Alena G. Thiele, Dipl Troph,a​ Ruth Gausche,b​ Cornelia Lindenberg,​a Christoph Beger, MS,b​ Maria Arelin, MD,Growtha​ Carmen Rohde, PhD, and​a Ulrike Mütze, Final MD,​a Johannes HeightF. Weigel, MD,a​ Klaus Mohnike,Among MD,c​ Christoph d e a a,b​ a ChildrenBaerwald, MD,​ Markus Scholz, With PhD,​ Wieland Phenylketonuria Kiess, MD,​ Roland Pfäffle, MD,​ Skadi Beblo, MD

BACKGROUND AND OBJECTIVES: abstract

Growth is an important criterion to evaluate health in childhood and adolescence, especially in patients depending on special dietary treatment. Phenylketonuria (PKU) is the most common inherited disease of amino acid metabolism. Patients with PKU depend on a special phenylalanine-restricted diet, low in natural protein. The study aimed to evaluate growth, growth rate, and target height in 224 patients with METHODS: PKU. Retrospective, longitudinal analysis of standardized, yearly measurements of height, weight, and calculated growth rate (SD score [SDS]) of patients with PKU aged 0 to 18 years were conducted by using the national computerized CrescNet database. Inclusion was restricted to patients carried to term with a confirmed diagnosis of PKU or mild RESULTS: hyperphenylalaninemia determined by newborn screening and early treatment initiation. − ± P From birth to adulthood, patients withP PKU were significantlyP shorter than healthy German children (height SDS at 18 years: 0.882 0.108, < .001). They missed their target height by 3 cm by adulthood (women:P = .02) and 5 cm (men: = .01). In patients receiving casein hydrolysate during childhood, this was more pronounced compared with − − P patients receiving amino acid mixtures ( < .001). Growth rate was significantly reduced − P during their first 2 years of life and in puberty (growth rate SDS: 1.1 to 0.5 m/year, < CONCLUSIONS: .001 and 0.5; < .02). Early diagnosed, treated, and continuously monitored patients with PKU showed reduced height from birth onward. During the last 2 decades, this phenomenon attenuated, probably because of advances in PKU therapy related to protein supplements and special low-protein foods. aCenter for Pediatric Research Leipzig, Department of Women and Child Health, Hospital for Children and What’s Known on This Subject: There is Adolescents, University Hospitals, bCrescNet Growth Network, University Hospitals, dDepartment of Internal only limited knowledge on growth patterns in Medicine, University Hospitals, and eDepartment of Statistics and Epidemiology, Institute for Medical phenylketonuria (PKU). Data are heterogeneous, c Informatics, University of Leipzig, Leipzig, Germany; and Department of Pediatrics, University of Magdeburg, mostly indicating growth deficits and higher rate of Magdeburg, Germany overweight and obesity. Ms Thiele conceptualized and designed the study, performed data collection, conducted the What This Study Adds: This study is the first statistical analysis, interpreted data, and drafted the manuscript and incorporated comments by all coauthors; Dr Beblo conceptualized and designed the study, performed data collection, investigation of a large, regional cohort of patients performed statistical analysis, drafted the manuscript and incorporated comments by all with PKU who were diagnosed early, continuously co-authors, and critically reviewed and revised the manuscript; Ms Gausche administrated monitored, and showed reduced height from birth, data, supported and supervised data collection in the CrescNet database, assisted with the resulting in reduced final height. Patients on casein interpretation of data, and critically reviewed and revised the manuscript; Ms Lindenberg hydrolysate were more affected than those on amino assisted in data collection and critically reviewed and revised the manuscript; Mr Beger acid mixtures. partially performed the statistical analysis, graph-designs, and the data interpretation and critically reviewed and revised the manuscript; Dr Scholz partially performed the statistical analysis and data interpretation and critically reviewed and revised the manuscript; Dr Weigel initiated the preparing pilot study, performed data collection, performed the initial analysis, and To cite: Thiele AG, Gausche R, Lindenberg C, et al. Growth and Final Height Among Children With Phenylketonuria. Pediatrics. 2017;140(5):e20170015

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 140, number 5, November 2017:e20170015 Article Anthropometric measures are depend on a special Phe-restricted diseases (Leipzig and Magdeburg). ’ important for evaluating the somatic diet, which is low in natural protein The study was approved by the development and nutritional status and has substantial limitations on University of Leipzig s ethics of children and adolescents. Human food choice. Hence, supplementation committee (registration number 440- linear growth can be divided into of amino acids and micronutrients by 12-17122012; International Clinical partly overlapping growth phases: Phe-free amino acid6 mixtures (AAMs) Trials Registry Platform identifier fetal growth, 1infancy, childhood, is indispensable. Although well- DRKS00004942). and puberty. Dependent on established, the dietary treatment According to initial Phe the respective phase, growth is represents a semisynthetic diet ’ concentrations, Phe tolerance during influenced by varying genetic with potentially adverse effects childhood, and– genotype, patients factors and the endocrine system, as on patients development and 1 were classified as suffering from PKU well as nutrition. General growth growth. Insufficient micronutrient 19 21 or MHPA. ‍ ‍ retardation may be caused by 2 intake, micronutrient deficiencies, chronic diseases and malnutrition. osteopenia, and osteoporosis were Inclusion was restricted to patients Therefore, patients with specific detected, even in patients– with with a diagnosis of PKU or MHPA confirmed by newborn screening and nutrition requirements, markedly PKU who were diagnosed7 13 early and different from normal nutrition, continuously treated. ‍ ‍ – Several the initiation of dietary treatment (a protein- and/or Phe-restricted represent a high-risk group for studies have revealed10, growth14​ 18 and growth disturbances. This is weight impairments. ‍ ‍ Available diet and nutrient supplementation by Phe-free protein substitute) especially true in inherited metabolic data, however, are heterogeneous ’ diseases requiring a strict dietary because of different study designs, during the neonatal period. Patients treatment. There are limited data patient cohorts, and treatment born before term (ie, at <36 weeks about physical development in guidelines. With respect to height and gestation), receiving sapropterin as these patients, primarily because weight development, anthropogenic an additional or exclusive treatment, of the often low incidence of these and cultural influences must also with tetrahydrobiopterin deficiency diseases. Phenylketonuria (PKU; be considered. So far, there are no or additional chronic diseases, long- Online Mendelian Inheritance in conclusive data on longitudinal lasting concomitant medication for Man database identifier 261600) growth, growth rate, or target height other reasons than the treatment is the most common inherited in PKU. of PKU, and implementation of ∼ disease of amino acid metabolism, other diets were excluded from the The aim of this study was to conduct with an incidence of 1 in every analysis. Analyses were performed 3 an evaluation of growth, including 8000 across Europe. PKU was the separately for patients with PKU and the height and weight development µ first specifically treatable inherited those with MHPA (dried blood Phe 4 as well as growth rate, of a large, metabolic disease. It was also the concentrations <600 mol/L not homogeneous group of patients with first metabolic disorder for which Aundergoingnthropometric any dietaryData therapy). PKU. Data were analyzed by using routine newborn screening was 5 a computerized database, CrescNet, developed and introduced. Thus, a network for the continuous long- PKU became a research model for Anthropometric data (height, weight, term monitoring of the growth and therapeutic strategies and long-term and BMI) were obtained from the weight development of German outcomes in inherited metabolic national computerized database, children. We hypothesized that a PKU 22 diseases. PKU is caused by mutations CrescNet. This Internet-based diet may influence growth rates and ’ in the gene encoding phenylalanine network was established in 1998 at the adult heights of patients with (Phe) hydroxylase (ENZYME the University Children s Hospital PKU. database identifier EC 1.14.16.1), in Leipzig for the early23 detection of leading to deficient enzyme activity Methods growth disturbance ; it is being used and high Phe concentrations in blood by several hundred pediatricians and tissues. Untreated patients across Germany for entering height suffer from irreversible psychomotor We performed a retrospective, and weight at preventive medical retardation. Newborn screening longitudinal analysis of standardized, checkups from birth through and prompt initiation of dietary yearly measurements of the weight adolescence. The database currently ∼ treatment nowadays allow for and height as well as calculated contains anthropometric data from normal neurocognitive development. growth rates of patients with PKU 730000 children and adolescents. According to their residual Phe and mild hyperphenylalaninemia The height and weight of patients hydroxylase activity and individual (MHPA) from 2 German pediatric with PKU were measured at each Phe tolerance, patients with PKU centers for inherited metabolic clinic visit and entered in the Downloaded from www.aappublications.org/news by guest on October 2, 2021 2 Thiele et al CrescNet database. All available patients with PKU were divided with PKU (82% of total) and 41 with data points were included in the into 2 diet groups: (A) patients born MHPA (18% of total). analysis. Because of the variances in before 1980 who consumed a casein Patients with PKU born before individual patient ages at the time of hydrolysate (Berlophen) during 1990 received a casein hydrolysate data analysis and in the individual childhood (in at least the first 10 supplement for several years. patient frequency of follow-up years of life) and (B) patients born Since 1990, all patients with PKU appointments, the amount of data after 1989 who exclusively received had obtained AAMs from different differs among patients and the an AAM. Statistical Analysis manufacturers. In 27 patients with different investigated time points. PKU, born between 1971 and 1981, For the analysis of height, weight, and ± the diet was interrupted during BMI, the measurement point nearest Statistical analyses were performed childhood or adolescence, according to the birthday ( 6 months) was – by using IBM SPSS Statistics for to the former guidelines (at a median chosen. The individual target height ’ Windows 20 (IBM Corporation). age of 7.01 years [range: 6.0 15.0]; was calculated by using the parental 24 The anthropometric data, given as ref 28). Of these, 19 restarted therapy height when parents heights – SDSs, were averaged and compared before adulthood (at a median age were available. BMI was calculated t ’ with reference values by using of 14.0 years [range: 12.07 18.0]), by the ratio of weight in kilograms t 1-sample tests. Differences between following their treating pediatricians to height in meters squared. groups were calculated by using Aadvice.nalysis of Height, Weight, BMI, Growth velocity was defined as the ’ tests for independent samples. The and Growth Velocity According to difference between 2 body height comparison of patients final height Phenotype measurements divided by the time t to their target height was performed interval. This analysis only involved ± by using paired tests. growth rates from annual intervals ‍Figure 1 and Tables 1 and 2 show (365 120 days). We performed additional time series analysis of the same anthropometric the height development and growth To compare the PKU data to that of variables by linear mixed model, rate of patients with PKU and MHPA the healthy population, SD scores using package lme4 of the statistical during the first 18 years of life. (SDSs) of height, weight, BMI, and software suite R (R Foundation growth rate were calculated by From birth throughout childhood for Statistical Computing, Vienna, using the data of healthy German and adolescence, patients with PKU 25,26​ Austria; www.​r-​project.​org). childrenLaboratory. ‍ Data were significantly shorter than To compare PKU and MHPA, or healthy German children; height was ’ diet groups, we treated patient expressed as the mean height SDS identification as a random effect (Fig 1A) and confirmed by linear To evaluate patients lifetime by assuming a random intercept mixed model analysis (Table 3). metabolic control, their individual model, and we treated age, sex, The final height SDS at the age of 18 average Phe concentration per − ± and diagnosis or age, sex, diet, and years was significantly lower than year from birth onward to the P the interaction of age and diet as the reference height ( 0.882 age of 18 years was calculated ∼ fixed effects. Comparisons of PKU, 0.108, < .001), corresponding retrospectively from medical MHPA, and diet groups with the to a height deficit of 5 to 6 cm records. Phe concentrations were 29,30​ normal population were performed at full growth. ‍ The mean final measured in dried blood by liquid ± by testing the fixed intercept of a height of patients with PKU was chromatography/tandem mass – 27 covariable-free random intercept 163.3 5.9 cm (median: 163.4 cm, Proteinspectrometry Intake or by fluorometry. P ± model. Significance was accepted for range: 152.1 175.1 cm) in women – < .05. and 173.8 8.9 cm (median 173.2 Results cm, range 158.0 189.7) in men. In Phe tolerance, total protein intake, comparison, healthy German women and protein intake from casein Patients reached a mean height of 167 cm, hydrolysate or an AAM were and healthy German men31 reached a gathered from medical records. mean height of 180 cm. Individual Annually, the mean intake of A total of 233 white patients with target heights could be calculated for synthetic and natural protein was PKU or MHPA, born between 1969 23 women and 15 men; this analysis calculated (intake in grams per and 2014, could be identified. Of revealed a final height significantly ± 24 kilogram of body weight per day). these, 224 patients (105 female lower than their target height ± To investigate the influence of the patients, 119 male patients) could (mean SD of real final height versus type of protein supplement used, be included in the final analysis, 183 target height: women: 163.4 6.0 vs Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 140, number 5, November 2017 3 FIGURE 1 Longitudinal growth (height SDS) and growth rate (SDS) in patients with PKU and MHPA, compared with German reference data.26 A, PKU: height SDS. B, PKU: growth rate SDS. C, MHPA: height SDS. D, MHPA: growth rate SDS. Both groups showed reduced birth lengths and growth rates throughout childhood. No catch-up growth could be revealed. * Significant differences with reference data are present.25,‍26​

± P ± ± P 166.4 4.1 cm, = .02; men: 174.8 than the healthy population (Table 3). Supplemental Fig 4A). The BMI 8.1 vs 179.4 4.9 cm, = .01). To The initial growth rate of patients SDS of patients with PKU was not ’ analyze a potential influence of was significantly lower than the significantly different from that of maternal genotype on birth length, reference population s (Fig 1B). their healthy peers (Table 3). we compared birth length in patients From the age of 2 until 12 years, the Patients with MHPA also exhibited a with PKU from 11 mothers who growth rate normalized and reached significantly lower birth length SDS were heterozygotes for R408W, a values comparable to reference data. 20 and height SDS during the first 6 severe mutation,​ and the remaining Afterward, it decelerated again, P years, as well as a significantly lower cohort. No significant difference yielding a final negative SDS. The – initial growth rate, compared with could be detected ( = .53). growth rates of ages 16, 17, and 18 the reference (Fig 1 C D, Table 2). could not be statistically analyzed However, growth rates improved To better illustrate the data on height because no reference values were 25 after the first year of life and were development, cumulated height available. percentiles of the investigated cohort not significantly different from those are represented in comparison with The weight SDS of patients with of the reference population. Because the reference (ref 26; Fig 2 A and B). PKU was lower than that of healthy of the small number of patients German children (Table 3), reaching with MHPA, an evaluation of final In general, patients with PKU showed significance from the age of 2 years height is not yet possible. Regarding a significantly lower growth rate onward (Supplemental Table 9, weight and BMI, patients with MHPA Downloaded from www.aappublications.org/news by guest on October 2, 2021 4 Thiele et al

Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF 3.46 (0.46) (1.10) − 0.62 − 0.79 − 4.88 to − 0.82 − 1.14 to to 1.56 (0.24) (1.05) − 0.42 − 0.59 − 2.74 − 0.65 − 0.88 to to 0.28 ——— ——— ——— ——— ——— ——— ——— ——— (0.92) (0.35) − 0.39 − 0.6 − 0.58 − 1.47 − 0.77 to to 0.74 (0.88) (0.59) (0.82) (1.97) − 0.38 − 0.69 − 0.12 0.02 − 0.56 − 0.72 − 1.99 − 0.55 − 1.0 to − 0.75 to − 3.28 to ​ 52 to 0.65 (0.87) (0.40) (0.71) (1.41) − 0.36 − 1.03 − 0.18 0.23 − 0.53 − 0.19 − 1.91 − 0, − 0.7 to − 2.8 to − 0.85 to to to to 0.70 1.68 0.15 (0.94) (0.72) (1.34) (1.48) − 0.26 0.02 − 0.46 − 0.05 − 0.81 − 1.64 − 0.19 − 0.52 − 0.65 to to to 0.46 6.87 0.25 (0.95) (0.87) (2.98) (1.19) − 0.26 2.14 − 0.44 − 0.28 − 0.01 − 2.59 − 0.26 − 1.0 to − 0.62 to to to to 0.29 2.54 0.23 (0.91) (1.02) (1.54) (1.17) − 0.22 0.93 − 0.40 − 0.49 − 1.28 − 0.02 − 0.69 − 0.26 − 0.58 to to to to 0.07 3.46 0.58 (0.88) (1.07) (2.19) (1.46) − 0.39 1.16 0.28 − 0.55 − 0.83 − 1.72 − 1.14 − 0.01 − 0.71 to to to 0.23 0.67 0.58 (0.92) (1.07) (1.36) (1.41) − 0.51 0.32 0.2 to − 0.68 − 0.44 − 1.11 − 0.76 − 2.18 − 0.84 to to to 0.16 1.52 0.54 (0.98) (1.15) (1.29) − 0.36 0.28 − 0.55 − 0.51 − 1.17 − 0.32 0.02 to − 0.71 to 0.6 (1.29) to to to 0.3 0.07 0.75 (0.98) (1.11) (1.74) (1.84) − 0.38 − 0.5 − 0.55 − 1.07 − 0.31 − 0.07 − 1.36 − 0.44 − 0.72 to to to 0.95 0.20 (0.97) (0.93) (1.58) (1.48) − 0.48 − 0.07 0.14 − 0.5 − 0.65 − 0.08 − 0.68 − 0.36 − 0.82 to − 0.92 to to to 0.76 0.49 (0.91) (0.96) (1.73) (1.66) − 0.44 − 0.22 0.19 − 0.6 − 0.59 − 0.02 − 0.81 − 0.11 − 0.75 to − 0.98 to to to 0.53 0.02 (0.92) (0.86) (1.05) (1.40) − 0.37 − 0.23 0.02 − 0.54 − 0.57 − 0.41 − 0.49 − 0.49 − 0.68 to − 0.91 to to to 1.3 0.23 (1.0) (0.97) (0.94) (1.40) − 0.39 − 0.11 − 0.55 − 0.27 − 0.21 − 0.13 − 0.66 − 0.38 − 0.71 to − 0.64 to to to 0.73 (0.9) − 0.4 (0.79) (1.50) (1.34) − 0.15 − 0.25 0.08 − 0.55 − 0.44 − 0.70 − 0.51 − 0.57 − 0.74 to − 0.78 to to -0.25 27 23 22 19 21 17 13 10 6 6 6 4 5 5 4 (0.98) (0.73) (1.26) (1.17) − 0.21 − 0.17 − 0.92 − 0.41 − 0.44 − 0.75 − 1.16 − 1.24 − 1.4 to − 0.62 to − 0.70 to to 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 − 0.3 30 31 29 26 27 27 21 17 14 12 8 9 8 6 6 5 3 2 2 NA 95 100 117 120 118 108 99 98 101 96 91 87 77 71 76 NA — NA .005 .81 .33 .94 .95 .72 .54 .18 .23 .25 .20 .25 .98 .004 .02 NA NA <.001 <.001 .33 .07 .21 .57 .71 .03 .04 .06 .96 .96 .28 .003 .02 NA NA (1.07) (0.80) − 0.20 127 98 139 144 136 136 130 130 120 121 120 97 109 93 100 86 95 83 73 .002 .002 .005 .16 .002 .003 .02 .08 .12 .18 .07 .18 .40 .87 .23 .97 .1 .18 .28 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 − 0.49 − 0.49 − 0.68 − 0.77 to  Longitudinal Growth (Height SDS) and Rate (SDS) in Patients With PKU Compared German Reference Data  Longitudinal Growth (Height SDS) and Rate (SDS) in Patients With MHPA Compared German Reference Data

1 2 E E L L mean (SD) mean (SD) mean (SD) mean (SD) Age, y Age, y N N Height SDS, P Height SDS, P 95% CI N 95% CI N Growth rate SDS, P Growth rate SDS, P 95% CI 95% CI Mschr Kinderheilk . al. Perzentile f ü r den body mass index das Kindes und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Mschr et F, M, Geller K, Wabitsch from Kromeyer-Hauschild reference data are taken German 2001;149(8):807 – 818. CI, confidence interval; — , not applicable. Mschr Kinderheilk . al. Perzentile f ü r den body mass index das Kindes und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Mschr et F, M, Geller K, Wabitsch from Kromeyer-Hauschild reference data are taken German 2001;149(8):807 – 818. Age: For each patient, the measurement point nearest to birthday ( ± 6 mo) was chosen. 0 = at birth. CI, confidence interval; — , not applicable. TAB TAB

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Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF á developed similarly to their healthy group, which were apparently have reported far smaller cohorts í peers (Supplemental Table 10, modified by the kind of protein or cross-sectional18 data. Ald miz- Supplemental Fig 4B). supplement. There is no evidence for Echevarr a et al report on a similar either severe malnourishment or a study design; however, the cohort Patients with MHPA showed higher percentage of overweight or was heterogeneous, deriving from significantly higher weight SDS and obesity in patients with PKU. 19 different treatment centers BMI SDS than patients with PKU throughout Spain, the Baleares, and H(Tableeight 4).and Weight of Patients The study, through its longitudinal the Canary Islands, and there was With PKU According to Protein design and the large regional cohort, some discrepancy between height Supplementation During Childhood was ideal for analyzing growth measurements and longitudinal development. In this regard, the growth rates. computerized CrescNet database

The lower height SDS was observed has proved to be a valuable tool23,33​ In a subgroup of patients, we could in all patients, irrespective of diet for population-based studies. ‍ confirm our data by revealing a group; it was more pronounced The data were compared by using26 significantly shorter final height in patients receiving a casein the Kromeyer-Hauschild et al compared with their expected hydrolysate supplement during reference values for height, weight, target height according to the childhood and adolescence (group A) and BMI, which continue to be the formula24 by Hermanussen and compared with patients receiving current common reference values Cole. A direct comparison with an AAM (group B; Fig 3, Tables 5, in Germany. One might put forward healthy siblings was not possible 6, 7 and 8). The weight SDS was the criticism that these reference because of the limited availability significantly lower in group A than values were obsolete and imprecise of their growth data. However, the in group B and in healthy peers. In because they referred to pooled parents showed no sign of reduced addition, group B showed a higher data from 17 studies with different final height, which underlines weight SDS and BMI SDS than healthy methods of data collection performed the idea that the growth deficit ’ Proteinchildren I ntake(Fig 3, andTables Metabolic 5 through Control 8). between 1989 and 1999. However, in patients with PKU is disease- ± of Continuously Treated Patients the differences with recent reference and/or therapy-related (patients ± ’ With PKU data for height and weight, collected fathers: 179.4 7.9 cm, healthy ± by standardized measurement34 German men: 174.8 8.1, patients ± methods, were only marginal. mothers: 166.0 6.2 cm, healthy Total protein intake of continuously Human growth is divided into 4 German women: 166.4 4.1; treated patients with PKU during growth phases corresponding to ref 31). None of the previously their first 18 years of life was fetal growth, infancy, childhood, and published articles revealed such appropriate and greater than puberty, which are variously related homogenous results. the recommendation for the to genetic, endocrine, and nutritional 1 Intrauterine growth retardation healthy population (Supplemental influences. At birth, patients with is 1 symptom of the maternal PKU Table 11). Mean dried blood Phe PKU and MHPA already showed syndrome resulting from high concentrations remained in the a reduced body length compared maternal Phe concentrations during age-specific recommended range with the national reference data, 37 pregnancy. Even heterozygotes during the evaluation period (ref 32; suggesting intrauterine growth for PKU showed a reduced ability Supplemental Table 12). retardation. Importantly, none to metabolize Phe compared with Discussion of the patients was a premature mothers without any mutation infant. Our data confirm the findings 38,39​ in the PAH gene. ‍ In this from previous15,35,​ 36​ studies in smaller Anthropometric parameters are cohorts. ‍ ‍ In the current regard, heterozygotes with more important in evaluating the state of study, patients with PKU remained severe mutations display a more health in childhood and adolescence, shorter throughout childhood and pronounced decrease of Phe especially in patients who depend adolescence up to the age of 18 years, hydroxylation and, therefore, lower on special dietary treatment. In this compared with their healthy peers, plasma tyrosine concentrations longitudinal study, we investigated confirming the findings from earlier compared with heterozygotes38,40​ with the growth development of patients studies detecting growth retardation milder mutations. These effects with PKU and MHPA during their first in patients with– PKU who were presumably influence intrauterine

18 years of life. Patients with PKU diagnosed early10,14​ 18and continuously growth, depending on the maternal showed reduced height and growth monitored. ‍ ‍ However, the genotype and the related maternal35 rates, compared with the reference authors of most of these studies Phe hydroxylation capacity. In Downloaded from www.aappublications.org/news by guest on October 2, 2021 6 Thiele et al

Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF TABLE 3 Comparison of Patients With PKU and MHPA to the Healthy Population by Linear Mixed Model Revealed Significant Differences in Height PKU MHPA β (SE) P β (SE) P Height SDS −0.52 (0.06) <.001* −0.34 (0.1) <.001* Weight SDS −0.27 (0.07) <.001* −0.09 (0.1) .37 BMI SDS 0.04 (0.06) .53 0.20 (0.1) <.001* Growth rate SDS −0.12 (0.04) <.001* −0.11 (0.12) .37 German reference data are taken from Kromeyer-Hauschild K, Wabitsch M, Geller F, et al. Perzentile für den body mass index für das Kindes und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Mschr Kinderheilk. 2001;149(8):807–818. Negative values indicate smaller values compared with healthy children. * Indicates a significant P value. This significance was more pronounced in patients with PKU.

TABLE 4 Analysis of the Entire Cohort According to Age, Sex, and Diagnosis (PKU Versus MHPA) by Linear Mixed Model Age Sexa Diagnosisb β (SE) P β (SE) P β (SE) P Height SDS 0.01 (0.002) <.001* −0.14 (0.08) <.001* −0.01 (0.11) .92 Weight SDS 0.001 (0.003) .68 −0.34 (0.09) <.001* −0.26 (0.12) <.001* BMI SDS −0.01 (0.003) <.001* −0.34 (0.09) <.001* −0.35 (0.12) <.001* Growth rate SDS 0.03 (0.01) <.001* 0.09 (0.07) .16 −0.08 (0.12) .49 a Negative values indicate smaller values in girls. b Negative values indicate smaller values in patients with PKU. * Indicates a significant P value.

this cohort, an influence of maternal PKU from mothers heterozygous for The importance of nutrition in regard genotype on intrauterine growth R408W and the remaining cohort. to physical development could be could neither be confirmed nor impressively observed during the ’ disproved because of the limited data Final height depends on several 30 19th and 20th centuries, when on maternal genotypes. However, an variables; 1 of them is birth length,​ the population s height generally “ ” analysis of a small subgroup revealed whereas postnatal growth is increased, a phenomenon referred to

no significant differences regarding influenced by genetic and endocrine2 as secular trend. This was caused birth length between patients with factors as well as nutrient supply. by improved health care and sanitary

FIGURE 2 Cumulated growth data of all included patients and specific percentiles for height derived from these data in female patients (A) and male patients with PKU (B) compared with reference percentiles for the healthy German population.26

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Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF FIGURE 3 Comparison of height and weight (expressed as SDS) of patients with PKU according to their birth cohort and, therefore, therapy regimen and protein supplement during childhood and adolescence. A, Group A: height SDS. B, Group A: weight SDS. C. Group B: height SDS. D. Group B: weight SDS. Group A was born before 1980 and received a casein hydrolysate supplement. Group B was born after 1989 and received an AAM. Differences with the healthy population were more pronounced in patients receiving casein hydrolysate during childhood. Significant differences between group A and B regarding height SDS were found by t tests for independent samples at age 2 (P = 0.02); age 3 (P = 0.006); age 5 (P = 0.01); ages 6 and 10 (P = 0.001); ages 7 and 13 (P = 0.003); ages 8, 9, and 12 (P < 0.001); age 11 (P = 0.002); and age 14 (P = 0.01). Significant differences between group A and B regarding weight SDS were found by t tests for independent samples at ages 2, 5, and 14 (P = 0.002); age 3 (P = 0.008); age 4 (P =0.02); ages 6 and 8–13 (P < 0.001); age 7 (P = 0.001); age 15 (P = 0.04); age 16 (P = 0.04); and age 17 (P = 0.01).* Significant differences with reference data are present.26 + Significant differences between group A and group B, with P values <.05. # Significant differences between group A and B, with P values <.01.

conditions, as well as by better food exact amino acid composition of exhibited better growth. A former

availability and, 41therefore, improved Berlophen was unknown, varied cross-sectional study had already nutrient supply. between batches, and was not revealed more stunted growth in

standardized, and it did not contain older patients with PKU,44 compared All patients of our cohort were born any additional micronutrients. with later birth cohorts. The

in the eastern part of Germany Additional supplements42,43​ were nutrient supplementation by protein (formerly the German Democratic therefore required. ‍ A suboptimal supplements is indispensable for Republic). The products used for nutrient supply for these patients patients with PKU because their protein substitution changed with during childhood may thus have natural food choices are limited. the German reunification: although had a detrimental influence on Approximately 50% to 90% of the a casein hydrolysate supplement their growth. This is supported recommended daily protein and

(Berlophen) was used until 1989, by the observation that younger micronutrient requirements are45,46​ AAMs from several manufacturers patients with PKU, born after 1989 met by nutrient supplements. became available afterward. The and exclusively receiving an AAM, Over the last decades, there have Downloaded from www.aappublications.org/news by guest on October 2, 2021 8 Thiele et al

Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF 0.74 0.11 (1.10) (0.92) − 0.05 (1.68) (1.28) − 0.28 − 0.03 − 0.63 − 0.73 − 0.91 − 0.79 to − 1.22 to − 1.57 to − 1.55 to to 1.02 0.08 to (1.18) (0.89) 0.01 − 0.15 (1.43) − 0.36 (1.21) − 0.08 − 0.80 to − 0.71 − 1.41 − 0.68 − 1.13 to to 0.60 (0.84) − 0.02 (1.05) − 0.34 (0.86) − 0.08 − 0.26 − 0.36 − 0.71 to − 0.53 − 0.64 − 0.99 to − 1.01 to to 0.57 (0.78) − 0.05 (1.15) (0.84) − 0.01 − 0.23 − 0.31 − 0.37 − 0.62 − 0.68 − 0.69 to − 1.23 to − 1.13 to to 0.51 0.03 (0.66) (0.92) (0.77) − 0.38 − 0.17 − 0.21 − 0.282 − 0.68 − 0.71 − 0.41 to − 1.07 to − 1.04 to to 0.54 0.21 (0.65) (0.70) (0.83) − 0.54 − 0.43 − 0.07 − 0.01 − 1.03 − 0.99 − 0.22 to − 1.50 to − 1.55 to to 0.44 0.02 (0.71) (0.74) (0.82) − 0.50 − 0.49 − 0.12 − 0.003 − 0.85 − 0.88 − 0.22 to − 1.21 to − 1.28 to to 0.36 0.15 (0.74) (0.53) (0.68) − 0.85 − 0.42 − 0.19 − 0.06 − 1.29 − 0.99 − 0.28 to − 1.74 to 0.08 (0.93)0.16 (0.91)0.24 (0.91)0.17 (0.95)0.13 (1.06)0.13 (1.15) 0.435 − 1.55 to 0.21 (0.97) (0.73) − 0.03 (0.65) (0.73) − 0.59 − 0.52 − 0.05 − 0.22 − 0.3 to − 0.91 − 0.87 − 0.41 to − 1.22 to − 1.22 to th Cohort and, Therefore, Therapy Regimen and Protein Supplement During Childhood th Cohort and, Therefore, Therapy Regimen and Protein Supplement During Childhood to 0.15 (1.0) (0.75) − 0.11 − 0.3 (0.87) (0.89) − 0.63 − 0.72 − 0.37 − 0.11 − 1.07 − 1.16 − 0.50 to − 1.50 to − 1.61 to to 0.22 0.07 (1.0) (0.79) (0.72) (0.92) − 0.67 − 0.62 − 0.31 − 0.05 − 0.14 − 1.03 − 1.05 − 0.34 to − 1.38 to − 1.49 to to 0.21 0.01 (0.99) (0.81) (0.87) (1.06) − 0.47 − 0.52 − 0.28 − 0.03 − 0.19 − 0.88 − 1.01 − 0.38 to − 1.29 to − 1.51 to to 0.13 (1.04) (0.82) − 0.11 (0.60) (1.02) − 0.67 − 0.61 − 0.38 − 0.12 − 0.31 − 0.96 − 1.09 − 0.51 to − 1.24 to − 1.56 to to 0.09 (0.98) (0.82) − 0.11 (0.62) (0.85) − 0.28 − 0.43 − 0.3 − 0.37 − 0.14 − 0.57 − 0.82 − 0.51 to − 0.85 to − 1.21 to to 0.17 (0.99) (0.83) − 0.11 (0.67) − 0.19 (0.74) − 0.29 − 0.3 − 0.29 − 0.06 − 0.50 − 0.63 − 0.49 to − 0.80 to − 0.97 to to 0.22 (1.02) (0.85) − 0.08 (0.91) − 0.25 (0.95) − 0.51 − 0.24 − 0.01 − 0.27 − 0.63 − 0.90 − 0.46 to − 1.00 to − 1.29 to to 0.12 (0.96) (0.83) − 0.19 (0.91) − 0.22 (0.82) − 0.49 − 0.29 − 0.09 − 0.36 − 0.63 − 0.86 − 0.54 to − 1.05 to − 1.23 to to to 0.10 0.98 1.19 (0.83) (0.52) − 0.14 (1.41) (1.76) − 0.25 − 0.07 − 0.33 − 1.16 − 0.32 − 0.66 − 0.52 to − 2.51 to to 0.17 77 86 86 78 74 72 68 68 60 60 57 47 44 37 32 25 25 18 12 .56 .41 .41 .96 .63 .24 .33 .77 .73 .42 .72 .55 .25 .12 .31 .54 .58 .14 .94 25 6 21 25 21 21 20 20 19 18 19 8 19 11 23 16 23 18 18 (1.07) − 0.25 .34 <.001 <.001 .001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 .004 <.001 .003 <.001 .006 .002 .03 .008 (1.15) (1.32) − 0.12 (1.037) .050 .57 .005 .002 .003 <.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001 .001 .002 .05 .02 .05 .08 − 0.003 <.001 .001 <.001 .006 .003 .003 .003 .06 .18 .003 .03 .57 .98 .96 .08 .03 .04 .10 .04 − 0.31 − 0.07 − 0.48 − 0.48 − 0.66 − 0.72 to − 0.95 to − 1.20 to Adolescence, Group B: Born After 1989, Receiving an AAM  Comparison of Height and Weight (Expressed as SDS) Patients With PKU According to Their Bir Adolescence, Group A: Born Before 1980, Receiving a Casein Hydrolysate Supplement  Comparison of Height and Weight (Expressed as SDS) Patients With PKU According to Their Bir

6 5 E E L L mean (SD) mean (SD) mean (SD) mean (SD) 95% CI P P Weight SDS, 95% CI 95% CI Height SDS, P P 95% CI Weight SDS, n Age, y 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Age, yn Height- SDS, 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 TAB TAB Age: For each patient, the measurement point nearest to birthday ( ± 6 mo) was chosen. 0 = at birth. Differences with the healthy population were more pronounced in patients receiving casein hydrolysate during childhood. CI, confidence interval. Age: For each patient, the measurement point nearest to birthday ( ± 6 mo) was chosen. 0 = at birth. Differences with the healthy population were more pronounced in patients receiving casein hydrolysate during childhood. CI, confidence interval.

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Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF TABLE 7 Comparison of Patients With PKU and the Healthy Population According to Their Birth Cohort and, Therefore, Therapy Regimen and Protein Supplement During Childhood and Adolescence by Linear Mixed Model Group A (Berlophen) Group B (AAM) β (SE) P β (SE) P Height SDS −0.9 (0.15) <.001* −0.29 (0.07) <.001* Weight SDS −0.71 (0.14) <.001* 0.02 (0.08) .78 BMI SDS −0.3 (0.16) <.001 0.26 (0.08) <.001* Growth rate SDS −0.11 (0.12) .33 −0.08 (0.05) .11 Negative values indicate smaller values compared with healthy children. * Indicates a significant P value.

TABLE 8 Comparison of Patients With PKU According to Age, Sex and Diet (Group A With Berlophen Versus Group B With an AAM During Childhood and Adolescence) by Linear Mixed Model Age Sexa Dietb Age × Dietc β (SE) P β (SE) P β (SE) P β (SE) P Height SDS 0.02 (0.004) <.001* −0.15 (0.12) 0.23 −0.5 (0.16) <.001* −0.01 (0.01) <.001* Weight SDS 0.02 (0.04) <.001* −0.16 (0.14) 0.24 −0.49 (0.18) <.001* −0.03 (0.01) <.001* BMI SDS −0.0005 (0.005) .93 −0.16 (0.14) 0.25 −0.43 (0.18) <.001* −0.01 (0.01) <.001* Growth rate SDS 0.02 (0.01) .11 −0.01 (0.1) 0.89 −0.39 (0.25) .11 0.05 (0.03) .10 Patients receiving Berlophen during childhood had significantly deteriorated growth compared with patients with PKU on a modern AAM. a Negative values indicate smaller values in girls. b Negative values indicate smaller values for the Berlophen diet group (group A). c Negative values indicate smaller age increase values for the Berlophen diet group (group A). * Indicates a significant P value.

Acknowledgments

been continuous advancements in Interestingly, our younger patients, these supplements, improving their born after 1989, showed an increase We thank all participating patients composition toward becoming47 an of weight up to the average values for providing additional data, ’ adequate nutrient supply. of the reference population. Both especially for adding data on their improvements of the dietary In patients with PKU born before parents height; Beate Peinel, who treatment and the secular trend may 1980, dietary therapy was 42 performed some of the regular explain this finding. interrupted during childhood, 28 measurements of weight and according to the former guidelines. Conclusions height of the patients; Mandy Vogel Despite the chance of increased (former staff member of CrescNet) intake of natural protein, this did not for valuable discussions and help improve growth rate. Apparently, with the statistical analysis; and Patients with PKU who are diagnosed ü these children did not change their Drs Markus Ott, Oec. Troph., Andrea early, treated, and continuously basic eating habits sufficiently to S lzle, Troph., and Ms Janina Lahl, monitored show reduced height achieve catch-up growth. