Newborn Screening for Phenylketonuria: Predictive Validity as a Function of Age

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Newborn

Screening

for Phenylketonuria:

Predictive

Validity

as a Function

of Age

Edward

R. B. McCabe,

MD, PhD,

Linda

McCabe,

PhD,

Gayle

A. Mosher,

MS

Richard

J. Allen,

MD, and

Julian

L. Berman,

MDI

From the Departments of Pediatrics, Biochemistry, Biophysics, and Genetics, University

of Colorado School of Medicine; Department of Psychology, University of Colorado at

Denver; Departments of Pediatrics and Neurology, University of Michigan Medical School,

Ann Arbor; and Department of Pediatrics, University of Health Sciences, The Chicago

Medical School, North Chicago

ABSTRACT. Data from questionnaires were assembled

for 109 infants with phenylketonuria (PKU) and 114

control infants to assess the predictive validity of

new-born screening for PKU as a function of age. Patients

with PKU had values of <4 mg/dL in cord blood and in samples from days 1, 2, and 4 through 7. The proportion of patients with PKU expected to fall below screening cutoffs of 2, 4, and 6 mg/dL was predicted for each age range. Using a cutoff of 4 mg/dL, approximately one

third of patients with PKU would be missed by a sample taken from the neonate in the first 12 hours of life, and

nearly 10% would be missed with a sample from the second 12 hours of life. This study shows that not all

patients with PKU will be detected by newborn screening,

and that the phenomenon of early nursery discharges must be considered in developing appropriate screening strategies. Pediatrics 1983;72:390-398; phenylketonuria,

newborn screening.

Traditionally, the blood sample for the

phenyl-ketonuria (PKU) screening test has been drawn

from

the normal newborn prior to discharge from the hospital and usually on the third day of life.1

With

the increasing frequency of earlier discharge

from nurseries,2’3 coupled with the relatively poor compliance with follow-up screening and

recom-mendations against routine second testing for

PKU,4 the predictive validity of newborn screening

Received for publication June 21, 1982; accepted Dec 10, 1982. tDr Berman died in January 1983. This paper is dedicated to his memory.

Reprint requests to (E.R.B.M.) Department of Pediatrics, Box C233, University of Colorado Health Sciences Center, Denver,

CO 80262.

for PKU as a function of age becomes an important

issue.

Because PKU is an autosomal recessive disease,

each sibling of an identified patient has a 25%

chance of having this disorder. Many clinics aug-ment routine screening procedures for siblings of known patients with PKU by drawing serial blood samples from them. We decided to capitalize on this practice in order to compare, within the first 2

weeks of life, serial blood phenylalanine concentra-tions between affected and unaffected siblings of known patients with PKU.

METHODS

Q

uestionnaires were sent to 182 professionals in 26 countries requesting serial blood phenylalanine concentrations during the first 2 weeks of life from patients with classic PKU and newborn siblings of

known affected patients. This information was

so-licited from members of the Society for Inherited

Metabolic Diseases and the Society for the Study

of Inborn Errors of Metabolism, as well as addi-tional professionals suggested by members of these organizations. Information on the timing,

fre-quency, and source of feedings was also requested; however, insufficient data were received and the

issue of the effects of intake on screening could not

be addressed. Responses were received from 52

colleagues. In the course of this work, three

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con-tinuous values and were classified as parametric variables. The results from bacterial inhibition as-say and paper chromatography were given as

dis-crete values or ranges and were classified for statis-tical purposes as nonparametric. The breakdown of subjects by geographic source and variable type is

given in Table 1. The distribution of subjects by country and year of birth is given in Table 2.

Statistical comparisons of control and patient nonparametric data were made using the Mann-Whitney T test.5 Parametric data were analyzed statistically using the Statistical Package for the Social Sciences.6 In the following sections, the time interval “0 to 12 hours” does not include cord blood, but refers to samples taken from the infant after

the umbilical cord had been severed, up to 12 hours of age.

RESULTS

The blood phenylalanine concentrations

deter-mined by bacterial inhibition assay or paper

chro-matography in patients with PKU and control

sub-jects during the first two weeks of life are shown in

Fig 1. Each point or bar represents the phenylala-nine measurement as a discrete concentration or range, respectively, for an individual on that day.

These measurements are not continuous nor do they have equal intervals, eg, one is comparing

values reported as 2 v<4 v 2 to 4 mg/dL. Therefore,

these data have been analyzed using nonparametric

statistics,5 specifically the Mann-Whitney

T

test.

These data are summarized in Table 3. The group

with PKU and the control group can be

distin-guished statistically at the .05 level using cord blood

and samples obtained on days 2, 3, and 4 of life. However, the group with PKU has some values of

<4 mg/dL in samples taken on days 5 and 6, and

also has some values of 2, <2, and 1 mg/dL in

samples from cord blood, 0 to 12 hours, 12 to 24 hours, day 2, day 4, and day 7.

The blood phenylalanine concentrations deter-mined by fluorometric or column chromatographic

methods in patients with PKU and control

individ-uals during the first 2 weeks of life are summarized

in Table 4. These determinations meet the

assump-tions of parametric statistics, ie, the measurements are continuous, with equal intervals, and the group with PKU and the control group are distributed normally at each age range by

x2

analysis. These

groups are statistically distinguishable at the .05

level for cord blood and at the .001 level for all other age ranges. It is obvious upon comparison of the group with PKU and the control group that the magnitudes of the standard deviations differ for

these two groups.

In order for the variance of the group with PKU

and the control group to be more comparable, the data were analyzed using log transformation. The

standard deviations ofthe log-tranformed data were quite similar. In addition, the group with PKU and the control group again were normally distributed

at all age ranges using

x2

analysis. The antilogs of

these transformed data are summarized in Table 5. The transformed data show that the groups with PKU and the control group are statistically

distin-guishable at all age ranges: at the .004 level for cord

blood and at .001 level for all other age ranges. Because the original and the log-transformed data meet the criteria for normality of distribution, one can predict the percentage of individuals having phenylalanine levels below various defined cutoffs as shown in Fig 2. These results are summarized in Table 6, with the percentages representing the pro-portion of individuals that were below the cutoffs

of 2, 4, and 6 mg/dL. The percentages were obtained by z-transformation of the original phenylalanine concentration data and calculation of the propor-tion of the area of the normal distribution below the specified cutoff (Fig 2).

DISCUSSION

The ability of newborn screening for PKU to

identify affected patients reliably is a function of age at sampling and of the cutoff for calling a specimen positive. The results of this study show that, whereas cord blood phenylalanine concentra-tion in patients with PKU is slightly increased relative to that of control subjects,7 the cord blood sample is extremely unreliable for PKU screening, missing 70% to 80% of newborns with classic PKU

using a cutoff of 4 mg/dL, and should be considered

unacceptable for this purpose.

The blood phenylalanine concentrations of the

patients with PKU increased after birth and con-tinued to show a consistent increase through the first 14 days of life, confirming previous observa-tions.’2 The consequence of this increase is im-proved reliability of the PKU screen as a function

of age, within limits described by the nonlinearity ofthis increase, the variance ofblood phenylalanine concentrations within the PKU population, and the selection of the cutoff point for calling a given specimen positive. For example, using a cutoff point

of 4 mg/dL and the log-transformed data (Table 6),

there should be a 16-fold improvement in the reli-ability of the PKU screen when a sample is drawn on the third day of life (48 to 72 hours) compared with the second day of life (24 to 48 hours), with the projected proportion of patients with PKU who

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Simi-Parametric Data Nonparametric Both Types of Total

