several different effects from a single gene) and authorities, vested with the care of the underprivi- heterogeneity (a specifi c effect from several genes) leged in particular, need to focus their scarce may confound interpretation in any of these resources on preconception and prenatal care and families. on the necessary public education regarding infec- tious diseases, immunization, nutrition and genetic Consanguinity disorders. Consanguineous couples face increased risks of In preconception planning, careful attention to having children with autosomal recessive disor- broadly interpreted fetal “ toxins ” is necessary ders; the closer the relationship, the higher the and avoidance should be emphasized. Alcohol, risks. A study in the United Arab Emirates of 2,200 smoking, illegal drug use, certain medications and women ≥ 15 years of age (with a consanguinity rate X - ray exposure require discussion. Estimates of the of 25– 70 percent) concluded that the occurrence prevalence of the fetal alcohol spectrum disorder of malignancies, congenital abnormalities, mental approximate 1 percent in the USA but in certain retardation and physical handicap was signifi cantly regions and countries rates reach as high as 10 higher in the offspring of consanguineous percent.330,331 There is a limited list of known and couples.324,325 The pooled incidence of all genetic proven human drug teratogens.20,173 Maternal defects regardless of the degree of consanguinity use of specifi c teratogenic medications, such as was 5.8 percent, in contrast with a nonconsanguin- isotretinoin, may be missed, unless the physician eous rate of 1.2 percent, similar to an earlier expressly inquires about them. study.325,326 A Jordanian study also noted signifi - Preconception advice to avoid heat exposure in cantly higher rates of infant mortality, stillbirths early pregnancy is now appropriate. Our observa- and congenital malformations among the offspring tions (see Chapter 23 ) showed a 2.9 relative risk for of consanguineous couples. 327 A Norwegian study having a child with a NTD in mothers who used a of fi rst- cousin Pakistani parents yielded a relative hot tub during the fi rst 6 weeks of pregnancy. 332 risk for birth defects of about twofold.328 In that A report from the Spanish Collaborative Study study, 28 percent of all birth defects were attrib- of Congenital Malformations noted a 2.8 - fold CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 31 increased risk of DS in the offspring of women ≥35 making an appointment for genetic counseling years of age and who were taking oral contracep- should be informed about the importance of tives when they became pregnant.333 having their partner with them for the consulta- tion, avoiding subsequent misunderstanding about Identifi cation of p reconception o ptions risks, options and limitations. The time to deal with unwanted risks is not during Before prenatal genetic studies are performed, a the second trimester of pregnancy, as is so often couple should understand the inherent limitations the case in practice. Preconception counseling will both of the laboratory studies and, when relevant, identify specifi c risks and attendant options, which of ultrasound. For detection of chromosomal dis- include the following. orders, they should be aware of potential maternal 1. Decision not to have children (includes con- cell admixture and mosaicism (see Chapter 6 ). sideration of vasectomy or tubal ligation) When faced with potential X- linked hydrocepha- 2. A d o p t i o n lus, microcephaly or other serious X - linked disor- 3. In vitro fertilization ders and the realization of less than 100 percent 4. Gamete intrafallopian tube transfer or allied certainty of diagnosis, couples may elect fetal sex techniques determination as the basis for their decision to 5. A r t i fi cial insemination by donor keep or terminate a pregnancy at risk. For some 6. Ovum donation (includes surrogacy) biochemical assays and invariably for DNA linkage 7. Intracytoplasmic sperm injection analyses, results may be less than 100 percent 8. Carrier detection tests certain. 9. Prenatal diagnosis (CVS, amniocentesis, cor- The time taken to determine the fetal karyotype docentesis, ultrasound, MRI) or other biochemical parameters should be under- 10. Preimplantation genetic diagnosis stood before amniocentesis. The known anxiety of 11. Fetal treatment for selected disorders this period can be appreciably aggravated by a 12. Folic acid supplementation in periconcep- long, unexpected wait for a result. The need for a tional period (see Chapter 23 ) second amniocentesis is rarer nowadays but in 13. S e l e c t i v e a b o r t i o n some circumstances, fetal blood sampling remains an additional option that may need discussion. Despite the very unlikely eventuality that no result Genetic c ounseling a s a p relude to may be obtained because of failed cell culture or p renatal d iagnosis contamination, this issue must be mentioned. Prospective parents should understand their spe- The potential possibility for false- positive or cifi c indication for prenatal tests and the limita- false - negative results should be carefully discussed tions of such studies. Frequently, one or both when applicable. Any quandary stemming from members of a couple fail to appreciate how focused the results of prenatal studies is best shared imme- the prenatal diagnostic study will be. Either or both diately with the couple. The role of the physician may have the idea that all causes of mental retarda- in these situations is not to cushion unexpected tion or congenital defects will be detected or blows or to protect couples from information that excluded. It is judicious for the physician to urge may be diffi cult to interpret. All information that both members of a couple come for the con- available should be communicated, including the sultation before CVS or amniocentesis. Major inability to accurately interpret the observations advantages that fl ow from this arrangement include made. This is especially so with the advent of a clearer perception by the partner regarding risks the chromosomal microarray (see Chapter 10 ). and limitations, a more accurate insight into his DNA analysis of cultured amniocytes may yield an family history and an opportunity to detect an uninterpretable microdeletion/duplication which obvious (although unreported or undiagnosed) then requires parental studies in an effort to genetic disorder of importance (e.g. Treacher– determine signifi cance. The frequency with which Collins syndrome, facioscapulohumeral dystrophy no clear answer can be provided is still to be or one of the orofacial– digital syndromes). Women determined. 32 Genetic Disorders and the Fetus

Other key issues to be considered by the genetic repeat study and subsequent birth with a chromo- counselor and discussed when appropriate with somal (or detectable) anomaly. the consultand follow. 17. Failure to offer maternal serum screening or to correctly interpret and act on results. Informed c onsent 18. Failure to understand a laboratory report Patients should be told that prenatal diagnosis is coupled with failure to clarify the results by con- not error free. Although the accuracy rate for pre- tacting the laboratory. natal diagnostic studies exceeds 99 percent, it is not 19. Failure to detect obvious fetal defects on 100 percent. Errors have occurred in all of the fol- ultrasound. lowing ways and most, at least in the United States, 20. Failure to recommend periconception folic have been followed by frequently successful law- acid supplementation (see Chapter 21 ) with subse- suits75 – 77,334,335 (see Chapter 33 ). quent birth of a child with a neural tube defect. 1. Failure to offer prenatal diagnosis. 21. Failure to offer indicated carrier detection tests 2. Failure to provide accurate information (ethnicity; family history). regarding risks of occurrence or recurrence. 22. Failure to deliver a blood sample to the labora- 3. Failure to explain signifi cantly abnormal tory in a timely manner, with the subsequent birth results, with catastrophic consequences. of a child with spina bifi da and hydrocephalus. 4. Failure to provide timely results of prenatal 23. Failure to advise change or discontinuance of diagnosis, resulting in the birth of a child with a a teratogenic medication (e.g. valproic acid), chromosome abnormality. resulting in the birth of a child with spina bifi da. 5. Failure to communicate the recommendation 24. Delay/failure in making a timely diagnosis of from the laboratory to perform a second amnio- a serious genetic disorder in a previous child, centesis in view of failed cell culture, resulting in thereby depriving parents of risk data and of the the birth of a child with a detectable genetic defect. options for prenatal diagnosis (among others) in a 6. Failure to determine the correct fetal sex subsequent pregnancy, resulting in the birth of or genetic disorder, due to maternal cell another affected child. contamination. From a previous worldwide survey of prenatal 7. Failure to diagnose a defect because of a diagnosis335 and two formal amniocentesis sample or slide mix - up. studies,336,337 an error rate between 0.1 and 0.6 8. Failure to order indicated tests (e.g. karyotype percent seems likely. After communication of all of prospective mother when her sister or sibling’ s the necessary information concerning amniocen- child had DS, chromosome type unknown and tesis and prenatal genetic studies pertinent to the which in fact was due to an unbalanced couple and especially tailored to their particular translocation). situation, an informed consent form should be 9. Failure to analyze the fetal karyotype signed and witnessed. Consent forms used for correctly. minor surgery should suffi ce for CVS and amnio- 10. Failure to recognize signifi cant chromosomal centesis. However, each physician should have a mosaicism. specifi c form covering all key eventualities. 335 11. Incorrect interpretation (or erroneous reinter- It is crucial to ensure not only that the language pretation) of a biochemical or DNA assay. in the consent form is nontechnical and easily 12. Failure to run appropriate controls for a bio- understandable but also that the form is available chemical assay. in the language best understood by the couple. 13. Failure to order the correct test. Although the medicolegal validity of such forms 14. Failure to send or direct a sample for specifi c may still be questioned, the exercise ensures at least testing to a known laboratory. a basic discourse between doctor (or the doctor’ s 15. Failure to communicate critical laboratory staff) and patient. For patients who decline prena- results to the physician and depending upon a fax tal studies, maternal serum screening or specifi c or voicemail transmission. genetic tests, physicians are advised to document 16. Incubator failure or infection of cell cultures, their discussion and the patient’ s refusal in the resulting in failure of cell growth, no time for a medical record. In successful litigation, some CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 33 plaintiffs have claimed that prenatal diagnostic tests, 15 prenatal tests and 626 diagnostic tests studies or maternal serum screening were neither from 1987 to 2000. The uptake for predictive discussed nor offered by their physicians. testing was about 18 percent (range, 12.5 – 20.7 percent).128 Of the 15 who had prenatal tests, 12 Carrier d etection had an increased risk which led to pregnancy ter- Before any effort to make a prenatal diagnosis of mination in all but one.128 an autosomal recessive or sex - linked biochemical The motivations leading to the very diffi cult disorder, the carrier state should be documented decision to have or not to have a predictive test are (see above). For autosomal recessive disorders, being recognized as extremely complex.345 In a particular attention should be paid to the parents ’ Danish study before DNA tests were available, one ethnic origin (see Table 1.4 ). A previous birth of in 20 individuals at risk for Huntington disease an affected child with an autosomal recessive dis- committed suicide, more than double the popula- order might alert the physician to consanguinity. tion rate,346 highlighting earlier reports of high DNA mutation analysis facilitates carrier detection suicide rates347 and emphasizing the erosive effects for a host of disorders not previously detectable of uncertainty. However, a worldwide assessment prenatally (see Chapter 11 ). Recognition of com- of suicide rates, suicide attempts or psychiatric pound heterozygosity in a couple will infl uence hospitalizations after predictive testing did not discussions about prognosis and should also initi- confi rm a high rate of suicide.348 In their worldwide ate tracking of carriers through the respective questionnaire study sent to predictive testing families. centers, the authors noted that 44 individuals (0.97 percent) among 4,527 tested had fi ve suicides, 21 Presymptomatic or p redictive t esting suicide attempts and 18 hospitalizations for psy- Presymptomatic or predictive testing is available chiatric reasons. All those who committed suicide for a rapidly increasing number of disorders, espe- had signs of Huntington disease, while 11 (52.4 cially neuromuscular and neurodegenerative (see percent) of the 21 individuals who attempted Chapter 11 ). Huntington disease is the prototype suicide were symptomatic. Others have written and predictive testing using guidelines promul- about the psychologic burden created by knowl- gated by the World Federation of Neurology 180,338 edge of a disabling fatal disease decades before its and the International Huntington Association is onset.349 – 351 well established. Various programs report that a Hayden 352 warned that it is inappropriate to majority of patients are able to cope when it is introduce a predictive test that “ has the potential found that they are affected, 94– 99,339,340 and at least for catastrophic reactions, ” without a support after a 1 - year follow - up, potential benefi t has been program, including pretest and post- test coun- shown even in those found to be at increased seling and specifi ed standards for laboratory risk.341 A European collaborative study evaluated analyses. In one study, 40 percent of individuals 180 known carriers of the Huntington disease tested for Huntington disease and who received gene mutation and 271 noncarriers, all of whom DNA results required psychotherapy.353 A 5- year received a predictive test result. Although the longitudinal study of psychologic distress after follow- up was only 3 years for about half the predictive testing for Huntington disease focused group, pregnancies followed in 28 percent of non- on 24 carriers and 33 tested noncarriers. Mean carriers and only 14 percent of carriers.342 Prenatal distress scores for both carriers and noncarriers diagnosis was elected by about two - thirds of those were not signifi cantly different but carriers had less who were carriers. positive feelings. 354 A subgroup of tested persons As others earlier,343 we remain very concerned were found to have long - lasting psychologic about the use of a test that can generate a “ no distress. hope ” result. Even in sophisticated programs offer- On the other hand, an increasing number of ing Huntington disease tests, fewer than expected examples already exist (see Chapter 11 ) in which at- risk individuals requested testing. 344 A multi- presymptomatic testing is possible and important center Canadian collaborative study evaluated the to either the patient or future offspring or both. uptake, utilization and outcome of 1,061 predictive Uptake has been high by individuals at risk, espe- 34 Genetic Disorders and the Fetus cially for various cancer syndromes. 355 Use of DNA exercise of parental prerogatives. However, failure linkage or mutation analysis for ADPKD317,356 may to test because of parental refusal may invite the lead to the diagnosis of an unsuspected associated reporting of child neglect. 363 intracranial aneurysm in 8 percent of cases (or 16 No longer hypothetical is the prenatal diagnosis percent in those with a family history of intracra- request by a pregnant mother for fetal Huntington nial aneurysm or subarachnoid hemorrhage357 ) disease without the knowledge of her at- risk and pre- emptive surgery, with avoidance of a partner who does not wish to know his genetic life - threatening sudden cerebral hemorrhage. In status. In preserving the partner ’ s autonomy and a study of 141 affected individuals, 11 percent recognizing maternal rights, we have in the past decided against bearing children on the basis of the honored such requests. Mothers have in these cir- risk.358 These authors noted that only 4 percent of cumstances, faced with an affected fetus, elected to at - risk individuals between 18 and 40 years of age terminate the pregnancy, invoking miscarriage as would seek elective abortion for an affected fetus. the reason to her unknowing partner. Distressing The importance of accurate presymptomatic tests as it is to contemplate such a marital relationship, for potential at- risk kidney donors has been textured on the one hand by extreme care and on emphasized.359 Organ donation by a sibling of an the other hand by deceit born of sensitivity, con- individual with ADPKD, later found to be affected, sider our report of symptomatic Huntington has occurred more than once. disease at 18 months of age and diagnosed at the Individuals at 50 percent risk for familial poly- age of 3 years.364 These cases pose diffi cult ethical, posis coli (with inevitable malignancy for those moral and legal questions but at least in the United with this mutated gene) who undergo at least States, United Kingdom and Australia,365 a woman’ s annual colonoscopy could benefi t from a massive request for prenatal diagnosis would be honored. reduction in risk (from 50 percent to <1 percent) Homozygotes for Huntington disease are after DNA analysis. Individuals in whom this rare366,367 and reported in one out of 1,007 patients mutation was found with greater than 99 percent (0.1 percent). Counseling a patient homozygous certainty may choose more frequent colonoscopies for Huntington disease about the 100 percent and eventually elective colonic resections, thereby probability of transmitting the disorder to each saving the lives of the vast majority. The need for child is equivalent to providing a nonrequested involvement of clinical geneticists is especially predictive test, 368 while failing to inform the patient evident in this and other disorders in which of the risks would be regarded as the withholding complex results may emerge. Giardiello et al.360 of critical information. Pretest counseling in such showed that physicians misinterpreted molecular cases would take into consideration a family history test results in almost one - third of cases. on both sides and therefore be able to anticipate Families with specifi c cancer syndromes, such as the rare homozygous eventuality. multiple endocrine neoplasia, Li– Fraumeni syn- Identifi cation of specifi c mutations in the breast/ drome or von Hippel– Lindau disease, may also ovarian cancer susceptibility genes (BRCA1 and benefi t by the institution of appropriate surveil- BRCA2) has opened up diffi cult personal decision lance for those shown to be affected by molecular making as well as consideration concerning future analysis when they are still completely asympto- prenatal diagnosis. 369 DudokdeWit et al. laid out a matic, once again, in all likelihood, saving their detailed and systematic approach to counseling lives. For example, elective thyroidectomy is rec- and testing in these families. 370 In their model ommended for multiple endocrine neoplasia type approach, important themes and messages emerge. 2B by 5 years of age in the child with this mutation, 1. Each person may have a different method of given the virtual 100 percent penetrance of this coping with threatening information and treat- gene and the possible early appearance of cancer. 361 ment options. Predictive testing even of children at high genetic 2. Predictive testing should not harm the family risk poses a host of complex issues. 362 Where life- unit. threatening early- onset genetic disorders are con- 3. Special care and attention are necessary to cerned, testing in early childhood still requires the obtain informed consent, protect privacy and con- CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 35

