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Maternal Phenylketonuria Syndrome and Case Management Implications
Maternal Phenylketonuria Syndrome and Case Management Implications Patricia J. Gambol, RN, MSN, APNG
Well-established dietary protocols have prevented mental retardation for infants born with phenylketonuria (PKU). Dietary protocols for managing females with PKU in their reproductive years exist but are not followed by most of them. Infants who are born to mothers with PKU who are not on dietary treatment usually have serious medical problems, such as mental retardation, heart defects, and other serious congenital anomalies (e.g., orofacial clefting and bladder exstrophy)—a condition known as maternal PKU syndrome. The focus of this article is to review the pathophysiology, associated developmental issues, and existing management protocols used to manage these two separate but highly connected disorders. n 2007 Elsevier Inc. All rights reserved.
N THE MID-1960s, neonatal nurses initiated a new procedure on all newborns—a heel stick— to identify the genetic disorder phenylketonuria (PKU). These nurses understood that PKU was a genetic disorder that resulted in severe mental retardation if not identified and treated quickly with a diet low in phenylalanine (Phe). Preventing mental retardation through diet treatment was considered a medical marvel at this time. Thus, PKU screening became the benchmark for screening other newborn disorders. Twenty years later, pediatric nurses were assessing children born to females with PKU. These babies/children presented with myriad cognitive and physical problems, including microcephaly, dysmorphic facial features, delayed speech, mental retardation, and cardiac anomalies. Nurses now had a new condition to manage— maternal PKU (MPKU) syndrome—a condition that occurs when females with PKU do not adhere to strict dietary treatment. The key issue in managing infants born with PKU is parental compliance with protocols. Less obvious issues in managing PKU emerge as the child with PKU becomes older. Parental interest/compliance wanes, and dietary protocols are relaxed. Until recently, health care providers had no concrete evidence to continue the diet after the age of 6 years and did not encourage parents to maintain strict treatment guidelines. However, females with PKU who do not maintain dietary treatment are at high risk for having an infant with MPKU syndrome
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(Lee, Ridout, Walter, & Cockburn, 2005). Health care providers must realize that 75% of mothers with PKU are not in dietary control before pregnancy (Koch et al., 1999). LITERATURE REVIEW Initially, PKU was assigned to one of four classes of severity (i.e., severe, moderate, or mild PKU and mild hyperphenylalaninemia; Gutter et al., 1999). Scriver and Kaufman (2001) questioned the need to subdivide PKU by calling attention to the fact that all degrees of hyperphenylalaninemia are harmful to cognitive development and that such classifications are not relevant to treatment (National Institutes of Health (NIH), 2000). Consequently, in this article, the term PKU will apply to all levels of hyperphenylalaninemia.
Genetics The incidence of PKU varies among different nations and ethnic groups. It is 1 per 4,500 in
From the Saddleback Memorial Medical Center, Laguna Hills, CA. Address correspondence and reprint requests to Patricia J. Gambol, RN, MSN, APNG, Saddleback Memorial Medical Center, 24401 Calle de la Louisa, Suite 200, Laguna, CA 92653. E-mail: [email protected] 0882-5963/$ - see front matter n 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pedn.2006.08.002
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Ireland, 1 per 16,000 in Switzerland, and 1 per 16,000 in the United States (1 per 8,000 in Caucasians and 1 per 50,000 in Blacks). The clinical presentation of PKU is extremely variable because the Phe hydroxylase (PAH) gene has more than 400 known mutations that allow for more than 10,000 genotypic combinations (Dilella, Kwok, Ledley, Marvit, & Woo, 1986; Guldberg et al., 1998; Hofman, Steel, Kazazian, & Valle, 1991; Lapis, 2001; Wilcox & Cederbaum, 2002). PKU is an autosomal (non-gender-determining chromosome) disorder involving the PAH gene on chromosome 12. All human beings have two copies of the number 12 chromosome, one from each parent. PKU is a recessive disorder, which means that a person carrying the trait (a carrier) usually does not exhibit disease symptoms. A carrier has one normal functioning PAH gene on one chromosome 12 and an abnormal PAH gene on the other chromosome 12. The carrier’s one normal PAH gene produces enough enzyme to metabolize Phe, which is why they do not exhibit symptoms. When two unaffected PKU carriers mate, there is a one-in-four (25%) chance that their infant will have PKU. An infant born with two defective PAH genes cannot make enough enzymes to metabolize Phe and will have PKU. Carrier screening is possible but imprecise and impractical due to more than 400 PAH gene mutations. Prevention is possible only when a couple already has an infant with PKU. Genetic counseling can advise the couple that two options exist: preembryo selection using in vitro fertilization or prenatal amniocentesis/chorionic villus sampling. If parents choose one of these options, direct DNA analysis of the mother, father, and unborn fetus will support a prenatal diagnosis.
PKU Pathophysiology PKU is a genetic metabolic disorder that results from a deficiency of a liver enzyme known as PAH. This enzyme deficiency leads to elevated levels of the amino acid Phe in the blood and other tissues. Elevated Phe levels result in mental retardation, microcephaly, delayed speech, seizures, eczema, and behavior abnormalities. Current treatment for PKU involves strict metabolic control using a low-Phe diet that includes costly, unpalatable, specialized medical food to obtain strict metabolic control (Erbe & Levy, 2002; Wilcox & Cederbaum, 2002). Phe is one of the 10 essential amino acids needed for proper growth and development. The
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body cannot synthesize essential amino acids; thus, they must be ingested. Phe makes up approximately 5% of meat, cheese, eggs, and beans (Siegried & Centerwall, 2000). The two variables needed to cause PKU are a mutation in the PAH gene and exposure to Phe. In most cases, simply decreasing ingested Phe levels will prevent mental retardation. The metabolic pathway for Phe is in the liver; PAH converts Phe by hydroxylation to tyrosine in the hepatocyte (Reed & Charbonneau, 2004; Wilcox and Cederbaum, 2002). A liver transplant has bcuredQ PKU, but the severe medical consequences of transplantation abate this method of treatment unless other hepatic disorders are present. Two normal PAH genes or one normal and one defective gene will make enough enzyme to hydrolyze Phe into tyrosine. Individuals who inherit two defective PAH genes have no or minimal amounts of the enzyme and cannot metabolize Phe. Normal Phe levels are 1 to 2 mg/dl; the plasma Phe levels begin to rise as soon as infants with PKU ingest Phe (i.e., breast, cow, or soy milk); Phe builds up and can reach as high as 20 to 30 times the normal level. A blood level higher than 16.5 mg/dl is considered classic PKU (Reed & Charbonneau, 2004). These high blood Phe levels cross the blood–brain barrier and cause neurological damage to the developing brain. Two other substances are involved in the hydroxylation of Phe (dihydropteridine reductase [DHPR] and tetrahydrobiopterin [BH4]). BH4 and DHPR deficiencies, which present with high Phe levels on newborn screening, were previously lumped together under hyperphenylalaninemia and were considered as one disorder. It is now understood that these disorders are phenotypically distinct from PKU and are treated differently. For this reason and because only 1–2% of high Phe levels are caused by BH4 and DHPR deficiencies, only PKU caused by the defective PAH gene is addressed in this article (Scriver & Kaufman, 2001). All infants with PKU require some Phe in their diet for proper growth and development. If restriction of Phe is too severe, tissue breakdown may occur and levels of Phe will increase; hypoglycemic convulsions and death may occur. Infants with PKU obtain their Phe either from regular commercial formulas or from breastfeeding. Breast milk has a lower Phe content than commercial formulas and has immunological and psychological benefits (Overby, 2003). Duncan and Elder (1997) reported that breast-feeding is
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possible for infants with PKU and suggested various management methods. For example, one method of monitoring is calculating the amount of breast milk a baby takes every 10 minutes by weighing the baby before and after a feeding. Knowing this time/amount and the infant’s weekly blood Phe level will allow the health care provider to calculate how many minutes a day the infant needs to breast-feed. MPKU syndrome pathophysiology During pregnancy, the placenta naturally selects for higher concentrations of amino acids, including Phe. Phe levels are amplified (1.5 to 2 times), which multiplies the teratogenic effects on the developing fetus. This high Phe concentration results in serious fetal damage. Ninety percent are mentally retarded, and 25% have congenital anomalies. Common features of MPKU syndrome are intrauterine growth retardation, microcephaly, congenital heart defects, vertebral anomalies, and strabismus (Friedman & Hanson, 2002). Body systems have critical periods of development during embryogenesis. The critical period for the central nervous system, cranium, and heart is 5 to 8 weeks from the mother’s last menstrual period. Consequently, if a pregnant female with PKU is not in metabolic control before Week 5, her high blood Phe levels will increase, cross the placenta, and enter the fetus’s circulation and exert teratogenic effects on the developing fetus.
PKU/MPKU Syndrome and Developmental Issues High Phe levels in PKU and MPKU cause neurological damage to the developing infant, which makes it imperative to monitor the cognitive development of these children and adults. When assessing cognitive and social development, IQ scores and social support levels that are needed by children to function in their environment must be considered (American Association on Mental Retardation [AAMR], 2002). Mental retardation has been categorized as mild, moderate, severe, and profound with support levels referred to as intermittent, limited, extensive, and pervasive (AAMR, 2002). Fetuses exposed to high uterine Phe levels do not develop normally. Lipson et al. (1984) found similarities between the effects of high maternal Phe and embryonic exposure to alcohol; both syndromes exhibit characteristics of environmental teratogens such as prenatal-onset growth
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deficiency, alteration of morphogenesis, and alteration of nervous system performance (Friedman & Hanson, 2002). Rouse et al. (1997) reported findings of 572 pregnancies from the International Collaborative Study of Maternal Phenylketonuria (1984–1996). The offspring were examined for congenital heart disease, craniofacial abnormalities, microcephaly, and intrauterine and postnatal growth retardation. The mothers were grouped according to their Phe levels during critical gestational weeks and average Phe exposure throughout the pregnancy. These researchers found that the frequency of congenital abnormalities increased with increasing maternal Phe levels. For example, 85% of babies born to mothers who were in the highest Phe range had microcephaly compared with 3% of babies born to mothers who were in the lower Phe range. They concluded that women with PKU should begin low-Phe diets to achieve Phe levels of less than 6 mg/dl prior to conception and maintain these levels throughout the pregnancy. Lee et al. (2005), while analyzing United Kingdom PKU Registry data, found that women with PKU who started diet restrictions preconceptually had infants with higher birth weights, larger head circumferences, less congenital heart disease, and normal IQ and developmental quotients than mothers who started dietary restrictions after becoming pregnant. Levy, Buehler, and Bartley (1994) emphasized the need to identify and manage all women with PKU, even those who have never been treated with the low-Phe diet. They described a significant association between nontreated mothers with mild PKU and fewer diminished birth measurements and cognitive delays in their offspring. Waisbren et al. (2000) studied one hundred eighty-two 4-year-olds born to females with PKU. They found an inverse relationship between the children’s IQ and maternal metabolic control; increased length of poor, prenatal maternal metabolic control was associated with lower children’s IQ scores. Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks gestation scored 2 SD below the norm, whereas offspring whose mothers were in metabolic control prior to pregnancy had scores at the norm. Overall, 30% of children born to mothers with PKU had social and behavior problems. In contrast to MPKU syndrome, the deleterious environmental exposure that infants with PKU
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have is not related to high uterine Phe levels. Their environmental exposure occurs after birth. When infants with PKU ingest a protein meal, the Phe in the protein is not metabolized; high blood Phe levels cross the blood–brain barrier and cause damage to neurological processes. Koch and Wenz (1987) investigated cognitive development in untreated children with PKU and found that IQ falls to mild mental retardation at 1 year of age and deteriorates to severe mental retardation by 3 years of age. Smith, Beaslye, and Ades (1990) reported a loss of 10 IQ points in the first month of life; an additional 10 points is lost in the second month. About 1/3 of untreated infants exhibit a lack of growth of head circumference and infantile spasms according to electroencephalogram results (Reed & Charbonneau, 2004). Griffiths, Demelweek, Fay, Robinson, and Davidson (2000) emphasized the need for the early treatment of an infant with PKU. They studied 57 early-treated children and concluded that Phe control at the age of 2 years was predictive of future, overall cognitive success. Likewise, Koch and Wenz’s (1987) outcome data from the Collaborative Study of Children Treated for PKU indicated that IQ scores of early-treated children had a nearly normal distribution, with individual scores tending to be slightly lower than their siblings without PKU. In contrast, Fishler, Azen, Henderson, Freidman, and Koch (1987) revealed that the IQ scores of 38% of girls with PKU are below their peers by 1 year or more. Multiple factors other than high blood Phe levels contribute to cognitive development. Therefore, caution should be taken when one applies high Phe levels to predict overall cognitive success. Recent researchers report that mildly depressed IQ is common in treated patients with PKU. Griffiths et al. (2000) analyzed IQ scores of 57 early-treated children and found that early, continuous treatment did not necessarily lead to normalization of overall IQ. Further analysis revealed normalized verbal IQ, but performance IQ remained depressed. Azen, Koch, and Freidman (1991) tested well-controlled 12-year-olds with PKU and found that these children scored 17 points lower in arithmetic than they did at previous baseline levels. The International Collaborative Study of Maternal Phenylketonuria supported the findings of mildly depressed IQ when they analyzed 382 females with PKU between the ages of 15 and 22 years and found an average IQ of 83, which is 1 SD below the mean (Koch et al., 1999).
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If, indeed, dietary control at the age of 2 years predicts future cognitive successes, then, clearly, dietary control is paramount. However, there is controversy as to when to discontinue the Pherestricted diet. This confusion is illustrated in the nursing literature when Matthews (2001) disputed Fraser’s (2001) reinstitution of a PKU diet in a 50-year-old woman with mental retardation. In the past, strict dietary compliance was relaxed when the child was between 6 and 8 years of age. Current data now support a restricted, lifelong diet. Elevated Phe levels in adolescents and adults adversely affect aspects of cognitive function (NIH, 2000). In fact, improvement in cognitive functioning has been seen in late-treated individuals with severe retardation (Clark, Gates, Hogan, & MacDoanald, 1987; Koch & Wenz, 1987; Pietz et al., 1993; Potocnik & Widhalm, 1994). Weglage et al. (2000) studied 10- to 18-year-old patients with PKU and found significant problems such as depressive mood, anxiety, physical complaints, and social isolation problems that put adolescents at risk for unhealthy behavior. Waisbren and Levy (1991) found that depression and anxiety are lessened for adolescents with reinstitution of a Phe-restricted diet. Matthews, Barabas, Cusak, and Ferari (1987) measured social quotients of students with PKU who were on and off their diet and found deficits in self-help, socialization, and communication in students off the diet. Other researchers stress the positive impact a Pherestricted diet has on restful sleep. Reed and Charbonneau (2004) noted that there is some evidence to indicate that attention deficit hyperactivity disorder (ADHD) is more common in children treated early for PKU than in normal children. Riva et al. (1996) retrospectively compared the IQ of 26 school-age children with PKU who were breast-fed or formula fed for 20–40 days prior to intervention. They found a 12.9-point advantage in children who were breast-fed in the short time before being diagnosed with PKU.
STANDARD MANAGEMENT PROTOCOLS
Infant PKU Protocols Newborn PKU screening is mandatory across the United States; however, implementation is not consistent. Each state does not follow uniform guidelines for (a) defining blood Phe levels for positive screens, (b) reporting non-PKU hyper-
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phenylalaninemia, (c) reporting cases by gender, (d) mandating parents to consent to testing (i.e., 46 states permit parental refusal), and (e) billing for Phe blood test (American Academy of Pediatrics, 2001; NIH, 2000). While screening protocols need to be improved, dietary standards of care for infants are well established. Early dietary control in infants is paramount to ensuring cognitive success. When an infant is diagnosed with PKU, weekly monitoring of diet and blood Phe levels (kept between 2 and 6 mg/dl) is initiated. Outcomes are usually successful when there is strict implementation of dietary protocols and when access to information and health care is provided. For example, when an infant is born with PKU, parents should be clearly informed about the nature and management of the disorder. There is a plethora of information and support for parents raising these infants, including easy-to-read medical literature, cookbooks, coloring books for children, informative web sites (e.g., http://www.pkunet.org; http://pkunews.org), and numerous resource groups and individuals.
Child and Adolescent Protocols In contrast, dietary protocols for older children with PKU are less consistent. Formal recommendations for blood Phe levels do not exist for children more than 12 years. Most PKU clinics recommend the following: (a) yearly visits to genetic center, (b) monthly or quarterly monitoring of Phe blood levels, and (c) lifelong dietary treatment. A recent survey of PKU clinics found that many adolescents frequently miss appointments and never drink their unpalatable formula (Wappner, Sechin, Kronmal, Schuett, & Seashore, 1999). There are no PKU adolescent or adult clinics in the United States. Betz (1998) addressed the unique health concerns of adolescents with chronic health problems in her study of transitioning adolescent care from the pediatric setting to the adult setting. She noted that the transition usually begins around the age of 14 years because adult providers are better suited at this time to deal with increasing adult needs of adolescents; schools write individualized transition plan for their students when they reach 14 years old. Betz urged nurses caring for children with special needs to utilize Section 504 of the Rehabilitation Act of 1973 (P.L. 93–112) because this law mandates that children with diseases such as PKU receive extra school services. (See Betz, 1998, for further information on transitioning).
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Metabolic dietitians have attempted to deal with the unique problems of adolescent females with PKU by sponsoring a weeklong MPKU camp in the summer for girls more than 14 years old. The purpose of the camp is to develop camaraderie between females with PKU and to teach them about dietary self-management and MPKU syndrome (A. Wilson, personal communication, October 31, 2001; Genetic Disease Bulletin, 10/21/01).
