Jeffrey P. Brosco

Phenylketonuria Scientific Review Conference: State of the science and future research needs

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Evidence-based community pediatrics: building a bridge from bedside to neighborhood.

The American Academy of Pediatrics policy statement “The Pediatricians Role in Community Pediatrics” encourages all pediatricians to partner with their communities to create and disseminate innovative programs that improve child health. This article describes 4 pillars of a bridge to evidence-based community pediatrics for pediatricians interested in pursuing effective community action: (1) collaborate with the community to establish a specific, short-term, health-related goal; (2) identify evidence-based best practice(s) for achieving the shared goal; (3) collaborate with the community to adapt this best practice to the communitys unique assets and constraints; and (4) evaluate the project by using appropriate expertise. Practical elements of each pillar are described and illustrated by specific examples from community-based efforts of pediatricians and are accompanied by specific resources to aid pediatricians in their future community health work.

Adverse Medical Outcomes of Early Newborn Screening Programs for Phenylketonuria

OBJECTIVE. Despite the success of current newborn screening programs, some critics have argued that in the 1960s hundreds of children with false-positive results for phenylketonuria suffered death or disability from treatment with restrictive diets. Medically adverse outcomes after false-positive results may be a reason to be cautious when expanding current newborn screening programs. We sought to determine if newborn screening programs for phenylketonuria before 1980 led to adverse medical outcomes in children with false-positive results. PATIENTS AND METHODS. We examined the history of newborn screening programs for phenylketonuria in the United States. We reviewed the historical scholarship, conducted a systematic search for medical adverse outcomes, and interviewed key participants in the history of newborn screening programs. RESULTS. We found no population-based studies of early screening programs for phenylketonuria. One author reported 2 infants treated with restrictive diets after false-positive results for phenylketonuria who were developmentally delayed, and there is unpublished evidence of 4 additional cases of inappropriate treatment, although adverse outcomes were not documented. There were also 4 published reports of adverse medical outcomes after treating children with phenylketonuria variants, as screening for phenylketonuria revealed infants with intermediate or transiently high levels of phenylalanine. CONCLUSIONS. We found little evidence of death or disability that resulted from the inappropriate treatment of well children who were falsely identified by early newborn screening programs. Because the first decade of newborn screening typically reveals diagnostic and therapeutic complexity, systematic follow-up of screened populations and rapid dissemination of results may reduce morbidity/mortality rates.

What do residents learn by meeting with families of children with disabilities?: A qualitative analysis of an experiential learning module

Purpose: Attitudes of medical providers towards persons with disabilities can affect the quality of care their patients receive. The authors evaluated an experiential learning module to investigate what Paediatric and Medicine/Paediatric residents at the University of Miami/Jackson Memorial Hospital learn from visiting the homes of families with children who have disabilities. Methods: Families were recruited through a community-based parent organization. The families were instructed to discuss what it is like to have a child with a disability and to think about a primary message to give to residents during a 1–2 hour home visit. Since 1998, residents participated as part of the required Developmental Paediatrics rotation. They were instructed to write a one-page narrative description of their visit. The authors utilized the grounded theory of qualitative research and content analysis to count the key themes identified in the residents’ descriptions. Results: Twenty-four families and 63 residents participated in the learning module. The resident observations yielded four major themes. Twenty-four per cent stated families needed more information; 79% noted that families face various obstacles, including financial (33%), medical providers’ pessimism (29%), inter-personal family conflicts (27%) and medical system problems (22%); 49% of residents commented that families adjust and cope with their childs disability; and 27% of residents stated that the experience changed their insight about children with disabilities. Conclusion: The authors’ study suggests that a single home visit with the family of a child with a disability provides paediatrics and medicine/paediatrics residents with insights into the familys perspective on disability otherwise unattainable in a hospital-based training programme.

Parental Permission for Pilot Newborn Screening Research: Guidelines From the NBSTRN

There is broad recognition of the need for population-based research to assess the safety and efficacy of newborn screening (NBS) for conditions that are not on current panels. However, prospective population-based research poses significant ethical, regulatory, and logistical challenges. In the context of NBS, there have been a variety of approaches that address parental decision-making in pilot studies of new screening tests or conditions. This article presents an ethical and legal analysis of the role of parental permission by the Bioethics and Legal Work Group of the Newborn Screening Translational Research Network created under a contract from the National Institute of Child Health and Human Development to the American College of Medical Genetics and Genomics. Circumstances are outlined in which a waiver of documentation of permission or a waiver of permission may be ethically and legally appropriate in the NBS context. These guidelines do not constitute American Academy of Pediatrics policy.

The Lure of Treatment: Expanded Newborn Screening and the Curious Case of Histidinemia

In the last decade, universal newborn screening (NBS) has entered a new era of promise and controversy. With the use of tandem mass spectroscopy, states have substantially increased the number of conditions included in mandatory NBS programs.1 This expansion has mostly followed recommendations from an expert panel commissioned by the Maternal and Child Health Bureau, which proposed mandated screening for a core panel of 29 conditions and suggested that 25 additional conditions be reported to families, although accepted treatments are not yet available.2 The Presidents Council on Bioethics3 criticized the recommendations, arguing that mandated NBS should be restricted to conditions that adhere closely to Wilson and Jungners traditional principles for screening,4 especially the availability of treatment that is accepted as effective and accessible to patients. Others have countered that exclusive focus on treatment of the infant ignores other potential benefit to families and society and that the time has come to supplant treatment availability as the key criterion for NBS programs.5,6nnThese policy debates may seem to arise from access to new technology, but in fact similar issues arose in the early history of NBS. For example, NBS for phenylketonuria is justly celebrated as a public health success, but in the mid-1960s clinicians and policy makers faced profound ethical issues. NBS revealed many children with intermediate serum values of phenylalanine, and because clinicians did not know the natural history of these metabolic variants, they could not accurately weigh the risks and benefits of a restricted diet. A prospective, … nnAddress correspondence to Jeffrey P. Brosco, MD, PhD, PO Box 016820 (D-820), Miami, FL 33101. E-mail: jbrosco{at}miami.edu

The Political History of PKU: Reflections on 50 Years of Newborn Screening

* Abbreviations:n NBS — : newborn screeningn PKU — : phenylketonuriannJust over 50 years ago, Dr Robert Guthrie developed a simple screening test for phenylketonuria (PKU) that became the prototype for universal newborn screening programs. Historians Jeffrey Brosco and Diane Paul explore why PKU screening marked a historical turning point in public health. It is a story that has left a far more complex legacy than most pediatricians recognize.—Jeffrey P. BakerSection Editor, Historical PerspectivesnnPhenylketonuria, or PKU as it is more familiarly known, is a rare disorder, affecting only ∼1 in 15u2009000 people. In the United States, for example, ∼275 infants will be born with the disease each year.1 Thus in a lifetime of practice most pediatricians will not encounter a single case. Yet probably every pediatrician in the industrialized world has learned about PKU during medical school, many parents vividly remember the heel-stick test for their newborn, and scientists interested in genetics and metabolism say that they hope to “find another PKU.” Why has such a rare condition garnered so much attention?nnPKU is famous in part because it is widely seen as a victory for scientific medicine. If the condition is detected in the newborn period and a specialized diet is instituted, the profound cognitive impairment usually caused by PKU is averted. For the diet to be effective, however, the otherwise normal-appearing infant with PKU must be identified, among thousands of other nonaffected infants, in the first weeks of life. In the early 1960s, parents of children with intellectual disability began to advocate for state laws to test all newborns in the United States, and the first state laws for universal newborn screening (NBS) were implemented 50 years ago. By 1965, 32 American states had enacted screening laws, all but 5 making the test compulsory. By the mid-1970s, NBS for PKU had become routine in … nnAddress correspondence to Jeffrey P. Brosco, MD, PhD, Department of Pediatrics, University of Miami Miller School of Medicine, PO Box 016820, Miami, FL 33101. E-mail: jbrosco{at}miami.edu

Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation

The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype–phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.Genet Med 19 1, 121–126.

When a Family Requests a White Doctor

Parents sometimes request that a doctor of a particular race or ethnic group not care for their child. Such requests sometimes seem legitimate and other times seem offensive. The difference reflects a clash of fundamental values. Generally, we try to respect patient or parental preferences. Requests based on racist attitudes, however, do not seem worthy of respect. But where should we draw the line? In this ethics rounds, we present a situation in which parents requested a white doctor and analyze the ways in which doctors might think about and respond to such a request.

Universal State Newborn Screening Programs Can Reduce Health Disparities

Fifty years after the advent of state newborn screening (NBS) programs for a metabolic condition, there is evidence that the decision to mandate universal screening can reduce health disparities. When in-hospital screening for phenylketonuria began in the early 1960s, most hospitals simply added the procedure to the list of routine clinical practices for newborns, such as giving vitamin K. For a variety of reasons, including fear of missed cases, advocates managed to get state governments involved. By the late 1960s, most states required screening of all or almost all newborns.1 Although these advocates and state legislators did not describe their actions as addressing population-level health disparities, they believed that it was unfair for some infants to bear the consequences of late diagnosis of phenylketonuria simply because they were born in a hospital that did not provide the test. By making NBS for phenylketonuria universally available, they reduced the impact of unequal access to a new and effective therapeutic intervention– one cause of health disparities based on income, location, education, and race/ethnicity.2 n nRecent reports from states that perform NBS for severe combined immune deficiency (SCID) confirm this hypothesis. This is a rare condition that is typically diagnosed when an infant or young child has 1 or more unusual infections. Bone marrow transplantation is highly effective to treat this condition, and outcomes are better when performed in the newborn period. In 2010 SCID was added to the Recommended Uniform Screening Panel (RUSP), the list of conditions recommended for NBS by the US Secretary of Health and Human Services. Early reports of NBS for SCID have revealed that SCID is much more common in black and Hispanic individuals than previously suggested by clinical referrals to transplant centers. Data from the first 2 years of screening for SCID in California, for example, reveal rates of SCID among black, Hispanic, and Asian children that are much higher than would be predicted by birth rates.3 More importantly, only 2 of the 15 infants who have undergone lifesaving bone marrow transplantation because of the state NBS program begun in 2010 were non-Hispanic white. This contrasts with earlier clinical series in which more than 80% of bone marrow transplantations for SCID were performed in non-Hispanic white children. The difference in the frequency of SCID among various racial/ethnic groups had been thought to be genetic. However, data from the California NBS program suggest that differential access to specialty care is a more likely explanation and that universal screening for SCID reduces health disparities from that condition. n nIt may seem strange that we are only now confirming what seems like common sense. After all, the whole idea of having an RUSP is to reduce disparities based on geography. If there is good reason to screen for a specific condition, why should infants in one state receive the benefits while infants in neighboring states do not? Similar reasoning also prevailed in the recent decision to add critical congenital heart disease (CCHD) to the RUSP. A point-of-care procedure such as pulse oximetry does not require a state laboratory, and it could have simply been added to best practices in newborn clinical care. Although CCHD can be detected either during prenatal ultrasonography or through postnatal clinical observation, access to high-quality prenatal and postnatal care may vary by race/ethnicity, socioeconomic status, and location–some hospitals are better staffed and equipped to diagnose CCHD than others. In the absence of universal screening, the frequency of late detection of CCHD has been shown to be significantly higher in birth hospitals with a level I nursery only, and universal screening should in principle reduce disparities by birth hospital type.4 n nDiscovering a condition in the newborn period is not sufficient to eliminate disparities in outcomes owing to variability in uptake and adherence to follow-up and management by hospitals, clinicians, and families, which is often related to underlying social and environmental factors. Robust state public health programs form part of a system of care that goes beyond the NBS test to include contacting families and their physicians, confirming that diagnostic testing has been performed, providing training to clinicians, and ensuring that a family is connected to clinical resources. Even when such a system is in place, infants of less educated parents can be less likely to receive timely diagnosis and services.5 Special attention to historically underserved populations, including targeted interventions to improve short-term follow-up, may be needed to ensure that the benefits of early identification are universally obtained. n nChoices about which conditions to include in NBS can also alleviate or aggravate health disparities. Sickle cell disease (SCD) primarily affects infants of Hispanic or African American parents, for example, and universal NBS for SCD in combination with parental and clinical awareness and penicillin prophylaxis eliminated the majority of excess mortality resulting from that condition in young children.6 Although the full potential of SCD NBS was not realized owing to incomplete adherence to prophylaxis, the subsequent introduction of universal immunization with conjugate pneumococcal vaccine further lowered SCD-related deaths. n nChoices about NBS implementation procedures made after a condition is added to the RUSP can also potentially affect disparities. For example, the method of single-sample 2-tier screening for cystic fibrosis (CF) used in most US states–immunoreactive trypsinogen followed by testing for selected CFTR mutations in samples with elevated immunoreactive trypsinogen–detects fewer non-white infants who have CF because those CFTR mutations are less common in people of non-European ancestry who have CF. Other screening approaches for CF that provide comparable sensitivity across ethnic groups could avoid health care disparities among children with CF associated with differences in age at diagnosis.7 n nLike most NBS conditions, SCID is rare–approximately 1 case per 50 000 births–and screening and early intervention for SCID by itself will not reduce the broader disparities in health outcomes for children from Hispanic or African American families compared with children from other racial/ethnic groups. However, when all NBS conditions on the RUSP are combined, including hearing loss and CCHD, approximately 5 in 1000 newborns have a condition detectable by screening that can be addressed. The promise of NBS to improve health outcomes for all children, regardless of location, race, ethnicity, or socioeconomic status, should not be taken for granted. The history of NBS programs is replete with disruptive technologies and difficult political choices,1 and the future promises to bring many challenging new questions. As NBS programs evolve, we must ensure that they continue to reduce the persistent health disparities among historically underserved populations. Long-term follow-up studies will be needed to monitor use of health care services and health outcomes, including impact on health disparities. More important, NBS programs need to maintain their universal nature and public health follow-up structure to maximize their role in reducing population-based health disparities.