fi dentiality and safeguard “ divergent and confl ict- mutation has been found in 6 percent of Ashkenazi ing intrafamilial and intergenerational interests. ” Jews.377 Because of the ability to determine whether A French study noted that 87.7 percent of women a specifi c cancer will develop in the future, given who were fi rst- degree relatives of patients with identifi cation of a particular mutation, much ago- breast cancer were in favor of predictive testing. 371 nizing can be expected for many years. These Two specifi c groups of women are especially quandaries will not and cannot be resolved in involved. The fi rst are those who, at a young age, rushed visits to the physician’ s offi ce as part of have already had breast cancer, with or without a preconception or any other care. Moreover, devel- family history and in whom a specifi c mutation has oping knowledge about genotype – phenotype asso- been identifi ed. Recognizing their high risk for ciations and many other aspects of genetic breast and/or ovarian cancer, 372,373 these women epidemiology will increasingly require referral to have grappled with decisions about elective bilat- clinical geneticists. eral mastectomy and oophorectomy and mastec- tomy of a contralateral breast. Current estimates of Anticipation penetrance are 36– 85 percent lifetime risk for In 1991 the fi rst reports appeared of dynamic breast cancer and 16– 60 percent lifetime risk for mutations resulting from the unstable expansion ovarian cancer, depending upon the population of trinucleotide repeats. 378 Thus far, 17 such disor- studied. 374 This group of women may also consider ders with these unstable repeats have been prenatal diagnosis in view of their personal suffer- described (Table 1.6 ). All disorders described thus ing and intent not to have a child subject to the far are autosomal dominant or X - linked, except for same set of problems. Friedreich ataxia, which is autosomal recessive and The second group of women are of Ashkenazi also unique in having intronic involvement.379 Jewish ancestry. These women have about a 2 Typically for these disorders (except for Friedreich percent risk of harboring two common mutations ataxia), the carrier will have one normal allele and in BRCA1 (185delAG and 5382insC) and one in a second expanded allele. BRCA2 (6174delT) that account for the majority These disorders (except for Friedreich ataxia) of breast cancers in this ethnic group. 374,375 Regard- are also generally characterized by progressively less of a family history of breast or ovarian cancer, earlier manifestations and/or more severe expres- the lifetime risk of breast cancer among Jewish sion with succeeding generations. This genetic female mutation carriers was 82 percent in a study mechanism, called anticipation, is associated with of 1,008 index cases. 376 Breast cancer risk by 50 further expansion of the specifi c triplet repeat but years of age among mutation carriers born before there are also disorders with anticipation and no 1940 was 24 percent but 67 percent for those born apparent dynamic mutations (Box 1.3 ). Indeed, after 1940.376 Lifetime ovarian cancer risks were 54 these disorders characteristically have a direct rela- percent for BRCA1 and 23 percent for BRCA2 tion between the number of repeats and the sever- mutation carriers.376 ity of disease and an inverse relation between the It can easily be anticipated that with identifi ca- number of repeats and age of onset. These aspects tion of mutations for more and more serious/fatal of anticipation weigh heavily in preconception monogenic genetic disorders (including cardiovas- counseling when it becomes clear that the relatively cular, cerebrovascular, connective tissue and renal mild- to - moderate status of a mother with myot- disorders, among others), prospective parents may onic muscular dystrophy, for example, is likely to well choose prenatal diagnosis in an effort to avoid result in an affected child with severe congenital at least easily determinable genetic disorders. Dis- myotonic muscular dystrophy. 112 More recent covery of the high frequency (28 percent) of a studies have shown that triplet size in this disorder mutation (T to A at APC nucleotide 3920) in the correlates signifi cantly with muscular disability as familial adenomatous polyposis coli gene among well as mental and gonadal dysfunction.380 These Ashkenazi Jews with a family history of colorectal authors also noted that triplet repeat size did not cancer377 is also likely to be followed by thoughts correlate with the appearance of cataract, myoto- of avoidance through prenatal diagnosis. This nia, gastrointestinal dysfunction and cardiac 36 Genetic Disorders and the Fetus

Table 1.6 Dynamic mutations with triplet repeat expansion

Disease Chromosome Repeat Size in Size in Size in affecteda sequence normala carrier a

Dentatorubral pallidoluysian atrophy 12p12 - 13 CAG 7 – 34 – 49 – 75 Fragile X syndromeb Xq27.3 CGG 5 – 54 50 – 200 200 to > 2000 Fragile XE Xq27.3 GGC 6 – 25 116 – 133 200 to > 850 Friedreich ataxiab 9q13 GAA 7 – 40 50 – 200 200 to > 1200 Huntington disease 4p16.3 CAG 6 – 36 – 35 – 121 Kennedy disease (spinal bulbar Xq11 - 12 CAG 12 – 34 – 40 – 62 muscular atrophy) Machado– Joseph disease 14q32.1 CAG 13 – 36 – 68 – 79 Myotonic dystrophy type 1 19q13.3 CTG 5 – 37 – 50 to > 2000 Myotonic dystrophy type 2c 3q21.3 CCTG < 44 – 75 – 11,000 Spinocerebellar ataxia type 1 6p22 - 23 CAG 6 – 39 – 41 – 81 Spinocerebellar ataxia type 2 12q24.1 CAG 15 – 29 – 35 – 59 Spinocerebellar ataxia type 6 19p13 CAG 4 – 16 – 21 – 27 Spinocerebellar ataxia type 7 3p21.1 CAG 4 – 18 – 37 – 130 Spinocerebellar ataxia type 8 13q21 CTG 16 – 37 – > 90 Spinocerebellar ataxia type 10 d 22q13 - qter ATTCT 10 – 22 – > 19,000 Spinocerebellar ataxia type 12 5q31 - 33 CAG 7 – 28 – 66 – 78 Spinocerebellar ataxia type 17 6q27 CAG 27 – 44 – > 45 a Variable ranges reported and overlapping sizes may occur. b Mutation may not involve an expansion. c Expansion involves four nucleotides. d Expansion involves fi ve nucleotides.

Box 1.3 Selected genetic disorders with anticipation

Disorders with anticipation Familial chronic myeloproliferative disorders See Table 1.6 of disorders with trinucleotide Familial intracranial aneurysms repeats (exception: Friedreich ataxia) Familial pancreatic cancer Familial paraganglioma Disorders with suspected anticipation Familial Parkinson disease Adult - onset idiopathic dystonia Familial primary pulmonary hypertension Autosomal dominant acute myelogenous Familial rheumatoid arthritis leukemia Graves disease Autosomal dominant familial spastic paraplegia Hereditary nonpolyposis colorectal cancer Autosomal dominant polycystic kidney disease Hodgkin and non - Hodgkin lymphoma (PKD1) Holt – Oram syndrome Autosomal dominant rolandic epilepsy Lattice corneal dystrophy type I (LCDI) Beh ç et syndrome Li – Fraumeni syndrome Bipolar affective disorder M é ni è re disease Charcot – Marie – Tooth disease Obsessive - compulsive spectrum disorders Crohn disease Oculodentodigital syndrome Dyskeratosis congenita Paroxysmal kinesigenic dyskinesia (PKD) Facioscapulohumeral muscular dystrophy Restless legs syndrome Familial adenomatous polyposis Schizophrenia Familial amyloid polyneuropathy Total anomalous pulmonary venous return Familial breast cancer Unipolar affective disorder CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 37

Table 1.7 Examples of imprinting and human disease

Syndrome Chromosomal location Parental origin Selected references

Angelman syndrome 15q11 - q13 Maternal 383 Autism 15q11 - q13 Maternal 384 Beckwith – Wiedemann syndrome 11p15.5 Paternal 385 – 387 Birk Barel mental retardation syndrome 8q24 Maternal 388 Congenital hyperinsulinism 11p15 Maternal 389 Congenital myotonic muscular dystrophy 19q13.3 Maternal 390 Early embryonic failure 21 Maternal 391 Familial paraganglioma 11q23 Paternal 392 Hereditary myoclonus– dystonia 7q21 Maternal 393 Intrauterine and postnatal growth restriction 7 Maternal 394 Intrauterine growth restriction or miscarriage 16 Maternal 395 Mental retardation and dysmorphism 14 Paternal 396 Prader – Willi syndrome 15q11 - q13 Paternal 397 Progressive osseous heteroplasia 20q13.3 Paternal 399 Pseudohypoparathyroidism 20q13.3 Paternal 398 Rett syndrome Xq28 Paternal 400 , 401 Russell– Silver syndrome 7p11.2 Maternal 402 11p15 Maternal 402a Short stature 14 Maternal 403 Transient neonatal diabetes 6q22 - q23 Paternal 404 – 406

abnormalities. They hypothesized that somatic help. 408 Notwithstanding this limitation, mutation mosaicism with different amplifi cation rates in analysis does provide precise prenatal diagnosis various tissues may be one possible explanation for opportunities and detection of affected fetuses with the variable phenotypes. compound heterozygosity. Simple logic might have This phenomenon of parent- of - origin differ- concluded that genotype at a single locus might ence in the expression of specifi c genes introduces predict phenotype. For monogenic disorders, this genomic imprinting into the genetic counseling is frequently not the case. In the autosomal domi- considerations. Some genes are genetically marked nant Marfan syndrome (due to mutations in the before fertilization so that they are transcription- chromosome 15 fi brillin gene), family members ally silent at one of the parental loci in the off- with the same mutation may have severe ocular, spring.381 A number of disorders have been cardiovascular and skeletal abnormalities, while recognized in which genomic imprinting is espe- siblings or other close affected relatives with the cially important 382 (Table 1.7 ). In addition, parent - same mutation may have mild effects in only one of - origin affects anticipation in triplet repeat of these systems. 409 In Gaucher disease with one of expansions such as in Huntington disease. Paternal the common Ashkenazi Jewish mutations, only transmission of the gene is associated with earlier about one- third of homozygotes have signifi cant and more severe manifestations than would be the clinical disease.410 At least two- thirds have mild or case after maternal transmission. Families at risk late- onset disease or remain asymptomatic. Com- may not realize that Huntington disease may man- pound heterozygotes for this disorder involving ifest in childhood, not only in the teens but as early mutations L444P and N370S have included a as 18 months of age. 364,407 patient with mild disease fi rst diagnosed at 73 years of age, while another requiring enzyme replace- Genotype– p henotype a ssociations ment therapy was diagnosed at the age of 4 years.411 DNA mutation analysis has clarifi ed few genotype – In CF, a strong correlation exists between geno- phenotype associations but extensive databases will type and pancreatic function but only a weak 38 Genetic Disorders and the Fetus

Table 1.8 Selected monogenic disorders with established germline mosaicism

Disorder Inheritance

Achondrogenesis type II AD Achondroplasia AD Adrenoleukodystrophy X - L rec Albright hereditary osteodystrophy AD α - Thalassemia mental retardation syndrome X - L Amyloid polyneuropathy AD Aniridia AD Apert syndrome AD Becker muscular dystrophy X - L rec Cantu syndrome AD Central hypoventilation syndrome AD Cerebellar ataxia with progressive macular dystrophy (SCA7) AD Charcot– Marie – Tooth disease type 1B AD Coffi n– Lowry syndrome X - L dom Congenital contractural arachnodactyly AD Conradi – Hunnermann– Happle syndrome X - L dom Cowden disease AD Danon disease (lysosome- associated membrane protein- 2 defi ciency) X - L rec Dejerine – Sotas syndrome (HNSN III) with stomatocytosis AD Duchenne muscular dystrophy X - L rec Dyskeratosis congenita X - L EEC syndrome (ectrodactyly, ectodermal dysplasia, orofacial clefts) AD Epidermolysis bullosa simplex AR Fabry disease AR Facioscapulohumeral muscular dystrophy AD Factor X defi ciency AR Familial focal segmental glomerulosclerosis AD Familial hypertrophic cardiomyopathy AD Fibrodysplasia ossifi cans progressiva AD Fragile X syndrome (deletion type) X - L Hemophilia B X - L rec Herlitz junctional epidermolysis bullosa A rec Holt – Oram syndrome AD Hunter syndrome X - L rec Incontinentia pigmenti X - L dom Karsch – Neugebauer syndrome AD Lesch – Nyhan syndrome X - L rec Lissencephaly (males); “ subcortical band heterotopia” (almost all females) X - L rec Multiple endocrine neoplasia I AD Myotubular myopathy X - L rec Neurofi bromatosis type 1 AD Neurofi bromatosis type 2 AD Oculocerebrorenal syndrome of Lowe X - L Ornithine transcarbamylase defi ciency X - L rec Osteocraniostenosis AD Osteogenesis imperfecta AD Otopalatodigital syndrome X - L dom Pseudoachondroplasia AD Severe combined immunodefi ciency disease X - L rec Spondyloepimetaphyseal dysplasia AD CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 39

Table 1.8 Continued

Disorder Inheritance

Renal- coloboma syndrome AD Retinoblastoma AD Rett syndrome X - L dom Tuberous sclerosis AD von Hippel – Lindau disease AD von Willebrand disease (type 2b) X - L rec Waardenburg syndrome AD Wiskott – Aldrich syndrome X - L rec

AD, autosomal dominant; AR, autosomal recessive; X- L rec, X - linked recessive; X- L dom, X - linked dominant. association has been noted with the respiratory ferentiation) that results in functional mosaicism phenotype412 (see Chapter 17 ). Although individu- in females. Mosaicism might occur in somatic or als who are homozygous for the common CF germline cells. Its recognition is important, because mutation (Δ F508) can be anticipated to have a disorder may not be due to a new dominant classic CF, those with the less common mutation mutation, despite healthy parents. Erroneous (R117H) are likely to have milder disease.413 On counseling could follow, with the provision of risks occasion, an individual who is homozygous for the very much lower than would be the case if germline “ severe ” ΔF508 mutation might unexpectedly mosaicism existed. After the birth to healthy exhibit a mild pancreatic- suffi cient phenotype. parents of a child with achondroplastic dwarfi sm, Illustrating the complexity of genotype– phenotype random risks of one in 10,000 might be given for associations is the instance noted by Dork et al. 414 recurrence. of a mildly affected Δ F508 homozygote whose one However, germline mosaicism has been chromosome 7 carried both the common Δ F508 described after the birth of a second affected mutations and a cryptic R553Q mutation. Appar- child.418 Similarly, the birth of a male with Duch- ently, a second mutation in the same region may enne muscular dystrophy (DMD), no family modify the effect of the common mutation, per- history and no detectable mutation on DNA analy- mitting some function of the chloride channel 415 sis of maternal peripheral leukocytes might lead to and thereby ameliorating the severity of the disease. counseling based on spontaneous mutation rates. The extensive mutational heterogeneity in Once again, germline mosaicism is now well rec- hemophilia A416 is related not only to variable clini- ognized in mothers of apparently sporadic sons cal severity but also to the increased likelihood of with DMD and the risk of recurrence in such cases anti - factor VIII antibodies (inhibitors) developing. approximates 7 – 14 percent if the at - risk X - haplo- Miller et al. 417 found about a fi vefold higher risk type is determined. 419 Germline mosaicism has also of inhibitors developing in hemophiliac males been documented for other disorders (Table 1.8 ) with gene deletions compared with those without and undoubtedly occurs in some others yet to be deletions. discovered. Given the history of a previously affected off- Somatic cell mosaicism with mutations has been spring with a genetic disorder, the preconception recognized in a number of distinctly different dis- visit serves as an ideal time to refocus on any puta- orders, such as hypomelanosis of Ito, other syn- tive diagnosis (or lack thereof) and to do newly dromes with patchy pigmentary abnormalities of available mutation analyses when applicable. skin associated with mental retardation and in some patients with asymmetric growth restric- Mosaicism tion. 420,421 Germline mosaicism should be distin- Mosaicism is a common phenomenon (witness the guished from somatic cell mosaicism in which normal process of X- inactivation and tissue dif- there is also gonadal involvement. In such cases, the 40 Genetic Disorders and the Fetus patient with somatic cell mosaicism is likely to have passionate physician will need to be fully armed some signs, although possibly subtle, of the disor- with all the facts about the defect or be ready to der in question, while those with germline mosai- obtain an immediate expert clinical genetics con- cism are not expected to show any signs of the sultation for the couple. disorder. Examples of somatic and gonadal mosai- Care should be taken in selecting a quiet, com- cism include autosomal dominant osteogenesis fortable, private location that is safe from interrup- imperfecta, 422,423 Huntington disease424 and spinoc- tion. Ptacek and Eberhardt, 427 in reviewing the erebellar ataxia type 2. 425 Lessons from these and literature, noted consensus recommendations in the other examples quoted for germline mosaicism breaking bad news that included the foregoing and indicate a special need for caution in genetic coun- sitting close enough for eye contact without physi- seling for disorders that appear to be sporadic. cal barriers. Identifying a support person if the Very careful examination of both parents for partner cannot/will not attend the consultation is subtle indicators of the disorder in question is nec- important and knowledge of available resources is essary, particularly in autosomal dominant and valuable. All of the above points are preferences sex - linked recessive conditions. The autosomal that have been vocalized by parents receiving bad dominant disorders are associated with 50 percent news about their infants.428 risks of recurrence, while the sex - linked disorders Almost all couples would have reached this have 50 percent risk for males and 25 percent risk juncture through maternal serum screening, an for recurrence in families. Pure germline mosai- ultrasound study or amniocentesis/CVS for mater- cism would likely yield risks considerably lower nal age, for established known carriers, because of than these fi gures, such as 7– 14 percent for females a previously affected child, being an affected parent with gonadal mosaicism and X - linked DMD. A or having a family history of a specifi ed disorder. second caution relating to counseling such patients Not rarely, an anxious patient insists on a prenatal with an apparent sporadic disorder is the offer of study. On one such occasion, the patient stated, prenatal diagnosis (possibly limited) despite the “ My neighbor had a child with Down syndrome,” inability to demonstrate the affected status of the only to discover from the requested amniocentesis parent. study that her fetus also had a serious abnormality. Chromosomal mosaicism is discussed in Chapter Physicians are advised not to dissuade patients 6 but note can be taken here of a possibly rare (and away from prenatal diagnosis but rather to inform mostly undetected) autosomal trisomy. A history them about the risks of fetal loss balanced against of subfertility with mostly mild dysmorphic fea- the risk of fetal defects, distinctly different from tures and normal intelligence has been reported in recommendations for accepted indications. at least 10 women with mosaic trisomy 18.426 Recognition of a fetal abnormality by imaging, molecular or cytogenetic study may reveal, for the fi rst time, the genetic disorder in an asymptomatic Genetic c ounseling w hen the f etus parent. Robyr et al.429 described 20 such parents i s a ffected with disorders including spinal muscular atrophy, The fateful day when the anxious, waiting couple DiGeorge syndrome, osteogenesis imperfecta, hears the grim news that their fetus has a malfor- arthrogryposis and Noonan - like syndrome. mation or genetic disorder will live on in their Not infrequently, second- trimester ultrasound memories forever. Cognizance of this impact studies reveal fetal abnormalities of uncertain eti- should inform the thoughts, actions and commu- ology. For example, on one (legal) case, sequential nications of the physician called on to exercise con- observations noted prominent lateral cerebral ven- summate skill at such a poignant time. Couples tricles, multiple thoracic hemivertebrae and intra- may have traveled the road of hope and faith for uterine growth restriction. Amniocyte chromosome many years, battling infertility only to be con- studies were normal. The parents were not coun- fronted by the devastating reality of a fetal anomaly. seled about the potential for mental retardation With hopes and dreams so suddenly dashed, despite no defi nitive diagnosis. The child was born doubt, anger and denial surface rapidly. The com- with holoprosencephaly with marked psychomo- CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 41 tor delay. Diagnostic uncertainty must be shared there is a failure to reconcile cytogenetic or molecu- with parents at risk. lar results with expected high- resolution ultra- sound observations. Maternal cell contamination Decision m aking (see Chapter 6 ), while extremely unlikely in almost The presence of both parents for the consultation all circumstances, requires exclusion in some concerning possible elective abortion for a fetal others. Some prenatal diagnoses may not easily be defect is critical in this situation. All the principles interpretable and a phenotype may not be predict- governing the delivery of genetic counseling and able with certainty. A de novo supernumerary chro- discussed earlier apply when parents need to decide mosome fragment in the prenatal cytogenetic whether or not to continue their pregnancy. A brief analysis (see Chapter 6 ) is a key example that can explanation of some of the key issues follows, mostly be settled by a chromosomal microarray culled from over 45 years of experience in this very study. The sensitive counselor should offer a second subject. opinion to anxious parents facing an uncertain pre- Doubt and disbelief crowd the parental senses in natal diagnosis. The “ compleat physician” antici- the face of such overwhelming anxiety. Was there pates virtually all of the patient ’ s questions, answers a sample mix- up? How accurate is this diagnosis? them before they are asked and raises all the issues How competent is the laboratory? Have they made without waiting for either parent to vocalize them. errors in the past? How can we be certain that there Occasionally, it is apparent that there are power- has been no communication failure? Is there ful disparate attitudes to abortion between the another couple with the same name? There are spouses. Such differences would best be considered endless questions and endless doubts. Each and during the preconception period, rather than for every one needs to be addressed carefully, slowly the fi rst time when faced with a serious fetal defect. and deliberately, with painstaking care to provide Resolution of this confl ict is not the province of the the necessary assurance and reassurance. Needless physician or counselor, nor should either become to say, the clinical geneticist must have thoroughly arbitrator in this highly charged and very personal checked all the logistics and potential pitfalls before dispute, in which religious belief and matters of initiating this consultation. Errors have indeed conscience may collide. The physician’ s or coun- occurred in the past. selor’ s duty is to ensure that all facts are known and The central portion of the communication will understood and that the pros and cons of various focus on the nature of the defect and the physician possible scenarios are identifi ed in an impartial or counselor providing the counseling should be manner. A return appointment within days should fully informed about the disorder, its anticipated be arranged. Questions of paternity have also sud- burden, the associated prognosis, life expectancy denly emerged in this crisis period and can now be and the possible need for lifetime care. A clear settled, sometimes with painful certainty. understanding of the potential for pain and suffer- ing is necessary and an exploration concerning the Elective a bortion: d ecision and s equel effect on both parents and their other children is Among the greatest challenges clinical geneticists second only to a discussion about the potential and genetic counselors face is the consultation in effects on the child who is born with the condition which the results of prenatal studies indicating a in question. Any uncertainties related to diagnosis, serious fetal defect are communicated to parents prognosis, pleiotropism or heterogeneity should for the fi rst time. The quintessential qualities a emerge promptly. Questions related to possible counselor will need include maturity, experience, future pregnancies should be discussed, together warmth and empathy, sensitivity, knowledge, with recurrence risks and options for prenatal communication skill and insight into the psychol- diagnosis. ogy of human relationships, pregnancy and griev- The question concerning a repeat prenatal study ing. Ample time (with follow- up visits) is critical. is invariable, at least if not stated then certainly in The principles and prerequisites for counseling the mind of the parents. There are occasions when discussed earlier apply fully in these circumstances a repeat test might be appropriate, especially if and the fact that this is a parental decision, not a 42 Genetic Disorders and the Fetus