MPKU Protocols In the United States, no formal standards of care exist for women of childbearing age with PKU. Clinics vary in their target range for blood Phe levels for women who are pregnant (e.g., b10 to b 15 mg/dl). Conversely, clinics in United Kingdom and Germany have established lower acceptable target ranges (e.g., 1–4 mg/dl). The United Kingdom has recently adopted the following specific guidelines to deal with M PKU: (a) provide services according to needs assessment, (b) provide clearly written information, (c) provide schoolaged children with support to become responsible for dietary management and obtaining finger sticks, (d) offer detailed fetal ultrasound and the choice of pregnancy termination to women who conceive with blood concentrations more than 11.6 mg/dl (United Kingdom Consensus Report, 1999). PKU clinics in the United States recognize that an unplanned pregnancy in a female with PKU may result in serious fetal consequences if the mother is not in metabolic control. The NIH (2000) PKU Consensus Statement presented three key areas that are required to successfully manage women with PKU: (a) a comprehensive, multidisciplinary, integrated system for the delivery of care to patients with PKU; (b) a reliable home-testing method to monitor Phe levels; and (c) outreach programs for women with PKU of childbearing age, with special focus on social support, positive attitudes toward metabolic control of Phe, and conscious reproductive choice. The Guidelines for Adolescent Preventive Services of the American Medical Association (AMA) (1996) has recommended that all health care providers screen for risk behaviors including sexual activity, alcohol, and drug use. The AMA developed a screening questionnaire for adolescents, consisting of a brief medical history, biomedical health concerns, and a list of healthrisk behaviors that together form a health-risk behavior profile. Unfortunately, Epner, Levenberg, and Schoeny (1998) surveyed 15 primary care
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providers in Chicago and found that none used this screening questionnaire. Physicians, advanced practice nurses (APNs), and metabolic dietitians taking care of females with PKU should routinely discuss PKU pregnancy and the potential for severe birth defects during clinic visits. However, parents have reported their inability to bhearQ clearly during clinic visits because they are distracted and worried about their child’s care and development. Further complicating the pregnancy issue is the fact that most parents do not discuss sex and childbearing with their daughters (Pueschel & Yeatman, 1977). The author has observed no formal assessment of sexual or drug health in two of the three Illinois state-approved PKU clinics. It has been reported that 50% of pediatricians do not assess sexual health (Knight et al., 1997).
HEALTH SYSTEM GAPS Genetics, pathophysiology, cognitive and social development, and standard care protocols have been reviewed. Thus, it is critical that females with PKU are identified and managed to prevent MPKU syndrome. Currently, the only intervention that is effective in managing females with PKU is excellent dietary protocols. Unfortunately, there are no other consistently used protocols to meet the myriad of health care issues of females with PKU. Inconsistent health care system factors magnify the MPKU problem: (a) infants at risk for MPKU syndrome are not identified because females with mild PKU have not been followed; (b) parents’ refusal to have their infants tested for PKU, resulting in infants and children with mental retardation; (c) adolescents with PKU are not routinely screened for high-risk behaviors (e.g., sexual activity, drugs, and alcohol); and (d) cost and quality outcomes regarding the care of females with PKU are neither assessed nor accounted for. At the health care provider level, inconsistent or incomplete care is provided for children/adolescents with PKU and their families. Few specific interventions for cognitive and social delays in females with PKU are implemented; adolescent risk behavior assessments are not systematically conducted; and family health assessments are ignored. Seventy-five percent of mothers with PKU are not in metabolic compliance when they become pregnant. The following is a case study
that exemplifies problems encountered by adolescents with PKU. A comprehensive case management approach is described to meet the health care gaps noted previously. CASE STUDY Jana, a 17-year-old with a history of nontreated mild PKU, was seen in the pediatric genetic clinic for consultation. Jana was 8 weeks pregnant with her first child and had a blood Phe level of 11.9 mg/dl. She was accompanied by her 20-year-old boyfriend, Tony, the father of the baby. Verbal and written information regarding MPKU syndrome was provided to Jana and Tony. He is a Roman Catholic, and she is a Protestant; termination of the pregnancy was not an option. Jana was instructed to start a low-Phe diet and was given a commercial Phe-restricted protein formula to drink. Formula costs were US$20.00 a day, and Jana’s mother’s health insurance covered the cost. Four days later, Jana returned to the clinic and stated that she was unable to drink the formula; her blood Phe level was 13.6. Pherestricted protein bars were prescribed, costing US$30.80 a day. Unfortunately, the HMO refused to pay for the bars because they bare not a medication.Q The Illinois PKU association was called, and they donated US$840.00 to pay for the bars. The health care team (i.e., metabolic dietician, registered nurses, and a pediatric metabolic geneticist) followed up this young woman for the next 12 weeks, during which time blood Phe levels were reduced to acceptable pregnancy levels.
Previous History Jana was born in California and diagnosed at birth with PKU. Jana’s blood Phe levels plus her growth and development were followed up at a child developmental center until she was 7 1/2 years old. She was followed up weekly, then monthly, and then yearly. Her blood Phe levels averaged about 11 mg/dl. She was on a Pherestricted diet. Growth parameters followed her growth curve from birth through the age of 7 years (with weight = 50% and height = 90%). Jana’s mother was educated about MPKU syndrome twice: when Jana was 2 years old and, again, when she was 7 years old. She was informed about the deleterious effects high Phe levels have on an unborn fetus and was told that Jana would probably need to go on a
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Phe-restricted diet if she becomes pregnant. Developmental testing showed no significant delays, but Jana had some behavioral problems in school including trouble sitting still, talking out of turn, and defiance. Jana’s health care providers never addressed the possibility that Jana’s high Phe levels may have been related to her bbadQ behavior. Jana was never seen again for PKU management until she became pregnant.
Case Management A management plan for females with PKU coordinated by an APN needs to be incorporated into the health care system to compensate for fragmented, incomplete, and unorganized care. Nurse case managers are successful in providing cost-effective, positive patient outcomes and are rated as highly satisfactory by patients and families. For these reasons, APNs are needed to assess, diagnose, plan, and implement care for females with PKU. Constructing management models and implementing clear, concise protocols may decrease the incidence of this preventable disorder. To effectively manage these children and adolescents, the APN must have a thorough understanding of developmental and family concepts and measures. Developmentally, females with PKU and their offspring are at increased risk for cognitive, behavioral, and social delays (Griffiths et al., 2000; Reed & Charbonneau, 2004; Rouse et al., 1997; Waisbren et al., 2000; Yachmink, 2003). Bennett and Guralnick (1991) reported that developmental lags are reduced if interventions are initiated early and are family focused. However, there is no research on interdisciplinary approaches connecting identification of these cognitive and social delays to appropriate interventions.
Developmental Concerns Developmental assessment should be done consistently throughout childhood and adolescence. The most used developmental screening tool for children from birth to 6 years of age is the Denver II. Delays in fine and gross motor development and cognitive and language can be detected; families referred to early intervention programs (Bennett & Guralnick, 1991). There are multiple screening tools that are appropriate for the child older than 6 years and that focus on school and educational problems. Aylward (1994) has a comprehensive
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description of screening tools including language (Peabody Picture Vocabulary Test; Early Language Milestone Scale; Receptive–Expressive Emergent Language Scale), behavioral/ adaptive functioning (Vineland Adaptive Behavior Scales; Minnesota Child Development Inventory, American Association on Mental Deficiency Adaptive Behavior Scale), cognitive/intellectual functioning (Wechsler Intelligence Scale for Children, Stanford–Binet, Kaufman Brief Intelligence Test), academic achievement (Wechsler Individual Achievement Test, Kaufman Test of Educational Achievement), attention (testing for ADHD), behavior (Achenbach Child Behavior Checklist, Louisville Behavior Checklist), visual/motor (Bender Visual Motor Gestalt Test, Revised Visual Retention Test), and school performance problems. Vessey and Rumsey (2004) provide additional, age-appropriate screening measures for anxiety, self-concept, and temperament. The school-age child’s activities are centered on school, where problem-solving skills can be learned and tested. The female with PKU who is not achieving academically or socially in school may exhibit behavioral and self-concept problems related to being different from their peers. There are different types of mandated educational support under the Individuals with Disabilities Act, including additional professional testing and social services. Adolescence Although most adolescents develop abstract thinking and have the ability to understand the consequences of their behaviors and actions, personal stress, peer pressure, and new or unfamiliar phenomena may trigger unhealthy, high-risk behaviors including alcohol and drug use and sexual experimentation (Sieving, McNeely, & Blum, 2000). The Risk Behavior Intention Scale (Siegel, Aten, Roughmann, Klaus, & Enaharo, 1998) may be used to assess unhealthy behaviors. This tool, in conjunction with the AMA (1996) adolescent health risk survey, may be a useful assessment tool. However, there is little evidence that these questionnaires are being used routinely by health care providers (Epner et al., 1998; Ford, 1998; Knight et al., 1997). When APNs are counseling an adolescent with PKU, they should be aware of the following protective factors that may decrease the probability of high-risk behaviors: positive social skills, suitable adults mentors, cohesive family, and
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maternal disapproval of the behavior (Bier, Rosenfield, Spitalny, Zansky, & Bontempo, 2000; Dittus & Jaccard, 2000; Sieving et al., 2000; Steele, 1989). Mentor mothers (mothers who have young children with PKU) have a positive effect on pregnant females with PKU. These mothers are familiar with the diet and accompanying stress that management of PKU places on the family. They make home visits to aid with cooking, shopping, and meal planning, which facilitated greater metabolic compliance than the control group without such mentoring.