Data Data

Pa- Control Pa- Control Pa- Control Pa- Control

tients Subjects tients Subjects tients Subjects tients Subjects

with with with with

PKU PKU PKU PKU

0 0 0 0 4 0 4 0

2 0 0 0 0 0 2 0

2 0 0 0 6 0 8 0

1 0 2 0 0 2 3 2

2 3 0 0 0 0 2 3

0 0 4 0 0 0 4 0

0 0 0 0 12 0 12 0

7 6 0 0 0 0 7 6

3 9 0 0 0 0 3 9

0 0 0 0 2 0 2 0

0 1 0 0 0 0 0 1

9 0 0 0 0 0 9 0

2 0 0 0 0 0 2 0

5 1 0 0 0 0 5 1

5 0 0 0 0 0 5 0

0 0 1 6 11 1 12 7

6 39 0 0 0 0 6 39

2 0 6 0 0 0 8 0

2 1 0 0 1 0 3 1

0 24 0 0 0 0 0 24

0 0 0 0 2 0 2 0

0 2 0 0 1 0 1 2

4 5 0 0 0 0 4 5

0 11 0 0 0 0 0 11

53 102 16 8 40 4 109 114

TABLE 1. Subjects by Geographic Source and Type of Variable*

Australia

New South Wales, Oliver Latham

Labora-tory, North Ryde

Victoria, Royal Children’s Hospital, Mel-bourne

Canada

Ontario, Hospital for Sick Children,

To-ronto

Quebec, Montreal Children’s Hospital, Montreal

Norway

National Hospital of Norway, Oslo

Poland

National Research Institute for Mother and

Child, Warsaw Sweden

University Hospital, Umea

United Kingdom England

Children’s Hospital, Birmingham

Queen Mary’s Hospital for Children, Surrey

Northern Ireland

Queen’s University, Belfast United States

California, Children’s Hospital Medical Center, Oakland

Colorado, University of Colorado School of Medicine, Denver

Georgia, Emory University School of Med-icine, Atlanta

Illinois, Children’s Memorial Hospital, Chicago

University of Health Sciences, Chicago Medical School, Chicago

University of Illinois Medical Center,

Chicago

Indiana, Indiana University School of Med-icine, Indianapolis

Kentucky, University of Kentucky,

Lexing-ton

Massachusetts, State Laboratory Institute, Jamaica Plain

Michigan, University of Michigan Medical

Center, Ann Arbor

New York Department of Health, Albany Upstate Medical Center, Syracuse

Ohio, Children’s Hospital, Cincinnati Children’s Hospital, Columbus

Rhode Island, Rhode Island Hospital, Prov-idence

Washington, University of Washington, Seattle

Wisconsin, University of Wisconsin Hos-pital, Madison

Totals

* Abbreviation used is: PKU, phenylketonuria.

1 0 0 0 0 0 1 0

0 0 1 0 1 1 2 1

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Cord Blood O-l2hrs 12-24 hrs 2nd day 3rd day 4thday 5th day 6thday 7th day 10th day 14th day

Age

Fig 1. Blood phenylalanine concentrations determined infants with phenylketonuria (PKU) and in control

in-by bacterial inhibition assay or paper chromatography in fants during first 2 weeks of life.

TABLE 3. Blood Phenylalanine Concentrations Measured by Bacterial Inhibition Assay or Paper Ch in Patients with Phenylketonuria (PKU) and Control Subjects During First 2 Weeks of Life

romatography

Age Blood Sample Blood Phenylalanine (mg/dL)

Taken . . .

Patients with PKU Control Subjects

Median Range No. Median Range No.

Mann-Whitney

T Values

P Values

At birth (cord 2 2 to 3 5 2 2 4

blood)

0-12 hours 2.5 2 to 2-4 2 2 2 1

12-24hours 2-4 lto6 5 <2 <2 4

2nd day 8-12 2 to >20 17 <2 <2 to 3 6

3rd day 12 8-10 to >20 12 <2 <2 to 2 6

4th day 20 2 to >20 21 <2 <2 to 3 3

Sthday 9 <4to16 2 ... ... ...

6th day 20 <4 to 32 3 . . . . . . . . .

7th day >20 2to >20 6 2.5 2 to 3 2

10th day >20 >20 1 . . . . . . . . .

l4thday >20 >20 3 ... ... ...

2.03

0.70 1.53

3.53

3.44 2.70

... . . .

1.73

. . . ...

.0424

.4839 .1260

.0005

.0007 .0069

... ...

.0836

... ...

TABLE 4. Blood Phenylalanine Concentrations Measured by Fluorometric or Column

Chromatographic Methods in Patients with Phenylketonuria (PKU) and Control Subjects during First 2 Weeks of Life-Untransformed Data

Age Blood Sample Taken

Blood Phenylal anine (mg/dL) Student T

Values

P Values

. .

Patienta with PKU Control Sub

. jects

Mean ± SD No. Mean ± SD No.

At birth (cord blood) 3.1 ± 1.6 19 2.2 ± 1.1 49 2.23 .035

0-12 hours 5.2 ± 2.1 12 2.4 ± 0.8 30 4.46 .001

12-24 hours 6.5 ± 2.3 21 2.0 ± 0.7 64 8.99 <.001

2nd day 10.9 ± 5.5 31 2.0 ± 0.8 71 8.98 <.001 3rd day 15.8 ± 7.0 36 2.0 ± 1.0 65 11.76 <.001 4th day 20.4 ± 6.9 25 2.2 ± 0.9 33 13.15 <.001

5th day 27.9 ± 14.2 22 2.1 ± 0.5 11 8.51 <.001

6th day 28.9 ± 10.4 16 2.2 ± 1.0 6 10.14 <.001

7th day 34.1 ± 14.8 13 2.3 ± 0.6 21 7.77 <.001 10th day 35.3 ± 13.4 15 1.9 ± 0.9 9 9.64 <.001

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TABLE 5. Blood Phenylalanine Concentrations Measured by Fluorometric or Column Chromatographic Methods in Patients with Phenylketonuria (PKU) and Control Subjects During First 2 Weeks of Life-Log Transformed Data

Age Blood Blood Phenylalanine (mg/dL) Student P

Sample Taken . . . T Values

Patients with PKU Control Subjects Values

Mean Range No. Mean Range No.

-1 SD +1 SD -2 SD +2 SD -1 SD +1 SD -2 SD +2 SD

At birth (cord 2.8 1.9 4.3 1.2 6.6 19 1.8 0.8 4.1 0.3 9.4 49 2.99 .004

blood)

0-12 hours 4.8 3.1 7.6 1.9 11.9 12 2.3 1.5 3.4 1.0 5.1 30 4.96 <.001

12-24 hours 6.2 4.4 8.7 3.2 12.1 21 1.9 1.3 2.7 0.9 3.9 64 13.91 <.001

2nd day 9.8 6.2 15.5 3.9 24.5 31 1.8 1.2 2.8 0.8 4.2 71 17.56 <.001

3rd day 14.5 9.4 22.3 6.1 34.4 36 1.8 1.1 3.0 0.6 5.2 65 21.39 <.001

4th day 18.8 11.8 30.0 7.4 47.8 25 2.0 1.3 3.1 0.8 4.7 33 18.70 <.001

5th day 24.6 14.3 42.2 8.4 72.3 22 2.1 1.7 2.6 1.4 3.2 11 18.70 <.001

6th day 27.3 19.4 38.4 13.8 53.9 16 2.1 1.3 3.2 0.9 5.1 6 12.84 <.001

7th day 31.6 21.1 47.3 14.1 71.0 13 2.2 1.6 2.9 1.2 3.9 21 20.72 <.001

10th day 32.6 21.1 50.4 13.6 77.9 15 1.6 0.9 3.0 0.5 5.7 9 12.61 <.001

14th day 35.8 25.5 50.2 18.2 70.5 8 2.3 1.7 3.2 1.2 4.5 7 15.66 <.001

PKU POPULATION - NORMAL DISTRIBUTION

Number

of

Patients

10 12

Blood Phenylalanine (mg/dI)

Fig 2. Examples of use of z-scores to determine percent ofpatients with phenylketonuria (PKU) with blood

phen-ylalanine concentrations <4 mg/dL (shaded area).

larly, using the cutoff of 2 mg/dL, and again the log-transformed data (Table 6), there is a 65-fold improvement in reliability comparing samples drawn in the first 12 hours of life with those drawn

in

the second 12 hours of life, decreasing the pro-jected proportion of patients with PKU who are

missed from 2.6% to 0.04%. The results of this study also indicate that, whereas the reliability of the PKU screen does increase with the age at which the specimen is drawn, actual false-negative results

exist and have been documented as late as 7 days

of age.

The data on documented, false-negative results from PKU screens were supplied by two centers.

Dr Barbara Cabalska (Poland) supplied data on

four patients, three male and one female, who were screened by Guthrie bacterial inhibition assay

mi-tially on days 1, 2, 4, and 7 of life and had blood

phenylalanine levels of 2 mg/dL (personal com-munication, 1981). These patients were subse-quently determined to have PKU at 129, 325, 90,

and 84 days of age, respectively. Their newborn samples were retrieved and repeat Guthrie testing confirmed the previous measurements of 2 mg/dL.

Dr Bridget Wilcken (Australia) provided

informa-tion on an infant who was tested by bacterial inhi-bition assay on the fifth day of life and had a blood

phenylalanine concentration <4 mg/dL (personal communication, 1981). At 11 months of age, this patient had a serum phenylalanine concentration

of 33.5 mg/dL. The original blood filter paper sam-ple was retrieved and repeat Guthrie tests for

phe-nylalanine were >2 mg/dL and <4 mg/dL on three occasions. Part of the original blood specimen was

examined by thin-layer chromatography and the phenylalanine concentration was not increased. This boy had a male sibling, whose blood sample for newborn screening, taken on the sixth day of

life, showed the phenylalanine concentration to be <4 mg/dL. At 27 months of age he was also deter-mined to have classic PKU: his serum phenylala-nine concentration was 39.6 mg/dL and he had phenylketones in the urine. This patient’s original blood specimen could not be retrieved for retesting. Both of these brothers were born at an isolated hospital and each was the only baby born at that time, thus the hospital staffcould not have confused their blood specimens with those of other infants.

In addition to the four cases with confirmed

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TABLE 6. Percent of Patients with Phenylketonuria (PKU) Below Cutoff Using

z-Transformation

Age Blood Sample Taken 2 m

Original g/dL

Log

4 m

Original g/dL

Log

6 m

Original g/dL

Log

At birth (cord blood) 24.5 20.0 71.2 79.1 96.5 96.2

0-12 hours 6.4 2.6 28.4 34.1 64.8 68.8

12-24 hours 2.5 0.04 14.0 9.7 41.3 46.4

2nd day 5.3 0.02 10.6 2.4 18.7 14.0

3rd day 2.4 <0.003 4.6 0.15 8.1 2.1

4th day 0.38 <0.003 0.87 0.05 1.8 0.73

5th day 3.4 <0.003 4.6 0.04 6.2 0.44

6th day 0.48 <0.003 0.84 <0.003 1.4 <0.003

7thday 1.5 <0.003 2.1 <0.003 2.9 <0.003

lothday 0.66 <0.003 0.96 <0.003 1.4 0.01

14th day 0.15 <0.003 0.26 <0.003 0.43 <0.003

bacterial inhibition assay at 8#{189}and 11 months of age revealed phenylalanine levels of 20 mg/100 dL for the specimens from both children. Laboratory error is a concern that has been discussed4’12”3; however, our data document that not all false-negative phenylalanine screen results are due to laboratory or administrative error. The relative magnitude of these respective factors in the

popu-lation of patients with PKU who are missed cannot

be ascertained from this report. Only those

individ-uals who subsequently come to attention, and for whom PKU is diagnosed, will be counted in this pool.

As in the reports of Holtzman et al,’2’14 the data from the present study allow prediction of patients with PKU who are missed at various ages. These

results show that a cutoff of 6 mg/dL, as has been

proposed by some,’5”6would predict a false-negative

rate of >10% through day 2 of life even with the use of log-transformed data (Table 6). It is inter-esting that the predicted percentages of patients with PKU below 4 mg/dL are quite similar when

these results are compared with those of Holtzman et al.12”4 When data from three centers’#{176}” and from a previous report by Holtzman et al9 were pooled,12

they yielded predictions similar to those in Table 6. It should be noted that every precaution has been taken to exclude patient information that would have been included in these previously published data sets.

The similarity in the percentages of false-nega-tive screen results predicted by our study and the independent results of others suggests that the magnitude of this problem may be more sizeable than has been previously recognized, and will

be-come even greater if the mean age at nursery dis-charge continues to decrease without changes in

screening strategy. Despite the increased potential

for false-negative PKU screen results early in life,

it is extremely important to note that the majority

of patients with PKU will not be missed when tested any time after birth using cutoffs of 2 or 4 mg/dL. Therefore, regardless of age at discharge,

infants should be screened before leaving the hos-pital. Decisions regarding the need for repeat

test-ing of these newborns will depend upon the screen-ing strategy selected.17

The acceptable level of false-negative screen

re-sults is a public health decision and must be made

at the appropriate jurisdictional level. The various

strategies that might minimize the rate of false-negative PKU screen results would include the following.

Threshold Adjustment

If it is considered desirable to minimize false-negative PKU screen results to the lowest possible

rate compatible with an acceptable rate of false-positive screen results, then one might select 2 mgI

dL as the threshold value, with any specimen

reg-istering >2 mg/dL considered a positive sample. The New England (Dr Harvey Levy, personal com-munication, 1982) and Commonwealth of Virginia’8 Newborn Screening Programs do not find that a

threshold value of 2 mg/dL gives a prohibitive rate

of false-positive values. Using the Guthrie bacterial inhibition assay, the Virginia program found that

1/3,615 newborns required retesting, and that

drop-ping their cutoff from 4 mg/dL to 2 mg/dL slightly more than doubled their rate of false-positive screen results.’8 With a threshold of 2.5 mg/dL, using the Guthrie test, the Danish neonatal screening pro-gram finds approximately 3/10,000 newborns who require a repeat test.’9 It is not valid to use the data