Table 1.9 The frequency of emotions and somatic symptoms of 84 women and 68 men: overall and 24 months after terminating a pregnancy for fetal abnormality 430

Women (%) Men (%) Women after 24 months (%) Men after 24 months (%)

Feeling Sadness 95 85 60 47 Depression 79 47 12 6 Anger 78 33 27 7 Fear 77 37 46 17 Guilt 68 22 33 7 Failure 61 26 24 14 Shame 40 9 18 4 Vulnerability 35 0 18 0 Relief 30 32 16 16 Isolation 27 20 11 6 Numbness 23 0 0 0 Panic spells 20 0 5 0 Withdrawal 0 32 0 13 Left out 0 12 0 0

Somatic symptom Crying 82 50 22 5 Irritable 67 38 19 3 No concentration 57 41 7 1 Listlessness 56 17 2 0 Sleeplessness 47 19 2 1 Tiredness 42 21 6 3 Loss of appetite 31 10 0 0 Nightmares 24 7 5 0 Palpitations 17 – 6 0 Headaches 9 8 2 0

medical “ recommendation, ” should not need The importance of continuing follow- up visits reiteration. with couples who have terminated pregnancy for Anticipatory counseling in these consultations fetal defects cannot be overemphasized. In an has been characterized by in - depth discussions of important study on the psychosocial sequelae in two areas: fi rst, all medical and scientifi c aspects of such cases, White- van Mourik et al. 430 showed the the prenatal diagnosis made (and discussed earlier) long - range effects (Table 1.9 ). Displays of emo- and second, recognition and vocalization of emo- tional and somatic symptoms 1– 2 years after abor- tional responses and reference to experiences tion were not rare and included partners. Although (preferably published) of other couples in like cir- some couples grew closer in their relationships, cumstances when it was helpful. These sessions separations, especially because of failed communi- have then included explorations concerning guilt, cation, increased irritability and intolerance, were a possible feeling of stigma (because of abortion), noted in 12 percent of the 84 patients studied. 430 anger, upset and how other couples have coped. All Marital discord in these circumstances has been of this anticipatory counseling has been tinctured noted previously. 431,432 At least 50 percent of with support and hope when possible. Many couples admitted to having problems in their couples have expressed their appreciation of this sexual relationship. In addition, many couples approach and indicated the benefi ts of having had indicated changed behavior toward their existing these discussions before elective termination. children, including overprotectiveness, anxiety, CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 43 irritability and consequent guilt and indiffer- of dealing with an existing fetal defect. In later ence.430 Women with secondary infertility and consultations, the thorny territory of predictive those younger than 21 years of age (or immature genetic testing of children can be reviewed at women) had the most prolonged emotional, physi- length.437 – 440 Fanos437 emphasized that testing ado- cal and social diffi culties. 430 lescents “ may alter the achievement of develop- Grief counseling becomes part of the consulta- mental tasks, including seeking freedom from tion after elective termination, in which full recog- parental fi gures, establishment of personal iden- nition of bereavement is necessary. The psychology tity, handling of sexual energies and remodeling of mourning has been thoroughly explored by both of former idealizations of self and others.” Fanos Parkes433 and Worden.434 Worden emphasized how also emphasized that parental bonding may be important it is for a bereaved individual to com- compromised by genetic testing when the child ’ s plete each of four stages in the mourning process. genetic health is questionable. Parents may react to 1. Acceptance of the loss. the possible loss or impairment of a child by devel- 2. Resolving the pain of grieving. oping an emotional distance, recognized as the 3. Adjusting to life without the expected child. vulnerable child syndrome.441 Other aspects, 4. Placing the loss in perspective. including interference with the normal develop- The importance of allowing parents the option of ment of a child’ s self- concept, introduce issues of holding tthe fetus (or later, the child), when appro- survivor guilt or increase levels of anxiety already priate, is well recognized. 435,436 These authors have initiated by family illnesses or loss. 441 Predictive also called attention to the complex tasks of testing of children for later - manifesting neurode- mourning for a woman who is faced with one generative or other disorders would rarely be rec- defective twin when pregnancy reduction or birth ommended, except in circumstances in which early might occur. diagnosis could offer preventive or therapeutic Notwithstanding anticipated loss and grief, benefi t. Seller et al., 436 refl ecting our own experience, emphasized that many couples recover from the Perinatal g enetic c ounseling trauma of fetal loss “ surprisingly quickly. ” Insinu- ation of this reality is helpful to couples in consul- A similar spectrum of issues and concerns is faced tations both before and after elective termination. after the detection and delivery of a child with a Moreover, couples’ orientation toward the griev- genetic disorder or an anomaly. Pregnancy with a ing process achieves an important balance when defective fetus may have been continued from the they gain suffi cient insight into the long- term emo- fi rst or second trimester or a diagnosis may be tional, physical, economic and social consequences made in the third trimester or at the delivery of a they might have needed to contemplate if prenatal living or stillborn child. The principles and pre- diagnosis had not been available. requisites for genetic counseling discussed earlier apply equally in all these circumstances.442 Special Testing the o ther c hildren attention should be focused on assuaging aspects Invariably, parents faced with the news of their of guilt and shame. Diffi cult as it may be for some affected fetus question the need to test their other physicians, 443,444 close rapport, patient visitation children. Answers in the affi rmative are appropri- and sincerity are necessary at these times, even ate when diagnosis of a disorder is possible. Carrier when faced with commonly experienced anger. A detection tests, however, need careful considera- misstep by the physician in these circumstances tion and are most appropriately postponed until in failing to continue (it is to be hoped) the the late teens, when genetic counseling should be rapport already established during pregnancy care offered. Given the complex dilemmas and far- provides the spark that fuels litigation in relevant reaching implications of testing asymptomatic cases. children for disorders that may manifest many Despite anger, grief and the gamut of expected years later, parents would best be advised to delay emotions, the attending physician (not an inexpe- consideration of such decisions while in the midst rienced healthcare provider) should take care to 44 Genetic Disorders and the Fetus urge an autopsy when appropriate. Diagnosis of ation compounded by fetal or congenital abnor- certain disorders (e.g. congenital nephrosis) can be mality. 446 The birth (or prenatal detection) of twins made by promptly collected and appropriately pre- discordant for a chromosomal disorder is not rare, pared renal tissue for electron microscopy, if muta- given the increased frequency of multiple preg- tion analysis (see Chapters 10 and 23 ) is unavailable. nancy associated with advanced maternal age In circumstances in which parents steadfastly with- and the use of assisted reproductive techniques. hold permission for autopsy (which is optimal), Pregnancy reduction (see Chapter 28 ) or the death magnetic resonance imaging could provide some of one twin or delivery of both evokes severely useful acceptable alternative when fetal anomalies confl icting emotions that may well affect the are expected. 445 The autopsy is the last opportunity mother ’ s care for the surviving child.447 Consider- parents will have to determine causation, which able psychologic skill must be marshaled by physi- may ultimately be critical in their future child - cians if meaningful care and support are to be bearing plans and also for their previous children. provided. 448 A formal protocol for evaluating the cause of still- Supporting telephone calls from doctor and staff birth or perinatal death is important (Box 1.4 ) to and encouragement to attend appointments every secure a defi nitive diagnosis, thereby laying the 6 weeks, or more frequently when appropriate, are foundation for providing accurate recurrence risks often appreciated by patients. Review of the and future precise prenatal diagnosis. In addition, autopsy report and discussion with reiterative in the face of known or suspected genetic disorders counseling should be expected of all physicians. in which mutation analysis now or in the future Frequently, parents receive an autopsy report by may be critical, care should be taken to obtain mail without further opportunity for explanation tissue for DNA banking or for establishing a cell and discussion. In one study, 27 percent failed to line. Later, parents may return and seriously ques- receive autopsy results.449 Providing contact with tion the failure of the physician to secure tissues or support groups whose focus is the disorder in DNA that would have been so meaningful in future question is also valuable. In the United States, the planning (e.g. X- linked mental retardation, spinal vast majority of these groups have combined to muscular atrophy). form the Alliance of Genetic Support Groups, Psychologic support is important for couples which acts as a central clearinghouse and referral who have lost an offspring from any cause, a situ- center.