Family Influences As noted, a cohesive family is a protective factor in reducing high-risk behaviors among adolescents. Family perceptions, needs, and strengths have to be integrated into any comprehensive case management approach (Allen et al., 2000). Koop (1987) highlighted the importance of a strong, cohesive family and called for familycentered care for children with special care needs. Factors essential for family-centered care include the following: recognizing that family is the constant in the child’s life; implementing appropriate programs that meet family needs; recognizing family strengths and respecting different coping methods; understanding and incorporating the developmental needs of children and their families into health care delivery systems; and assuring that the design of health care delivery systems is feasible, accessible, and responsive to family needs. In addition, researchers have found that families develop unique paths to manage problems and present a broad range of needs (Diel, Moffit, & Wade, 1991; Knafl, Breitmayer, Gallo, & Zoeller, 1996). The author found that most PKU clinics do not provide family-centered care. APNs should use a consistent family theory and select measures of family factors to frame their family interactions and interventions. There are four family frameworks that nurses have found useful: Resiliency Model for Family Adaptation (McCubbin, Thompson, & McCubbin, 1996), the Contingency Model (Hymovich & Hagopian, 1992), the Calgary Family Assessment Model (Wright & Leahey, 2000), and Family Management Style (Knafl et al., 1996; Knafl & Santacroce, 2004). The Resiliency Model is based upon family stress theory and emphasizes those family strengths that allow families to adapt successfully to having a family member with a chronic illness/disability.
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Valid, reliable tools that measure family coping, hardiness, life events, resources, coping, and problem solving, as well as adolescent coping and decision making instruments, have been developed (McCubbin et al., 1996). The Contingency Model includes a very comprehensive approach to how families function and manage when faced with chronic illness/disability. Hymovich and Hagopian have developed several assessment forms for collecting family and child/ adolescent data, goal setting, and long-term follow-up. The Calgary Family Assessment Model is a systems-based approach and provides suggested interventions for working intensively with families to change family dynamics and understanding and management of the illness/disability (Berman et al., 1999). Assessment tools include ecomaps, genograms, and intensive interviews. Finally, Knafl et al.’s Family Management Style Framework provides a categorization of families into five styles: thriving, accommodating, enduring, struggling, and floundering. The factors that distinguish each style includes child identity, illness view, management mindset, parental mutuality, parenting philosophy, management approach, family focus, and future expectations. In questioning families as to how they define the illness situation, their management behaviors, and perceived consequences, clinicians can use this information to determine management style and to tailor interventions that maximize family strengths and provide specific types of support (Knafl & Santacroce, 2004).
Case Management Approach Jana exemplifies the problems that can occur when an integrated, comprehensive approach is not implemented. The suggested case management approach would provide a continuum of care in an integrated (home, school, ambulatory care) setting. The primary goal of this approach is to reduce MPKU syndrome by managing the care of the female with PKU according to her risk (medical, developmental, and family) level, including preconception metabolic compliance, interdisciplinary collaboration, continuity of care, and continuing assessment of developmental and family factors. As effective care managers, APNs must meet the multiple needs of females with PKU; improve health, cognitive, and developmental outcomes; and reduce the incidence of impaired infants of females with PKU.
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REFERENCES Allen, E., Fine, M., & Demo, D. (2000). An overview of family diversity: Controversies, questions, and values. In D., Demo, K., Allen, & M., Fine (Eds.) Handbook of family diversity. (pp. 1 – 13). Philadelphia: Oxford University Press. American Academy of Pediatrics. (2001). Policy Statement: Maternal Phenylketonuria, 107, 427 – 428. American Association on Mental Retardation. (2002). Definition of mental retardation. Retrieved July 8, 2006, from http:// www.aamr.org/Policies/faq _ mental _ retardation.shtml. American Medical Association. (1996). Guidelines for Adolescent Preventive Services (GAPS) (3rd ed.). Chicago, IL: Department of Adolescent Health. Aylward, G. P. (1994). Practitioner’s guide to developmental and psychological testing. New York: Plenum Medical Book Company. Azen, C., Koch, R., & Friedman, E. (1991). Intellectual development in 12-year-old children treated for phenylketonuria. American Journal of Diseases in Children, 145, 35 – 39. Bennett, F., & Guralnick, M. (1991). Effectiveness of developmental intervention in the first five years of life. Pediatric Clinics of North America, 38, 1513 – 1528. Berman, H., Harris, D., Enright, R., Gilpin, M., Cathers, T., et al. (1999). Sexuality and the adolescent with a physical disability: Understandings and misunderstandings. Issues in Comprehensive Pediatric Nursing, 22, 183 – 196. Betz, C. (1998). Facilitating the transition of adolescents with chronic conditions form pediatric to adult health care and community settings. Issues in Comprehensive Nursing, 21, 97 – 115. Bier, S., Rossenfield, W., Spitalny, K., Ansky, S., & Bontempo, A. (2000). The potential role of an adult mentor in influencing high-risk behaviors in adolescents. Archives in Pediatrics and Adolescent Medicine, 154, 327 – 331. Clark, J., Gates, R., Hogan, S., & MacDonald, G. W. (1987). Neuropsychological studies on adolescents with phenylketonuria returned to phenylalanine-restricted diets. American Journal on Mental Retardation, 92, 255 – 263. Diel, S., Moffit, K., & Wade, L. (1991). Focus group interviews with parents of children with medically complex needs: An intimate look at their perceptions and feelings. Child Health Care, 12, 170 – 178. Dilella, A., et al. Kwok, S., Ledley, F., Marvit, J., & Woo, S. (1986). Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry, 25, 743 – 749. Dittus, P., & Jaccard, J. (2000). Adolescents’ perceptions of maternal disapproval of sex: Relationship to sexual outcomes. Journal of Adolescent Health, 26, 268 – 278. Duncan, L., & Elder, S. (1997). Breastfeeding the infant with PKU. Journal of Human Lactation, 13, 231 – 235. Epner, J., Levenberg, P., & Schoeny, M. (1998). Primary care providers’ responsiveness in health risk behavior reported by adolescent patients. Archives of Pediatrics and Adolescent Medicine, 152, 774 – 780. Erbe, R. W., & Levy, H. L. (2002). Neonatal screening. In D. L., Rimoin, J. M., Connor, R. E., Pyeritz, & B. R., Korf (Eds.) Emery and Rimoin’s principles and practice of medical genetics. (4th ed., pp. 826 – 841). New York: Churchill Livingstone. Fishler, K., Azen, C., Henderson, R., Freidman, E., & Koch, R. (1987). Psychoeducational findings among children treated for phenylketonuria. American Journal of Mental Retardation, 92, 65 – 73.
Ford, C. (1998). Preventing teen pregnancy with emergency contraception: An opportunity we should not be missing. Archives in Pediatrics and Adolescent Medicine, 152, 725 – 726. Fraser, A. (2001, April). Meal appeal. Nursing, 24 – 25. Friedman, J. M., & Hanson, J. W. (2002). Clinical teratology. In D. L., Rimoin, J. M., Connor, R. E., Pyeritz, & B. R., Korf (Eds.) Emery and Rimoin’s principles and practice of medical genetics (4th ed. pp. 1011 – 1045). New York: Churchill Livingstone. Genetic Disease Bulletin. (2001, October). Maternal PKU Camp/Conference. [WWW document] (http://www.dhs.ca.gov/ pchfh/GDB/html/NBS/PKUCampConference.htm). Griffiths, P., Demelweek, C., Fay, N., Robinson, P., & Davidson, D. (2000). Wechsler subscale IQ and subtest profiles in early treated phenylketonuria. Archives of Diseases in Childhood, 82, 209 – 215. Guldberg, P., Rey, F., Zschocke, J., Romano, V., Francois, B., Michiels, L., et al. (1998). A European multicenter study of phenylalanine hydroxylase deficiency: Classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. American Journal of Human Genetics, 63, 71 – 79. Gutter, F., Azen, C., Guldberg, P., Romstad, A., Hanley, W. B., Levy, H. L., et al. (1999). Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: Report from the maternal phenylketonuria collaborative study. Pediatrics, 104, 258 – 262. Hofman, K., Steel, G., Kazazian, H., & Valle, D. (1991). Phenylketonuria in US blacks: Molecular analysis of the phenylalanine hydroxylase gene. American Journal of Human Genetics, 48, 791 – 798. Hymovich, D., & Hagopian, G. (1992). Chronic illness in children and adults: A psychosocial approach. Philadelphia: W.B. Saunders. Knafl, K. A., Breitmayerm, B., Gallo, A., & Zoeller, L. (1996). Family response to childhood chronic illness: Description of management styles. Journal of Pediatric Nursing, 11, 315 – 326. Knafl, K. A., & Santacroce, S. (2004). Chronic conditions and the family. In P. J., Allen, & J., Vessey (Eds.) Primary care of the child with a chronic condition. (4th ed. pp. 44 – 59). St. Louis, MO: Mosby. Knight, J., Shrier, L., Bravender, T., Farrell, M., Vander Bilt, J., & Shaffer, H. (1997). A new brief screen for adolescent substance abuse. Archives in Pediatrics and Adolescent Medicine, 153, 591 – 596. Koch, R., Friedman, E., Azen, C., Hanley, W., Levy, H., Matalon, R., et al. (1999). The international collaborative study of maternal phenylketonuria status report 1998. Mental Retardation and Developmental Disabilities Research Reviews, 5, 121 – 177. Koch, R., & Wenz, E. (1987). Phenylketonuria. Annual Review of Nutrition, 7, 117 – 135. Koop, C. E. (1987). Surgeon general’s report: Child with special health care needs: Commitment to family-centered, coordinated care for child with special health care needs. Washington, DC: US Department of Health and Human Services. Lapis, P. (2001, November). Of mice and men—Long term reduction in serum Phe levels in a mouse model. Keynote speaker at PKU Organization of Illinois—32nd Annual Meeting, Chicago, IL.
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Lee, P. J., Ridout, D., Walter, J. H., & Cockburn, F. (2005). Maternal phenylketonuria: Report from the United Kingdom Registry 1978–97. Archives of Disease in Childhood, 90, 143 – 146. Levy, H., Waisbren, S., Lobbregt, D., Allred, E., Schuler, A., Trefz, F., et al. (1994). Maternal mild hyperphenylalaninemia: An international survey of offspring outcome. The Lancet, 344, 1589 – 1593. Lipson, A., Buehler, B., & Bartley, J. (1984). Maternal hyperphenylalaninemia. Journal of Pediatrics, 104, 216 – 220. Matthews, D. (2001, May). Questionable benefits of PKU treatment [Letter to the Editor] Nursing, 30. Matthews, W., Barabas, G., Cusack, E., & Ferrari, M. (1987). Social quotients of children with phenylketonuria before and after discontinuation of dietary therapy. American Journal of Mental Deficiency, 91, 92 – 99. McCubbin, H. I., Thompson, A. I., McCubbin, M. A. (Eds.). (1996). Family assessment: Resiliency, coping, and adaptation: Inventories for research and practice. Madison, WI: University of Wisconsin Publishers. National Institutes of Health. (2000). Phenylketonuria (PKU): Screening and management. NIH Consensus Statement, 17 (Website: www.nichd.nih.gov/publications/pubs/pki/index.htm). Overby, K. (2003). Pediatric health supervision. In C. D., Rudolph, & A. M., Rudolph (Eds.) Rudolph’s pediatrics (21st ed. pp. 1 – 54). New York: McGraw-Hill. Pietz, J., Schmidt, E., Matthis, P., Kobulka, B., Katcha, A., & de Sonneville, L. (1993). EEGs in phenylketonuria. I: Follow-up to adult-hood; II: Short-term diet-related changes in EEGs and cognitive function. Developmental Medicine and Child Neurology, 35, 54 – 64. Potocnik, U., & Widhalm, K. (1994). Long-term follow-up of children with classical phenylketonuria after diet discontinuation: A review. Journal of the American College of Nutrition, 13, 232 – 236. Pueschel, S., & Yeatman, S. (1977). An educational and counseling program for phenylketonuric adolescent girls and their parents. Social Work in Health Care, 3, 29 – 36. Reed, C. Y., & Charbonneau, R. M. (2004). Phenylketonuria. In P. J., Allen, & J. A., Vessey (Eds.) Primary care of the children with a chronic condition (4th ed., pp. 667 - 681). St Louis, MO: Mosby. Riva, E., Agostoni, C., Biasucci, G., Trojan, S., Luotti, D., & Fiori, L. (1996). Early breastfeeding is linked to higher intelligence quotients in dietary treated phenylketonuric children. Academy of Pediatrics, 85, 56 – 58. Rouse, B., Azen, C., Koch, R., Matalon, R., Hanley, W., de la Cruz, F., et al. (1997). Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies, malformations, and early neurological sequelae. American Journal of Medical Genetics, 69, 89 – 95. Scriver, C., & Kaufman, S. (2001). Hyperphenylalaninemia: Phenylalanine hydroxylase deficiency. In C., Scriver, A., Sly, W., Sly, & D., Valle (Eds.) The metabolic and molecular
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bases of inherited disease (pp. 1667 – 1707). New York: McGraw-Hill. Siegel, D. M., Aten, M., Roughmann, K., & Enaharo, M. (1998). Early effects of a school-based human immunodeficiency virus infection virus infection and sexual risk prevention intervention. Archives of Pediatrics and Adolescent Medicine, 152, 961 – 970. Siegried, S., & Centerwall, W. (2000). The discovery of phenylketonuria: The story of a young couple, two retarded children, and a scientist. Pediatrics, 105, 89 – 103. Sieving, R., McNeely, C., & Blum, R. (2000). Maternal expectations, mother–child connectedness, and adolescent sexual debut. Archives in Pediatrics and Adolescent Medicine, 154, 809 – 816. Smith, I., Beaslye, M., & Ades, A. (1990). Intelligence and quality of dietary treatment in phenylketonuria. Archives of Disease in Childhood, 65, 472 – 478. Steele, S. (1989). Phenylketonuria: Counseling and teaching functions of the nurse on an interdisciplinary team. Issues in Comprehensive Pediatric Nursing, 12, 395 – 409. United Kingdom Consensus Report. (1999). Management of PKU. [WWW document] (http://web.ukonline.co.uk/nspku/ mgtofpku.htm). Vessey, J. A., & Rumsey, M. (2004). Chronic conditions and child development. In P.J., Allen, & J. A., Vessey (Eds.) Primary care of the child with a chronic condition (4th ed. pp. 23 - 43). St. Louis, MO: Mosby. Waisbren, S., Hanley, W., Levy, H., Shifrin, G., Allred, E., Azen, C., et al. (2000). Outcome at age 4 in offspring of women with maternal phenylketonuria: The maternal PKU collaborative study. Journal of the American Medical Association, 283, 756 – 762. Waisbren, S., & Levy, H. (1991). Agoraphobia in phenylketonuria. Journal of Inherited Metabolic Diseases, 14, 755 – 764. Wappner, R., Sechin, C., Kronmal, R., & Seashore, M. (1999). Management of phenylketonuria for optimal outcomes: A review of guidelines for phenylketonuria management and a report of surveys of parents, patients, and clinic directors. Pediatrics, 104, 68 – 76. Weglage, J., Grenzebach, M., Pietch, M., Feldmann, R., Linnenbank, R., Denecke, J., et al. (2000). Behavioural and emotional problems in early-treated adolescents with phenylketonuria in comparison with diabetic patients and healthy controls. Journal of Inherited Metabolic Diseases, 23, 487 – 496. Wilcox, W., & Cederbaum, S. D. (2002). Amino acid metabolism. In D. L., Rimoin, J. M., Connor, R. E., Pyeritz, & B.R., Korf, (Eds.) Emery and Rimoin’s principles and practice of medical genetics (4th ed. pp. 2405 – 2440). New York: Churchill Livingstone. Wright, L., & Leahey, M. (2000). Nurses and families: A guide to family assessment and intervention (3rd ed.). Philadelphia: F.A. Davis. Yachmink, Y. (2003). Developmental delays: Maturational lags to mental retardation. In C. D., Rudolph, & A. M., Rudolph (Eds.) Rudolph’s pediatrics (21st ed. pp. 438 – 441). New York: McGraw-Hill.
Well-established dietary protocols have prevented mental retardation for infants born with phenylketonuria (PKU). Dietary protocols for managing females with PKU in their reproductive years exist but are not followed by most of them. Infants who are born to mothers with PKU who are not on dietary treatment usually have serious medical problems, such as mental retardation, heart defects, and other serious congenital anomalies (e.g., orofacial clefting and bladder exstrophy)—a condition known as maternal PKU syndrome. The focus of this article is to review the pathophysiology, associated developmental issues, and existing management protocols used to manage these two separate but highly connected disorders. n 2007 Elsevier Inc. All rights reserved.
N THE MID-1960s, neonatal nurses initiated a new procedure on all newborns—a heel stick— to identify the genetic disorder phenylketonuria (PKU). These nurses understood that PKU was a genetic disorder that resulted in severe mental retardation if not identified and treated quickly with a diet low in phenylalanine (Phe). Preventing mental retardation through diet treatment was considered a medical marvel at this time. Thus, PKU screening became the benchmark for screening other newborn disorders. Twenty years later, pediatric nurses were assessing children born to females with PKU. These babies/children presented with myriad cognitive and physical problems, including microcephaly, dysmorphic facial features, delayed speech, mental retardation, and cardiac anomalies. Nurses now had a new condition to manage— maternal PKU (MPKU) syndrome—a condition that occurs when females with PKU do not adhere to strict dietary treatment. The key issue in managing infants born with PKU is parental compliance with protocols. Less obvious issues in managing PKU emerge as the child with PKU becomes older. Parental interest/compliance wanes, and dietary protocols are relaxed. Until recently, health care providers had no concrete evidence to continue the diet after the age of 6 years and did not encourage parents to maintain strict treatment guidelines. However, females with PKU who do not maintain dietary treatment are at high risk for having an infant with MPKU syndrome
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(Lee, Ridout, Walter, & Cockburn, 2005). Health care providers must realize that 75% of mothers with PKU are not in dietary control before pregnancy (Koch et al., 1999). LITERATURE REVIEW Initially, PKU was assigned to one of four classes of severity (i.e., severe, moderate, or mild PKU and mild hyperphenylalaninemia; Gutter et al., 1999). Scriver and Kaufman (2001) questioned the need to subdivide PKU by calling attention to the fact that all degrees of hyperphenylalaninemia are harmful to cognitive development and that such classifications are not relevant to treatment (National Institutes of Health (NIH), 2000). Consequently, in this article, the term PKU will apply to all levels of hyperphenylalaninemia.
Genetics The incidence of PKU varies among different nations and ethnic groups. It is 1 per 4,500 in
From the Saddleback Memorial Medical Center, Laguna Hills, CA. Address correspondence and reprint requests to Patricia J. Gambol, RN, MSN, APNG, Saddleback Memorial Medical Center, 24401 Calle de la Louisa, Suite 200, Laguna, CA 92653. E-mail: [email protected] 0882-5963/$ - see front matter n 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pedn.2006.08.002
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Ireland, 1 per 16,000 in Switzerland, and 1 per 16,000 in the United States (1 per 8,000 in Caucasians and 1 per 50,000 in Blacks). The clinical presentation of PKU is extremely variable because the Phe hydroxylase (PAH) gene has more than 400 known mutations that allow for more than 10,000 genotypic combinations (Dilella, Kwok, Ledley, Marvit, & Woo, 1986; Guldberg et al., 1998; Hofman, Steel, Kazazian, & Valle, 1991; Lapis, 2001; Wilcox & Cederbaum, 2002). PKU is an autosomal (non-gender-determining chromosome) disorder involving the PAH gene on chromosome 12. All human beings have two copies of the number 12 chromosome, one from each parent. PKU is a recessive disorder, which means that a person carrying the trait (a carrier) usually does not exhibit disease symptoms. A carrier has one normal functioning PAH gene on one chromosome 12 and an abnormal PAH gene on the other chromosome 12. The carrier’s one normal PAH gene produces enough enzyme to metabolize Phe, which is why they do not exhibit symptoms. When two unaffected PKU carriers mate, there is a one-in-four (25%) chance that their infant will have PKU. An infant born with two defective PAH genes cannot make enough enzymes to metabolize Phe and will have PKU. Carrier screening is possible but imprecise and impractical due to more than 400 PAH gene mutations. Prevention is possible only when a couple already has an infant with PKU. Genetic counseling can advise the couple that two options exist: preembryo selection using in vitro fertilization or prenatal amniocentesis/chorionic villus sampling. If parents choose one of these options, direct DNA analysis of the mother, father, and unborn fetus will support a prenatal diagnosis.
PKU Pathophysiology PKU is a genetic metabolic disorder that results from a deficiency of a liver enzyme known as PAH. This enzyme deficiency leads to elevated levels of the amino acid Phe in the blood and other tissues. Elevated Phe levels result in mental retardation, microcephaly, delayed speech, seizures, eczema, and behavior abnormalities. Current treatment for PKU involves strict metabolic control using a low-Phe diet that includes costly, unpalatable, specialized medical food to obtain strict metabolic control (Erbe & Levy, 2002; Wilcox & Cederbaum, 2002). Phe is one of the 10 essential amino acids needed for proper growth and development. The
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body cannot synthesize essential amino acids; thus, they must be ingested. Phe makes up approximately 5% of meat, cheese, eggs, and beans (Siegried & Centerwall, 2000). The two variables needed to cause PKU are a mutation in the PAH gene and exposure to Phe. In most cases, simply decreasing ingested Phe levels will prevent mental retardation. The metabolic pathway for Phe is in the liver; PAH converts Phe by hydroxylation to tyrosine in the hepatocyte (Reed & Charbonneau, 2004; Wilcox and Cederbaum, 2002). A liver transplant has bcuredQ PKU, but the severe medical consequences of transplantation abate this method of treatment unless other hepatic disorders are present. Two normal PAH genes or one normal and one defective gene will make enough enzyme to hydrolyze Phe into tyrosine. Individuals who inherit two defective PAH genes have no or minimal amounts of the enzyme and cannot metabolize Phe. Normal Phe levels are 1 to 2 mg/dl; the plasma Phe levels begin to rise as soon as infants with PKU ingest Phe (i.e., breast, cow, or soy milk); Phe builds up and can reach as high as 20 to 30 times the normal level. A blood level higher than 16.5 mg/dl is considered classic PKU (Reed & Charbonneau, 2004). These high blood Phe levels cross the blood–brain barrier and cause neurological damage to the developing brain. Two other substances are involved in the hydroxylation of Phe (dihydropteridine reductase [DHPR] and tetrahydrobiopterin [BH4]). BH4 and DHPR deficiencies, which present with high Phe levels on newborn screening, were previously lumped together under hyperphenylalaninemia and were considered as one disorder. It is now understood that these disorders are phenotypically distinct from PKU and are treated differently. For this reason and because only 1–2% of high Phe levels are caused by BH4 and DHPR deficiencies, only PKU caused by the defective PAH gene is addressed in this article (Scriver & Kaufman, 2001). All infants with PKU require some Phe in their diet for proper growth and development. If restriction of Phe is too severe, tissue breakdown may occur and levels of Phe will increase; hypoglycemic convulsions and death may occur. Infants with PKU obtain their Phe either from regular commercial formulas or from breastfeeding. Breast milk has a lower Phe content than commercial formulas and has immunological and psychological benefits (Overby, 2003). Duncan and Elder (1997) reported that breast-feeding is
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possible for infants with PKU and suggested various management methods. For example, one method of monitoring is calculating the amount of breast milk a baby takes every 10 minutes by weighing the baby before and after a feeding. Knowing this time/amount and the infant’s weekly blood Phe level will allow the health care provider to calculate how many minutes a day the infant needs to breast-feed. MPKU syndrome pathophysiology During pregnancy, the placenta naturally selects for higher concentrations of amino acids, including Phe. Phe levels are amplified (1.5 to 2 times), which multiplies the teratogenic effects on the developing fetus. This high Phe concentration results in serious fetal damage. Ninety percent are mentally retarded, and 25% have congenital anomalies. Common features of MPKU syndrome are intrauterine growth retardation, microcephaly, congenital heart defects, vertebral anomalies, and strabismus (Friedman & Hanson, 2002). Body systems have critical periods of development during embryogenesis. The critical period for the central nervous system, cranium, and heart is 5 to 8 weeks from the mother’s last menstrual period. Consequently, if a pregnant female with PKU is not in metabolic control before Week 5, her high blood Phe levels will increase, cross the placenta, and enter the fetus’s circulation and exert teratogenic effects on the developing fetus.
PKU/MPKU Syndrome and Developmental Issues High Phe levels in PKU and MPKU cause neurological damage to the developing infant, which makes it imperative to monitor the cognitive development of these children and adults. When assessing cognitive and social development, IQ scores and social support levels that are needed by children to function in their environment must be considered (American Association on Mental Retardation [AAMR], 2002). Mental retardation has been categorized as mild, moderate, severe, and profound with support levels referred to as intermittent, limited, extensive, and pervasive (AAMR, 2002). Fetuses exposed to high uterine Phe levels do not develop normally. Lipson et al. (1984) found similarities between the effects of high maternal Phe and embryonic exposure to alcohol; both syndromes exhibit characteristics of environmental teratogens such as prenatal-onset growth
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deficiency, alteration of morphogenesis, and alteration of nervous system performance (Friedman & Hanson, 2002). Rouse et al. (1997) reported findings of 572 pregnancies from the International Collaborative Study of Maternal Phenylketonuria (1984–1996). The offspring were examined for congenital heart disease, craniofacial abnormalities, microcephaly, and intrauterine and postnatal growth retardation. The mothers were grouped according to their Phe levels during critical gestational weeks and average Phe exposure throughout the pregnancy. These researchers found that the frequency of congenital abnormalities increased with increasing maternal Phe levels. For example, 85% of babies born to mothers who were in the highest Phe range had microcephaly compared with 3% of babies born to mothers who were in the lower Phe range. They concluded that women with PKU should begin low-Phe diets to achieve Phe levels of less than 6 mg/dl prior to conception and maintain these levels throughout the pregnancy. Lee et al. (2005), while analyzing United Kingdom PKU Registry data, found that women with PKU who started diet restrictions preconceptually had infants with higher birth weights, larger head circumferences, less congenital heart disease, and normal IQ and developmental quotients than mothers who started dietary restrictions after becoming pregnant. Levy, Buehler, and Bartley (1994) emphasized the need to identify and manage all women with PKU, even those who have never been treated with the low-Phe diet. They described a significant association between nontreated mothers with mild PKU and fewer diminished birth measurements and cognitive delays in their offspring. Waisbren et al. (2000) studied one hundred eighty-two 4-year-olds born to females with PKU. They found an inverse relationship between the children’s IQ and maternal metabolic control; increased length of poor, prenatal maternal metabolic control was associated with lower children’s IQ scores. Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks gestation scored 2 SD below the norm, whereas offspring whose mothers were in metabolic control prior to pregnancy had scores at the norm. Overall, 30% of children born to mothers with PKU had social and behavior problems. In contrast to MPKU syndrome, the deleterious environmental exposure that infants with PKU
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have is not related to high uterine Phe levels. Their environmental exposure occurs after birth. When infants with PKU ingest a protein meal, the Phe in the protein is not metabolized; high blood Phe levels cross the blood–brain barrier and cause damage to neurological processes. Koch and Wenz (1987) investigated cognitive development in untreated children with PKU and found that IQ falls to mild mental retardation at 1 year of age and deteriorates to severe mental retardation by 3 years of age. Smith, Beaslye, and Ades (1990) reported a loss of 10 IQ points in the first month of life; an additional 10 points is lost in the second month. About 1/3 of untreated infants exhibit a lack of growth of head circumference and infantile spasms according to electroencephalogram results (Reed & Charbonneau, 2004). Griffiths, Demelweek, Fay, Robinson, and Davidson (2000) emphasized the need for the early treatment of an infant with PKU. They studied 57 early-treated children and concluded that Phe control at the age of 2 years was predictive of future, overall cognitive success. Likewise, Koch and Wenz’s (1987) outcome data from the Collaborative Study of Children Treated for PKU indicated that IQ scores of early-treated children had a nearly normal distribution, with individual scores tending to be slightly lower than their siblings without PKU. In contrast, Fishler, Azen, Henderson, Freidman, and Koch (1987) revealed that the IQ scores of 38% of girls with PKU are below their peers by 1 year or more. Multiple factors other than high blood Phe levels contribute to cognitive development. Therefore, caution should be taken when one applies high Phe levels to predict overall cognitive success. Recent researchers report that mildly depressed IQ is common in treated patients with PKU. Griffiths et al. (2000) analyzed IQ scores of 57 early-treated children and found that early, continuous treatment did not necessarily lead to normalization of overall IQ. Further analysis revealed normalized verbal IQ, but performance IQ remained depressed. Azen, Koch, and Freidman (1991) tested well-controlled 12-year-olds with PKU and found that these children scored 17 points lower in arithmetic than they did at previous baseline levels. The International Collaborative Study of Maternal Phenylketonuria supported the findings of mildly depressed IQ when they analyzed 382 females with PKU between the ages of 15 and 22 years and found an average IQ of 83, which is 1 SD below the mean (Koch et al., 1999).
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If, indeed, dietary control at the age of 2 years predicts future cognitive successes, then, clearly, dietary control is paramount. However, there is controversy as to when to discontinue the Pherestricted diet. This confusion is illustrated in the nursing literature when Matthews (2001) disputed Fraser’s (2001) reinstitution of a PKU diet in a 50-year-old woman with mental retardation. In the past, strict dietary compliance was relaxed when the child was between 6 and 8 years of age. Current data now support a restricted, lifelong diet. Elevated Phe levels in adolescents and adults adversely affect aspects of cognitive function (NIH, 2000). In fact, improvement in cognitive functioning has been seen in late-treated individuals with severe retardation (Clark, Gates, Hogan, & MacDoanald, 1987; Koch & Wenz, 1987; Pietz et al., 1993; Potocnik & Widhalm, 1994). Weglage et al. (2000) studied 10- to 18-year-old patients with PKU and found significant problems such as depressive mood, anxiety, physical complaints, and social isolation problems that put adolescents at risk for unhealthy behavior. Waisbren and Levy (1991) found that depression and anxiety are lessened for adolescents with reinstitution of a Phe-restricted diet. Matthews, Barabas, Cusak, and Ferari (1987) measured social quotients of students with PKU who were on and off their diet and found deficits in self-help, socialization, and communication in students off the diet. Other researchers stress the positive impact a Pherestricted diet has on restful sleep. Reed and Charbonneau (2004) noted that there is some evidence to indicate that attention deficit hyperactivity disorder (ADHD) is more common in children treated early for PKU than in normal children. Riva et al. (1996) retrospectively compared the IQ of 26 school-age children with PKU who were breast-fed or formula fed for 20–40 days prior to intervention. They found a 12.9-point advantage in children who were breast-fed in the short time before being diagnosed with PKU.
STANDARD MANAGEMENT PROTOCOLS
Infant PKU Protocols Newborn PKU screening is mandatory across the United States; however, implementation is not consistent. Each state does not follow uniform guidelines for (a) defining blood Phe levels for positive screens, (b) reporting non-PKU hyper-
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phenylalaninemia, (c) reporting cases by gender, (d) mandating parents to consent to testing (i.e., 46 states permit parental refusal), and (e) billing for Phe blood test (American Academy of Pediatrics, 2001; NIH, 2000). While screening protocols need to be improved, dietary standards of care for infants are well established. Early dietary control in infants is paramount to ensuring cognitive success. When an infant is diagnosed with PKU, weekly monitoring of diet and blood Phe levels (kept between 2 and 6 mg/dl) is initiated. Outcomes are usually successful when there is strict implementation of dietary protocols and when access to information and health care is provided. For example, when an infant is born with PKU, parents should be clearly informed about the nature and management of the disorder. There is a plethora of information and support for parents raising these infants, including easy-to-read medical literature, cookbooks, coloring books for children, informative web sites (e.g., http://www.pkunet.org; http://pkunews.org), and numerous resource groups and individuals.
Child and Adolescent Protocols In contrast, dietary protocols for older children with PKU are less consistent. Formal recommendations for blood Phe levels do not exist for children more than 12 years. Most PKU clinics recommend the following: (a) yearly visits to genetic center, (b) monthly or quarterly monitoring of Phe blood levels, and (c) lifelong dietary treatment. A recent survey of PKU clinics found that many adolescents frequently miss appointments and never drink their unpalatable formula (Wappner, Sechin, Kronmal, Schuett, & Seashore, 1999). There are no PKU adolescent or adult clinics in the United States. Betz (1998) addressed the unique health concerns of adolescents with chronic health problems in her study of transitioning adolescent care from the pediatric setting to the adult setting. She noted that the transition usually begins around the age of 14 years because adult providers are better suited at this time to deal with increasing adult needs of adolescents; schools write individualized transition plan for their students when they reach 14 years old. Betz urged nurses caring for children with special needs to utilize Section 504 of the Rehabilitation Act of 1973 (P.L. 93–112) because this law mandates that children with diseases such as PKU receive extra school services. (See Betz, 1998, for further information on transitioning).
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Metabolic dietitians have attempted to deal with the unique problems of adolescent females with PKU by sponsoring a weeklong MPKU camp in the summer for girls more than 14 years old. The purpose of the camp is to develop camaraderie between females with PKU and to teach them about dietary self-management and MPKU syndrome (A. Wilson, personal communication, October 31, 2001; Genetic Disease Bulletin, 10/21/01).
MPKU Protocols In the United States, no formal standards of care exist for women of childbearing age with PKU. Clinics vary in their target range for blood Phe levels for women who are pregnant (e.g., b10 to b 15 mg/dl). Conversely, clinics in United Kingdom and Germany have established lower acceptable target ranges (e.g., 1–4 mg/dl). The United Kingdom has recently adopted the following specific guidelines to deal with M PKU: (a) provide services according to needs assessment, (b) provide clearly written information, (c) provide schoolaged children with support to become responsible for dietary management and obtaining finger sticks, (d) offer detailed fetal ultrasound and the choice of pregnancy termination to women who conceive with blood concentrations more than 11.6 mg/dl (United Kingdom Consensus Report, 1999). PKU clinics in the United States recognize that an unplanned pregnancy in a female with PKU may result in serious fetal consequences if the mother is not in metabolic control. The NIH (2000) PKU Consensus Statement presented three key areas that are required to successfully manage women with PKU: (a) a comprehensive, multidisciplinary, integrated system for the delivery of care to patients with PKU; (b) a reliable home-testing method to monitor Phe levels; and (c) outreach programs for women with PKU of childbearing age, with special focus on social support, positive attitudes toward metabolic control of Phe, and conscious reproductive choice. The Guidelines for Adolescent Preventive Services of the American Medical Association (AMA) (1996) has recommended that all health care providers screen for risk behaviors including sexual activity, alcohol, and drug use. The AMA developed a screening questionnaire for adolescents, consisting of a brief medical history, biomedical health concerns, and a list of healthrisk behaviors that together form a health-risk behavior profile. Unfortunately, Epner, Levenberg, and Schoeny (1998) surveyed 15 primary care
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providers in Chicago and found that none used this screening questionnaire. Physicians, advanced practice nurses (APNs), and metabolic dietitians taking care of females with PKU should routinely discuss PKU pregnancy and the potential for severe birth defects during clinic visits. However, parents have reported their inability to bhearQ clearly during clinic visits because they are distracted and worried about their child’s care and development. Further complicating the pregnancy issue is the fact that most parents do not discuss sex and childbearing with their daughters (Pueschel & Yeatman, 1977). The author has observed no formal assessment of sexual or drug health in two of the three Illinois state-approved PKU clinics. It has been reported that 50% of pediatricians do not assess sexual health (Knight et al., 1997).
HEALTH SYSTEM GAPS Genetics, pathophysiology, cognitive and social development, and standard care protocols have been reviewed. Thus, it is critical that females with PKU are identified and managed to prevent MPKU syndrome. Currently, the only intervention that is effective in managing females with PKU is excellent dietary protocols. Unfortunately, there are no other consistently used protocols to meet the myriad of health care issues of females with PKU. Inconsistent health care system factors magnify the MPKU problem: (a) infants at risk for MPKU syndrome are not identified because females with mild PKU have not been followed; (b) parents’ refusal to have their infants tested for PKU, resulting in infants and children with mental retardation; (c) adolescents with PKU are not routinely screened for high-risk behaviors (e.g., sexual activity, drugs, and alcohol); and (d) cost and quality outcomes regarding the care of females with PKU are neither assessed nor accounted for. At the health care provider level, inconsistent or incomplete care is provided for children/adolescents with PKU and their families. Few specific interventions for cognitive and social delays in females with PKU are implemented; adolescent risk behavior assessments are not systematically conducted; and family health assessments are ignored. Seventy-five percent of mothers with PKU are not in metabolic compliance when they become pregnant. The following is a case study
that exemplifies problems encountered by adolescents with PKU. A comprehensive case management approach is described to meet the health care gaps noted previously. CASE STUDY Jana, a 17-year-old with a history of nontreated mild PKU, was seen in the pediatric genetic clinic for consultation. Jana was 8 weeks pregnant with her first child and had a blood Phe level of 11.9 mg/dl. She was accompanied by her 20-year-old boyfriend, Tony, the father of the baby. Verbal and written information regarding MPKU syndrome was provided to Jana and Tony. He is a Roman Catholic, and she is a Protestant; termination of the pregnancy was not an option. Jana was instructed to start a low-Phe diet and was given a commercial Phe-restricted protein formula to drink. Formula costs were US$20.00 a day, and Jana’s mother’s health insurance covered the cost. Four days later, Jana returned to the clinic and stated that she was unable to drink the formula; her blood Phe level was 13.6. Pherestricted protein bars were prescribed, costing US$30.80 a day. Unfortunately, the HMO refused to pay for the bars because they bare not a medication.Q The Illinois PKU association was called, and they donated US$840.00 to pay for the bars. The health care team (i.e., metabolic dietician, registered nurses, and a pediatric metabolic geneticist) followed up this young woman for the next 12 weeks, during which time blood Phe levels were reduced to acceptable pregnancy levels.
Previous History Jana was born in California and diagnosed at birth with PKU. Jana’s blood Phe levels plus her growth and development were followed up at a child developmental center until she was 7 1/2 years old. She was followed up weekly, then monthly, and then yearly. Her blood Phe levels averaged about 11 mg/dl. She was on a Pherestricted diet. Growth parameters followed her growth curve from birth through the age of 7 years (with weight = 50% and height = 90%). Jana’s mother was educated about MPKU syndrome twice: when Jana was 2 years old and, again, when she was 7 years old. She was informed about the deleterious effects high Phe levels have on an unborn fetus and was told that Jana would probably need to go on a
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Phe-restricted diet if she becomes pregnant. Developmental testing showed no significant delays, but Jana had some behavioral problems in school including trouble sitting still, talking out of turn, and defiance. Jana’s health care providers never addressed the possibility that Jana’s high Phe levels may have been related to her bbadQ behavior. Jana was never seen again for PKU management until she became pregnant.
Case Management A management plan for females with PKU coordinated by an APN needs to be incorporated into the health care system to compensate for fragmented, incomplete, and unorganized care. Nurse case managers are successful in providing cost-effective, positive patient outcomes and are rated as highly satisfactory by patients and families. For these reasons, APNs are needed to assess, diagnose, plan, and implement care for females with PKU. Constructing management models and implementing clear, concise protocols may decrease the incidence of this preventable disorder. To effectively manage these children and adolescents, the APN must have a thorough understanding of developmental and family concepts and measures. Developmentally, females with PKU and their offspring are at increased risk for cognitive, behavioral, and social delays (Griffiths et al., 2000; Reed & Charbonneau, 2004; Rouse et al., 1997; Waisbren et al., 2000; Yachmink, 2003). Bennett and Guralnick (1991) reported that developmental lags are reduced if interventions are initiated early and are family focused. However, there is no research on interdisciplinary approaches connecting identification of these cognitive and social delays to appropriate interventions.
Developmental Concerns Developmental assessment should be done consistently throughout childhood and adolescence. The most used developmental screening tool for children from birth to 6 years of age is the Denver II. Delays in fine and gross motor development and cognitive and language can be detected; families referred to early intervention programs (Bennett & Guralnick, 1991). There are multiple screening tools that are appropriate for the child older than 6 years and that focus on school and educational problems. Aylward (1994) has a comprehensive
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description of screening tools including language (Peabody Picture Vocabulary Test; Early Language Milestone Scale; Receptive–Expressive Emergent Language Scale), behavioral/ adaptive functioning (Vineland Adaptive Behavior Scales; Minnesota Child Development Inventory, American Association on Mental Deficiency Adaptive Behavior Scale), cognitive/intellectual functioning (Wechsler Intelligence Scale for Children, Stanford–Binet, Kaufman Brief Intelligence Test), academic achievement (Wechsler Individual Achievement Test, Kaufman Test of Educational Achievement), attention (testing for ADHD), behavior (Achenbach Child Behavior Checklist, Louisville Behavior Checklist), visual/motor (Bender Visual Motor Gestalt Test, Revised Visual Retention Test), and school performance problems. Vessey and Rumsey (2004) provide additional, age-appropriate screening measures for anxiety, self-concept, and temperament. The school-age child’s activities are centered on school, where problem-solving skills can be learned and tested. The female with PKU who is not achieving academically or socially in school may exhibit behavioral and self-concept problems related to being different from their peers. There are different types of mandated educational support under the Individuals with Disabilities Act, including additional professional testing and social services. Adolescence Although most adolescents develop abstract thinking and have the ability to understand the consequences of their behaviors and actions, personal stress, peer pressure, and new or unfamiliar phenomena may trigger unhealthy, high-risk behaviors including alcohol and drug use and sexual experimentation (Sieving, McNeely, & Blum, 2000). The Risk Behavior Intention Scale (Siegel, Aten, Roughmann, Klaus, & Enaharo, 1998) may be used to assess unhealthy behaviors. This tool, in conjunction with the AMA (1996) adolescent health risk survey, may be a useful assessment tool. However, there is little evidence that these questionnaires are being used routinely by health care providers (Epner et al., 1998; Ford, 1998; Knight et al., 1997). When APNs are counseling an adolescent with PKU, they should be aware of the following protective factors that may decrease the probability of high-risk behaviors: positive social skills, suitable adults mentors, cohesive family, and
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maternal disapproval of the behavior (Bier, Rosenfield, Spitalny, Zansky, & Bontempo, 2000; Dittus & Jaccard, 2000; Sieving et al., 2000; Steele, 1989). Mentor mothers (mothers who have young children with PKU) have a positive effect on pregnant females with PKU. These mothers are familiar with the diet and accompanying stress that management of PKU places on the family. They make home visits to aid with cooking, shopping, and meal planning, which facilitated greater metabolic compliance than the control group without such mentoring.
Family Influences As noted, a cohesive family is a protective factor in reducing high-risk behaviors among adolescents. Family perceptions, needs, and strengths have to be integrated into any comprehensive case management approach (Allen et al., 2000). Koop (1987) highlighted the importance of a strong, cohesive family and called for familycentered care for children with special care needs. Factors essential for family-centered care include the following: recognizing that family is the constant in the child’s life; implementing appropriate programs that meet family needs; recognizing family strengths and respecting different coping methods; understanding and incorporating the developmental needs of children and their families into health care delivery systems; and assuring that the design of health care delivery systems is feasible, accessible, and responsive to family needs. In addition, researchers have found that families develop unique paths to manage problems and present a broad range of needs (Diel, Moffit, & Wade, 1991; Knafl, Breitmayer, Gallo, & Zoeller, 1996). The author found that most PKU clinics do not provide family-centered care. APNs should use a consistent family theory and select measures of family factors to frame their family interactions and interventions. There are four family frameworks that nurses have found useful: Resiliency Model for Family Adaptation (McCubbin, Thompson, & McCubbin, 1996), the Contingency Model (Hymovich & Hagopian, 1992), the Calgary Family Assessment Model (Wright & Leahey, 2000), and Family Management Style (Knafl et al., 1996; Knafl & Santacroce, 2004). The Resiliency Model is based upon family stress theory and emphasizes those family strengths that allow families to adapt successfully to having a family member with a chronic illness/disability.
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Valid, reliable tools that measure family coping, hardiness, life events, resources, coping, and problem solving, as well as adolescent coping and decision making instruments, have been developed (McCubbin et al., 1996). The Contingency Model includes a very comprehensive approach to how families function and manage when faced with chronic illness/disability. Hymovich and Hagopian have developed several assessment forms for collecting family and child/ adolescent data, goal setting, and long-term follow-up. The Calgary Family Assessment Model is a systems-based approach and provides suggested interventions for working intensively with families to change family dynamics and understanding and management of the illness/disability (Berman et al., 1999). Assessment tools include ecomaps, genograms, and intensive interviews. Finally, Knafl et al.’s Family Management Style Framework provides a categorization of families into five styles: thriving, accommodating, enduring, struggling, and floundering. The factors that distinguish each style includes child identity, illness view, management mindset, parental mutuality, parenting philosophy, management approach, family focus, and future expectations. In questioning families as to how they define the illness situation, their management behaviors, and perceived consequences, clinicians can use this information to determine management style and to tailor interventions that maximize family strengths and provide specific types of support (Knafl & Santacroce, 2004).
Case Management Approach Jana exemplifies the problems that can occur when an integrated, comprehensive approach is not implemented. The suggested case management approach would provide a continuum of care in an integrated (home, school, ambulatory care) setting. The primary goal of this approach is to reduce MPKU syndrome by managing the care of the female with PKU according to her risk (medical, developmental, and family) level, including preconception metabolic compliance, interdisciplinary collaboration, continuity of care, and continuing assessment of developmental and family factors. As effective care managers, APNs must meet the multiple needs of females with PKU; improve health, cognitive, and developmental outcomes; and reduce the incidence of impaired infants of females with PKU.
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