DISORDER AND INCIDENCE

CHARACTERISTICS

ETIOLOGY AND RECURRENCE RISKS

CONSIDERATIONS AND COMMENTS

Chromosomal Disorders

Autosomal

Down syndrome (Trisomy 21) 1 in 700 neonates; incidence increases with advanced maternal age (eg, risk at maternal age 25 is 1 in 1,350; at age 35, 1 in 384; at age 45, 1 in 28)

Brachycephaly: oblique palpebral fissures; epicanthal folds; Brushfield spots; flat nasal bridge; protruding tongue; small, low-set ears; clinodactyly; simian crease; congenital heart defects; hypotonia; mental retardation; growth retardation; dry, scaly skin; increased risk for childhood leukemia and early-onset Alzheimer’s disease

• Extra copy of number 21 chromosome (total of three copies).

• 94% of cases are trisomy (karyotype 47, +21) for three distinct number 21 chromosomes due to nondisjunction (failure of chromosomal separation during meiosis); recurrence risk 1%, plus maternal age-related risk if older than age 35.

• 4% of cases have a translocation—the extra number 21 is attached to another chromosome, usually a number 13 or number 14; half of these translocations are new occurrences, the other half are inherited from a parent.

• 2% of cases are mosaic— affected individual has two different cell lines, one with the normal number of chromosomes and the other cell line trisomic for the number 21 chromosome; due to a postconception error in chromosomal division during mitosis.

• Recurrence risk for parents of affected are dependent on one or more of the following: chromosomal type of disorder, maternalage, parental karyotype, family history, and sex of transmitting parent and other chromosome involved (if translocation).

• May demonstrate nuccal thickening prenatally on ultrasound examination.

• Associated with moderate mental retardation.

• No phenotypic differences between trisomy Down syndrome and translocation Down syndrome.

• Chromosome analysis should be performed on all persons with Down syndrome.

• Prenatal maternal serum screening can adjust risk for the pregnancy.

Trisomy 13 (Patau syndrome) 1 in 5,000 live births

Holoprosencephaly; cleft lip or palate, or both; abnormal helices; cardiac defects; rocker-bottom feet; overlapping positioning of fingers; seizures; severe mental retardation

• Extra number 13 chromosome (total of three copies): Either trisomy form, due to nondisjunction, with less than a 1% recurrence risk; or translocation form, with recurrence risk less than that of translocation Down syndrome and dependent on other factors, including chromosomes involved.

• 44% die within the first month; 18% survive first year of life.

Trisomy 18 (Edwards syndrome) 1 in 6,000 live births

Small for gestational age (may be detected prenatally); feeble fetal activity; weak cry; prominent occiput; low-set, malformed ears; short palpebral fissures; small oral opening; overlapping positioning of fingers (fifth digit over fourth, index over third); nail hypoplasia, short hallux; cardiac defects; inguinal or umbilical hernia; cryptorchidism in males; severe mental retardation

• Extra number 18 chromosome (total of three copies): Majority due to trisomy with less than 1% recurrence risk.

• Most trisomy 18 conceptions miscarry; 90% die within first year of life.

Sex Chromosome

Klinefelter syndrome 1 in 700 males; 47, XXY abnormality in 90%; other 10% have more than two X chromosomes in addition to the Y chromosome or have mosaicism (about 20%)

Body habitus may be tall, slim, and underweight; long limbs; gynecomastia; small testes; inadequate virilization; azoospermia or low sperm count; cognitive defects; behavioral problems

• Due to nondisjunction during meiosis, except for cases of mosaicism, which are due to mitotic nondisjunction.

• No distinguishing features prenatally.

• Diagnosis may not be suspected or pursued before puberty.

• Diagnosis in childhood is beneficial in planning for testosterone replacement therapy, in addition to accurate understanding of learning or behavioral problems.

• Tend to be delayed in onset of speech, have difficulty in expressive language; may be relatively immature; may have history of recurrent respiratory infections.