Box 1.4 Protocol for evaluating the cause of stillbirth or perinatal death

1. Review genetic, medical and obstetric 8. Obtain heparinized cord or fetal blood history. sample for chromosomal or DNA analysis. 2. Determine possible consanguinity. 9. Obtain fetal serum for infectious disease 3. Gently and persistently recommend that studies (e.g. parvovirus, cytomegalovirus, parents permit a complete autopsy. toxoplasmosis). 4. Obtain photographs, including full face and 10. Obtain fetal tissue sample (sterile fascia profi le, whole body and, when applicable, best) for cell culture aimed at chromosome detailed pictures of any specifi c abnormality analysis or biochemical or DNA studies. (e.g. of digits). 11. Obtain parental blood samples for chromo- 5. Obtain full - body skeletal radiographs. some analysis, when indicated. 6. Consider full - body magnetic resonance 12. Communicate fi nal autopsy results and imaging,390 if autopsy is not permitted. conclusions of special analyses. 7. Carefully document any dysmorphic 13. Provide follow - up counseling, including a features. summary letter. CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 45

that parents have the time to make these various Family m atters decisions and assist by keeping the child in the Beyond all the “ medical ” steps taken in the wake ward for some hours when necessary. of stillbirth or perinatal death due to fetal defects Both parents should be encouraged to return for are critical matters important to the family and its continuing consultations during the mourning future. Active, mature and informed management period. 452 Mourning may run its course for 6 – 24 is necessary in these diffi cult and frequently poign- months. These consultations will serve to explore ant situations. Regardless of the cause of the child’ s aspects of depression, guilt, anger, denial, possible defect(s), maternal guilt is almost invariable and marital discord and physical symptoms such as fri- sometimes profound. Recognition of a defi nitive gidity or impotence. Impulsive decisions for steri- cause unrelated to a maternal origin should be lization should be discouraged in the face of explained in early discussions and reiterated later. overwhelming grief. Advice should be given about For autosomal recessive disorders or with even safe, reliable and relatively long- term contracep- more problematic X- linked disorders, maternal tion. 453 Similarly, parents should be fully informed “ culpability ” is real and not easily assuaged. The about the consequences of having a “ replacement fact that we all carry harmful genes, some of which child” very soon after their loss. 454,455 That child we may have directly inherited, while others may may well become a continuing vehicle of grief for have undergone mutation, may need in - depth dis- the parents, who may then become overanxious cussion. Mostly, it is possible and important to and overprotective. Subsequently, they may bedevil reassure mothers that the outcome was not due to the future of the replacement child with constant something they did wrong. Where the converse is references to the lost baby, creating a fantasy image true, much effort will be needed for management of perfection that the replacement child could of guilt 450 and shame, and for planning actions that never fulfi ll. Such a child may well have trouble promise a better future with ways to avert another establishing his or her own identity. adverse outcome. Attention to details that have a very important The s urviving c hildren role in the mourning process include ensuring that Distraught parents frequently seek advice about the child be given a name and, in the case of the how to tell their other children. Responses should death of a defective fetus in the third trimester, that be tailored to the age of the child in question, to the parents ’ wishes for a marked grave be deter- the child’ s level of understanding and against a mined. As noted earlier, most caretakers feel that background of the religious and cultural beliefs of parents are helped by both seeing and holding the the family. A key principle to appreciate is that baby.435,436,451 Although some may experience initial having reached the stage of cognizance regarding revulsion when the subject is mentioned, gentle the loss, a child needs and seeks personal security. coaxing and explanations about the experiences of Hence, the parents’ attention should be focused on other couples may help grieving parents. Even with love, warmth and repetitive reassurance, especially badly disfi gured offspring, it is possible for parents about (possibly) unstated feelings of previous to cradle a mostly covered baby whose normal wrongdoing and personal culpability. Advice about parts, such as hands and feet, can be held. Impor- grieving together instead of being and feeling over- tant mementos that parents should be offered are whelmed in front of their children is also helpful photographs, a lock of hair, the baby ’ s name band advice. Focusing on the children ’ s thoughts and or clothing.447,448 Ultimately, these concrete activities is benefi cial rather than lapsing into a emblems of the baby’ s existence assist parents in state of emotional paralysis, which can only the mourning process, although the desperate serve to aggravate the family ’ s psychodynamics emptiness that mothers especially feel is not easily adversely. remedied. Photos may also be helpful in providing comfort for other children and for grandparents. The e ffi cacy of g enetic c ounseling Parents will also vary in their choice of traditional or small, private funerals. Physicians should ensure The essential goal of the communication process 46 Genetic Disorders and the Fetus in genetic counseling is to achieve as complete an families highlight the need for very explicit understanding by the counselee(s) as possible, counseling. thereby enabling the most rational decision Important points made by Emery et al.457 in their making. Parental decisions to have additional prospective study of 200 counselors included the affected progeny should not be viewed as a failure demonstrated need for follow - up after counseling, of genetic counseling. Although the physician’ s especially when it is suspected that the comprehen- goal is the prevention of genetic disease, the orien- sion of the counselee(s) is not good. This seemed tation of the prospective parents may be quite dif- particularly important in chromosomal and ferent. A fully informed couple, both of whom had X - linked recessive disorders. They noted that the achondroplasia, requested prenatal diagnosis with proportion deterred from having children the expressed goal of aborting a normal unaffected increased with time and that more than one- third fetus so as to be able to raise a child like themselves. of their patients opted for sterilization within 2 Would anyone construe this as a failure in genetic years of counseling. counseling? A number of studies 457– 459 document the failure Clarke et al. 456 considered three prime facets that of comprehension by the counselee(s). The reports could possibly evaluate the effi cacy of genetic do not refl ect objective measures of the skill or counseling: (1) recall of risk fi gures and other rel- adequacy of genetic counseling and the possible evant information by the counselee(s); (2) the value of a summary letter to the patient of the effect on reproductive planning; and (3) actual information provided after the counseling visit. reproductive behavior. Their conclusions, refl ect- Sorenson et al. 460 prospectively studied 2,220 coun- ing a Western consensus, were that there are too selees who were seen by 