Читать книгу Genetic Disorders and the Fetus - Группа авторов - Страница 44

Physicians are now advised to determine whether a culprit gene has been found for a specific genetic disorder under discussion, since prenatal diagnosis would then be available for that couple or their children. Adult‐onset genetic disorders (breast/ovarian cancer, colon cancer, hypertrophic cardiomyopathy, long QT syndrome) serve as examples where prenatal diagnosis is an option. The long‐established prenatal diagnoses for both presymptomatic and symptomatic neurodegenerative disorders⁴³⁷ continue to be expanded to include disorders such as amyotrophic lateral sclerosis and frontotemporal dementia by analysis of the C9orf72 gene.⁴³⁸ In prenatal diagnosis discussions for all adult‐onset disorders, there is a natural focus on the tortured questions of personal existence and self‐extinction. One example is that of a young father with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) who, faced with our prenatal diagnosis of this disorder, by mutation analysis of the Notch3 gene, with his wife, elected termination.⁴³⁹ Mutation analysis in a subsequent pregnancy assured an unaffected fetus.⁴⁴⁰

These consultations may invoke deep personal emotional conflict, especially when pleiomorphic genes are concerned. For example, a parent with tuberous sclerosis and normal intelligence could not be certain that an affected child would not have intellectual disability. This was especially evident in our series of 50 couples having prenatal diagnosis for tuberous sclerosis.⁴³⁶ Discovery of fetal cardiac rhabdomyoma led to sequencing of both the TSC1 and TSC2 genes in the fetus and diagnosis in one of the asymptomatic parents. Parental decisions are neither simple nor predictable. In a UK study⁴⁴¹ of 644 deaf individuals and 143 with hearing impairment, 2 percent opined that they would prefer to have deaf children and would consider an elective abortion if the fetus was found to be hearing!

Prospective mothers with insulin‐dependent diabetes mellitus (IDDM) could find their disorder harder to control during pregnancy. Diabetes should be well controlled before pregnancy. The better the control, the lower the risk of having a child with congenital defects.^{442, 443} An Australian study noted that with good preconception care of type 1 IDDM, the major congenital malformation rate decreased from a high of 14 percent to 2.2 percent.⁴⁴⁴ Notwithstanding extant knowledge about IDDM and pregnancy, a report of 273 women noted rates of stillbirth (1.85 percent), perinatal mortality (2.78 percent), and congenital anomalies (6 percent).⁴⁴⁵ An important Stockholm study of 1,089 stillbirths usefully separated causes in preterm and term/post‐term births.⁴⁴⁶ Infection and intrauterine growth restriction/placental insufficiency accounted for over 44 percent of cases in about equal proportion.

The genetics of diabetes is complex with multiple types, both polygenic, multifactorial, syndromic, and monogenic in origin. The polygenic type 1 diabetes (T1DM) and type 2 diabetes (T2DM) have over 40 and 90 genes implicated, respectively. Between 1 and 5 percent of diabetes is monogenic and symptoms overlap with T1DM and T2DM diabetes.^{447, 448} Affected monogenic type patients mostly do not have islet autoantibodies, often have endogenous insulin production, and are frequently misdiagnosed.^{449, 450} Both T2DM and monogenic diabetes are often not insulin‐dependent, have a family history of diabetes, and can occur in the young. Usually, insulin resistance does not occur, nor does acanthosis nigricans in monogenic diabetics, who are mostly not obese.⁴⁴⁹

Diabetes diagnosed in the first year of life is monogenic and due to K_ATP channel mutations.⁴⁵¹ There are multiple types of monogenic autosomal dominant maturity‐onset diabetes of the young (MODY), four subtypes predominating with mutations in HNFIA (52 percent), GCK (32 percent), HNF4A (10 percent), and HNF1B (6 percent).⁴⁵²

A precise preconception molecular diagnosis is important so as to direct appropriate treatment. No pharmacologic treatment is indicated for the GCK‐MODY type, low dose sulfonylureas are prescribed for HNF1A‐MODY and HNF4A‐MODY, with high‐dose sulfonylureas for K_ATP channel‐related diabetes.⁴⁵¹

Pregestational T1DM and T2DM are associated with poorer pregnancy outcomes, including up to a fourfold higher rate of perinatal mortality.⁴⁵³ The poorer glycemic control at the time of conception and the first trimester, the higher the frequency of stillbirths, congenital abnormalities, perinatal morbidity and mortality, macrosomia, dystocia in labor, and maternal mortality.^454–458 Obesity, with its burden of obstetric complications and congenital anomalies⁴⁵⁷ (as discussed earlier), compounds all the problems in the diabetic mother.

Pregnant women with the chronic multifactorial autoimmune disease systemic lupus erythematosus (SLE) face a host of complications. This disorder, with its predilection for women of childbearing age, is more prevalent in non‐white populations and is characterized by involvement that includes renal, cardiovascular, musculoskeletal, neurological, rheumatological, and cutaneous systems.⁴⁵⁹ Adverse pregnancy outcomes include fetal death, preterm births, intrauterine growth restriction, and neonatal lupus.⁴⁶⁰ Women with anti‐Ro/anti‐La antibodies, the latter being specific for the diagnosis of SLE and Sjögren syndrome,⁴⁶¹ can be asymptomatic. Anti‐Ro antibodies may precede the clinical manifestations of SLE by an average of 3.6 years.⁴⁶² Note, however, these antibodies are found in up to 3 percent of the general population.⁴⁶³

The prime consequences of having anti‐Ro antibodies is the risk of fetal/neonatal heart block and neonatal lupus. In a study of 325 children with second‐ or third‐degree heart block, the overall mortality rate was 17.5 percent. Death in utero occurred in 6 percent.⁴⁶⁴ The risk of offspring being born with congenital heart block to a mother with anti‐Ro antibodies is between 0.2 and 2.0 percent, but 15–20 percent if there has been a previously affected fetus or neonate.^{464, 465} After two affected pregnancies, the subsequent pregnancy risk is 50 percent.⁴⁶⁶ Complex therapeutic considerations include fluorinated glucocorticoids (dexamethasome and betamethasome) and maternal fetal echocardiography monitoring.^{467, 468} Neonatal lupus with congenital heart block will usually require pacemaker implantation.^{469, 470} For mothers with a previous affected pregnancy, hydroxychloroquine has been recommended as a pre‐emptive treatment.^{471, 472} Fortunately, only a third of mothers carrying fetuses with complete heart block have an identified autoimmune disorder such as lupus or Sjögren disease.⁴⁷³

Certain genetic disorders may threaten maternal and fetal health in pregnancy and are discussed in detail in Chapter 31.