Turner syndrome (45, X) 1 in 2,500 female births

Webbing of neck and short stature; lymphedema of hands and feet as neonate; congenital cardiac defects (especially coarctation of the aorta); low posterior hairline; cubitus valgus; widely spaced nipples; underdeveloped breasts; immature internal genitalia (eg, streak ovaries); primary amenorrhea; learning disabilities

• About 50% due to a nondisjunctional error during meiosis (karyotype 45, X); 20% are mosaic due to nondisjunction during mitosis; 30% have two X chromosomes but one is functionally inadequate (eg, due to presence of abnormal gene); generally a sporadic occurrence.

• Webbing of neck and short stature may be detected prenatally by ultrasound.

• Early diagnosis enhances optimal health care management (eg, planning for administration of growth hormone therapy, estrogen replacement).

• Psychosocial implications associated with short stature, delayed onset of puberty.

• Infertility associated with ovarian dysgenesis; oocyte donation and adoption are generally the only options for having children.

Microdeletion/Microduplication

Fragile X 1 in 1,200 males; 1 in 2,500 females

Motor delays; hypotonia; speech delay and language difficulty; hyperactivity; classic features including long face, prominent ears, and macroorchidism manifest around puberty; autism (about 7% of males); mental retardation in most males; learning disabilities in most affected females

• Mutation in the fragile X menta l retardation gene (FMR-1), represented as a large DNA expansion of a normally present trinucleotide.

• Carrier mother of an affected male has a 50% risk for future affected males and 50% chance of transmitting the FMR-1 X chromosome to a daughter who would be a carrier, may be unaffected, or manifest features associated with the fragile X syndrome and has a 50% chance of transmitting that gene to future offspring.

• Both cytogenetic testing for expression of the fragile X site and DNA analysis to characterize the size of the DNA expansion are available, but the latter is superior. Testing for methylation status of the DNA increases sensitivity.

• Phenotypic expression of this gene in males and females is variable; genetic mechanisms determining expression of this gene are very complicated.

• Fragile X should be considered in the differential diagnosis of any male with mental retardation who is undiagnosed; it is the most common mental retardation in males.

Microdeletion/Microduplication

Prader-Willi syndrome Estimated incidence 1 in 25,000

Hypotonia and poor sucking ability in infancy; almondshaped palpebral fissures; small stature; small, slow growth of hands or feet; small penis, cryptorchidism; insatiable appetite, behavioral problems developing in childhood; below-normal intelligence or mental retardation

• Cytogenetic microdeletion in chromosome 15q11 to 13 identified in 50% to 70% of cases; deletion associated with paternally inherited number 15 chromosome.

• Generally sporadic occurrence; empiric recurrence risk 1.6%.

• Consider diagnosis in infants presenting with hypotonia and sucking problems where etiology is unknown.

• Associated with lack of a functioning paternal gene at this locus; presents clinical evidence for the necessity of two functioning genes, both a maternal and paternal contribution.

• Another distinct entity, termed Angelman syndrome, is associated with a deletion of the maternal contribution in this same cytogenetic region; it is also associated with mental deficiency, but with a different phenotypic presentation.

Mendelian Disorders—Single Gene

Autosomal Dominant

Achondroplasia 1 in 10,000 live births Increased incidence associated with advanced paterna l age (>40)

Megalocephaly; small foramen magnum and short cranial base with early spheno-occipital closure; prominent forehead; low nasal bridge; midfacia l hypoplasia; small stature; short extremities; lumbar lordosis; short tubular bones; incomplete extension at the elbow; normal intelligence

• Autosomal dominant inheritance; 80% to 90% are due to a new mutation and neither parent is affected.

• An affected parent has a 50% risk to transmit the gene to each child.

• Hydrocephalus can be a complication of achondroplasia and may be masked by megalocephaly.

• Risk for apnea secondary to cervical spinal cord and lower brain stem compression due to alterations in shape of cervical vertebral bodies; respiratory problems are also a risk because of the small chest and upper airway obstruction.

• Can be diagnosed prenatally by ultrasound.

Osteogenesis imperfecta (Type 1) 1 in 15,000 live births

Blue sclerae; fractures (variable number); deafness may occur

• Defect in the procollagen gene associated with decreased synthesis of a constituent chain important to collagen structure.

• Can occur as a new mutation in that gene or can be inherited from a parent who has a 50% recurrence risk to transmit the gene; most severe cases represent a sporadic occurrence within a family.

• There are at least four genera l classifications of osteogenesis imperfecta, each with varying clinical severity, presentation, and pattern of genetic transmission.

• Treatment with calcitonin and fluoride may be beneficial in reducing the number of fractures.

Breast and breast/ovarian cancer syndrome Accounts for 5% to 10% of breast cancer

Breast cancer (usually, but not exclusively, early-age onset, premenopausal); ovarian cancer

• Mutation in the BRCA-1 or BRCA-2 gene; poses increased susceptibility (not certainty) for breast (31% to 78%) and/or ovarian (3% to 54%) cancer.

• Studies have also noted increased risk for prostate cancer, colon cancer in some families; also an association between male breast cancer and BRCA-2 mutations.

• Individuals from Ashkenazi Jewish ancestry are at increased risk for mutations in BRCA-1 and BRCA-2.

Autosomal Dominant

Familial adenomatous polyposis (FAP) Accounts for about 1% of colon cancer

Associated with multiple adenomatous colorecta l polyps (classic: > 100; atypical: < 100), desmoid tumors, other Gi polyps, jaw cysts; family history of polyps or colorectal cancer; polyps progress to cancer; polyps can be present in childhood

• Mutations in the APC gene (a tumor suppressor gene). The majority of mutations result in a truncated protein.

• Genetic testing (protein truncation testing is available). If mutation is identified in affected person, relatives can be tested for the same finding. Relatives at risk, whether by family history or by genetic testing, should start cancer screening by age 18, if not earlier, if there are symptoms or as a baseline. Screening includes colonoscopy, ophthalmologic examination.

Autosomal Recessive

Sickle cell disease 1 in 400 live births of African Americans

Physically normal in appearance at birth; hemolytic anemia and the occurrence of acute exacerbations (crises), resulting in increased susceptibility to infection and vascular occlusive episodes

• Point mutation in the beta globin gene resulting in an altered gene product; red blood cells susceptible to sickling at times of low oxygen tension.

• Parents of an affected individua l are both unaffected carriers of one abnormal copy of the beta globin gene (sickle cell trait); together have a 25% risk for recurrence in any offspring.

• 1 in 10 African Americans is a carrier of the beta globin gene mutation; population screening is indicated for these individuals.

• Unaffected siblings of an affected individual have a twothirds, or 67%, risk to have the sickle cell trait and should be screened.

• See page 1704 for nursing care.

• Prenatal testing is available through DNA analysis from specimen obtained during chorionic villus sampling or amniocentesis.

Cystic fibrosis (CF) 1 in 2,000 live births (predominantly white)

Phenotypically normal at birth; may present with meconium ileus (10%) as neonate or later with persistent cough, recurrent respiratory problems, gastrointestinal complaints, malnutrition, abdomina l pain, or infertility

• Mutation in the CF transmembrane conduction regulator gene on chromosome 7 results in an abnormality of a protein integral to the cell membrane.

• Parents of an affected individual are both considered obligate carriers of one copy of the abnormal CF gene; thus, together they have a 25% recurrence risk with each conception.

• 1 in 20 individuals from Northern European ancestry is a carrier of a CF gene mutation.

• Many different mutations have been identified within the CF gene, the most common of which is Delta-F508, which accounts for about 70% of CF mutations. CF screening can identify about 85% of all CF mutations (95% in Jewish population).

• “General population” screening is recommended by the American College of Obstetrics and Gynecology.

• DNA analysis of the CF gene is advised for affected individuals and relatives of persons with CF.

• See page 1514 for nursing care.

Autosomal Recessive

Tay-Sachs disease 1 in 3,600 Ashkenazi Jews

Normal at birth; progressive neurodegenerative manifestations, including loss of developmental milestones and lack of central nervous system maturation; cherryred spot on macula

• Mutation in the gene for hexosaminidase A, an enzyme important to cellular metabolic processes, results in accumulation of metabolic by-products within the cell (especially brain), impairing functioning and causing the neurodegenerative effects.

• Parents of an affected individua l are both considered unaffected obligate carriers of one copy of the Tay-Sachs disease gene; together they have a 25% risk of recurrence in their offspring.

• About 1 in 25 Ashkenazi Jews is a carrier of the Tay-Sachs gene; about 1 in 17 French Canadians is a carrier of an abnormal Tay-Sachs gene (different mutation from that of the Jewish ancestry); persons of these ancestries should be screened.