205 professionals in 47 many subjective and variable factors involved in clinics located in 25 states and the District of the recall of risk fi gures and other genetic coun- Columbia. They gathered information not only on seling information to provide any adequate the counselees but also on the counselors and the measure of effi cacy. Further, assessing reproduc- clinics in which genetic counseling was provided. tive intentions may prejudge the service the coun- They, too, documented that 53 percent of counse- selee wishes as well as the fact that there are too lees did not comprehend their risks later, while 40 many confounding factors that have an impact on percent of the counselees given a specifi c diagnosis reproductive planning. Moreover, how many years did not appear to know it after their counseling. after counseling would be required to assess the They thoroughly explored the multiple and impact on reproductive planning? They regarded complex issues that potentially contributed to the evaluation of reproductive plans as “ a poor proxy obvious educational failure that they (and others) for reproductive behavior.” In dispensing with have observed. In another study of parents with a assessments of actual reproductive behavior in the DS child, Swerts 408 noted that of those who had face of counseling about such risks, they pointed genetic counseling, 45 percent recalled recurrence to the complex set of social and other factors that risks accurately, 21 percent were incorrect and 34 confound the use of this item as an outcome percent did not remember their risks. measure. They did, however, recommend that effi - The expected post- counseling letter to the refer- cacy be assessed against the background goals of ring physician with a copy (or a separate letter) to genetic counseling aimed at evaluation of the the patient plays a vital role in securing comprehen- understanding of the counselee(s) of their own sion of risks and issues. Printed materials, especially particular risks and options. covering risks, test limitations, psychologic and Evaluation of the effi cacy of genetic coun- social aspects, enrich the counseling benefi ts. 78 seling 12,169 should therefore concentrate on the Genetic counseling can be considered successful degree of knowledge acquired (including the reten- when counselees, shown to be well informed, make tion of the counselee(s) with regard to the indi- careful, rational decisions regardless of whether cated probabilities) and the rationality of decision their physicians consider their position to be ill making (especially concerning further reproduc- advised. Clearly, counselees and counselors may tion). Frequent contraceptive failures in high- risk differ in their perception of the consultation and CHAPTER 1 Genetic Counseling: Preconception, Prenatal and Perinatal 47 the degree of satisfaction. 461 Notwithstanding the counselee satisfaction. Efforts to educate the public obvious benefi ts of counseling, reproductive uncer- about the importance of genetics in their personal tainty is often not eliminated because it is related to lives have been made by one of us in a series of factors beyond the scope of counseling.462 books (translated into nine languages) over a In considering the effectiveness of genetic coun- quarter of a century.167,168,171 – 173,256 In addition to seling, Sorenson et al.460 summarized the essence of public education and its concomitant effect of edu- their conclusion. cating physicians generally, formal specialist certi- fi cation in the United States, Canada and the In many respects, an overall assessment of the United Kingdom, acceptance of clinical genetics as effectiveness of counseling, at least the counseling a specialty approved by the American Medical we assessed in this study, is confronted with the Association and new degree programs for genetic problem of whether the glass is half full or half counselors certifi ed by the National Board of empty. That is, about half of the clients who could Genetic Counselors will undoubtedly improve the have learned their risk did but about half did not. And, over half of the clients who could have effi cacy of genetic counseling. learned their diagnosis did but the remainder did not. In a similar vein, clients report that just over References half of their genetic medical questions and con- cerns were discussed but about half were not. The 1. Martin RH , Ko E , Rademaker A . Distribution of picture for sociomedical concerns and questions aneuploidy in human gametes: comparison between was markedly worse, however. And, reproduc- human sperm and oocytes. Am J Med Genet 1991 ; 39 : tively, just over half of those coming to counseling 321 . to obtain information to use in making their 2. Plachot M . Chromosome analysis of oocytes and reproductive plans reported counseling infl u- embryos. In: Verlinsky Y , Kuliev A , eds. Preimplanta- enced these plans but about half did not. Any tion genetics. New York: Plenum Press, 1991 : 103 . overall assessment must point to the fact that 3. Bou é J , Bou é A , Lazar P . Retrospective and prospective counseling has been effective for many clients but epidemiological studies of 1500 karyotyped spontane- ineffective for an almost equal number. ous human abortions. Teratology 1975 ; 12 : 11 . 4. Alberman ED , Creasy MR . Frequency of chromosomal A critical analysis of the literature by Kessler 463 con- abnormalities in miscarriages and perinatal deaths . J cluded that published studies on reproductive Med Genet 1977 ; 14 : 313 . outcome after genetic counseling reveal no major 5. Holmes - Seidle M , Ryyvanen M , Lindenbaum RH . impact of counseling. Moreover, decisions made Parental decisions regarding termination of pregnancy before counseling largely determined reproduction following prenatal detection of sex chromosome abnormality. Prenat Diagn 1987 ; 7 : 239 . after counseling. 6. Martinez - Frias ML , Bermejo E , Cereijo A , et al. Epide- A more recent study of patients ’ expectations of miological aspects of Mendelian syndromes in a genetic counseling revealed that the majority had Spanish population sample. II. Autosomal recessive their expectations fulfi lled, especially with per- malformation syndromes. Am J Med Genet 1991; 38 : 626 . 464 ceived personal control. When patients ’ expecta- 7. Njoh J , Chellaram R , Ramas L . Congenital abnormali- tions for reassurance and advice were met, they ties in Liberian neonates. West Afr J Med 1991 ; 10 : 439 . were subsequently less concerned and had less 8. Verma IC . Burden of genetic disorders in India . Indian anxiety compared with when such expectations J Pediatr 2001 ; 67 : 893 . were not fulfi lled. 8a. Lie RT , Wilcox AJ , Skjaerven R . Survival and repro- The limited effi cacy of genetic counseling duction among males with birth defects and risk of revealed in the study by Sorenson et al. 460 refl ects recurrence in their children. JAMA 2001 ; 285 : 755 . 9. Queisser - Luft A , Stolz G , Wiesel A , et al. Malforma- the consequences of multiple factors, not the least tions in newborn: results based on 30,940 infants and of which are poor lay understanding of science and fetuses from the Mainz congenital birth defect moni- a lack or inadequacy of formal training of coun- toring system (1990– 1998) . Arch Gynecol Obstet 465 selors in clinical genetics, which is no longer the 2002 ; 266 : 163 . case for genetic counselors, at least in the USA and 10. McKusick VA . Mendelian inheritance in man, 12th ed. Canada. Effi cacy, of course, is not solely related to Baltimore : Johns Hopkins University Press, 1998 . 48 Genetic Disorders and the Fetus

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