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status on blood phenylalanine concentrations at differing postnatal ages is yet to be determined. An alternative to simply lowering the threshold for all newborn samples would be to use an age-adjusted threshold. For example, if a false-negative rate of <1% was considered desirable, then, using the

log-transformed data in this report (Table 6) a program

would: refuse to accept samples, or demand repeat

samples, from all neonates tested when <12 hours

of age; use a cutoff of 2 mg/dL for samples collected

between 12 and 48 hours of age; and use a cutoff of 4 mg/dL on the third day of life or later (Table 6). This procedure would rely on accurate and complete age data being supplied with each specimen.

Repeat Testing

As an alternative or adjunct to threshold adjust-ment, a program might require a repeat specimen from all newborns or only for those screened before

a certain age. The Committee on Genetics of the

American Academy of Pediatrics17 has recently rec-ommended that all neonates tested before 24 hours

of age should be rescreened before 3 weeks of age.

Alternative Methodologies

The total cost of newborn screening for PKU is substantially increased when repeat specimens are

required.4 Certain hypothyroid screening programs have addressed this issue and have become more

efficient by designating that specimens in the lower 3% to 10% of thyroxine (T4) concentrations

undergo follow-up thyroid-stimulating hormone (TSH) screening using the initial blood blotter.2022

A similar strategy, with primary specimen backup, would benefit PKU screening. We propose the fol-lowing as a speculative example of such a strategy. The measurement of phenylalanine and tyrosine, and statistical manipulation of these measurements is recognized to be sensitive enough for detection of PKU heterozygotes.2328 The increased sophisti-cation of gas chromatography, high-performance

liquid chromatography, and derivative spectros-copy29 might provide a backup methodology for measurement of phenylalanine and tyrosine on the original blood blotters from those patients whose initial phenylalanine screening results were above a specified criterion. Such an approach, if found to be useful in the neonatal population, could have the advantages of improving both the specificity and

the sensitivity of the screening process as well as reducing the need for repeat specimens.

We

urge that professionals in this area develop innovative strategies to improve cost and diagnostic effectiveness of PKU screening.

ACKNOWLEDGMENTS

This work was supported, in part, by grants from the

Bureau of Community Health Services (MCT000252),

and from National Institute of Child Health and Human

Development (2P30ND04024), and General Clinical Re-search Centers Program of the Division of Research

Resources (RR69), National Institutes of Health.

The authors thank those who contributed data and

other respondents who supplied helpful comments and information.

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disorders: Desirable characteristics, experience and issues, in Kaback MM (ed): Genetic Issues in Pediatric and Obstetric Practice. Chicago, Yearbook Medical Publishers, Inc, 1981, pp 455-470

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PEUTZ-JEGHERS

SYNDROME

IN CHILDREN

In 1921, Peutz described familial gastrointestinal polyposis with

mucocuta-neous pigmentation. In 1949, Jeghers, McKusick, and Katz described the syndrome in detail and made it generally known by publishing their report in a

widely readjournal. J. A. Tovar et al (J Pediatr Surg 1983;18:1-6) have reported two new cases in sisters, and reviewed the literature on pediatric cases for the first time since 1961, when Wenzl et al reported on 54 cases seen under 17 years of age. The present authors found case reports on 68 more patients with the syndrome since then. Five were under 12 months of age at diagnosis. Mucocu-taneous pigmentation is rare before 2 years of age. Four children without these lesions were under 2 years of age when diagnosis was made on the basis of rectal

prolapse and/or the extrusion of polyps. Polyps occurred especially in the

jejunum (69% of all cases), and to a substantial but lesser extent in the stomach and rectum. Five children died of cancer: one gastric and one jejunal

adenocar-cinoma at 11 and 13 years of age, and two ovarian and one testicular neoplasm

at 4, 6, and 15 years. All but 16 of the 70 children had had surgery: 9 of them twice, 2 thrice, and 1 four times. Some of the polyps in the stomach, duodenum,

and colon were adenomatous and apparently more prone to malignant

transfor-mation than are the polyps of the jejunum and ileum, which are hamartomatous, according to the authors.

R. W. Miller

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1983;72;390

Pediatrics

Berman

Edward R. B. McCabe, Linda McCabe, Gayle A. Mosher, Richard J. Allen and Julian L.

Newborn Screening for Phenylketonuria: Predictive Validity as a Function of Age

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