• No treatment available; results in death in childhood.

• Prenatal and preimplantation testing are available.

X-Linked Recessive

Duchenne muscular dystrophy (DMD) 1 in 3,500 males

Phenotypically normal at birth; dramatically elevated creatinine kinase leve l (detectable as early as age 2 days); hypertrophy of the calves; history of tendency to trip and fall (at about age 3); Gowers’ sign (tendency to push off oneself when getting up from a sitting position)

• DNA mutation, generally a deletion, detectable in 70% of affected males.

• Carrier females have a 25% risk, with each pregnancy, to have an affected male, a 25% risk to have a carrier female, a 25% chance to have a healthy male, and a 25% chance to have a healthy noncarrier female.

• 1 in 1,750 females is a carrier of the DMD gene.

• In the case of an isolated affected male, the mother has a two thirds statistical risk that she is a carrier of the DMD gene and a one third chance that her affected son developed as the result of a new mutation in that gene (she is not a carrier).

• DNA testing is recommended for affected males; once type of gene mutation is known in that family, prenatal diagnosis and evaluation of potential female carriers can be carried out.

• DNA analysis may provide clues as to expected clinical severity.

Hemophilia A 1 in 7,000 males

Phenotypically normal at birth; bleeding tendency (ranging from frequent spontaneous bleeds associated with the severe form to bleeding only after trauma associated with the mild form)

• Deficiency of Factor VIII (antihemophilic factor) due to abnormality in this gene located on the X chromosome.

• Carrier females have a 25% risk, with each pregnancy, to have an affected son, a 25% risk to have a carrier daughter, and a 25% chance each to have a healthy unaffected daughter or son.

• Mates of affected males should be tested for carrier status. If the female is not a carrier, the affected male will not have any affected children.

• Frequency of carrier females is about 1 in 3,500.

• The severe form occurs in about 48% of cases.

• Moderate cases account for 31%.

• The mild form accounts for 21% of cases.

• See page 1712 for nursing care.

X-Linked Recessive

Glucose 6-phosphate dehydrogenase (G6PD)

10% to 14% of male live births of African American origin

Phenotypically normal at birth; many remain asymptomatic throughout life; may manifest acute hemolysis associated with exposure to outside factors (eg, certain medications)

• Abnormality of the G6PD gene on the X chromosome.

• Carrier females have a 25% risk, with each pregnancy, to have an affected male and 25% risk to have a carrier female.

• Be aware of drugs, such as antimalarial drugs or sulfonamides, or chemicals, such as phenylhydrazine (used in silvering mirrors, photography, soldering), associated with hemolysis in G6PDdeficient individuals.

Multifactorial Disorders

Neural tube defects 1 in 1,000 live births

Abnormalities of neural tube closure, ranging from anencephaly to myelomeningocele to spina bifida occulta

• Probably several genetic factors may predispose certain individuals or families to susceptibility, but certain environmental (eg, prolonged hyperthermia or folate deficiency) and other unknown factors play an additive rule in surpassing an arbitrary threshold, placing the developing fetus at risk.

• Recurrence risk for isolated neural tube defects range between 1% and 5%.

• Recurrence risk for isolated neural tube defects is dependent on the severity of the defect (ie, a defect in the neurulation [the cranial end of the neural tube] versus cannulation [the development of the caudal end]) and if there is a positive family history.

• Maternal screening can be performed prenatally (after 14 weeks’ gestation) through alpha-fetoprotein levels in maternal serum.

• Can be associated with chromosomal or genetic disorders.

Cleft lip and/or cleft palate 1 in 1,000 live births

Unilateral or bilateral; cleft lip and cleft palate may occur together or in isolation

• Failure of migration and fusion of the maxillary processes during embryogenesis.

• Recurrence risk for first-degree relatives of a person with an isolated cleft lip or cleft palate ranges between 2% and 6%.

• Clefting can occur as an isolated congenital abnormality or be one component of a syndrome, genetic defect, or chromosome abnormality, the latter three of which are associated with a recurrence risk specific to that disorder.

• Recurrence for isolated cleft lip or palate is dependent on the type of cleft, the sex of the affected individual, and the family history.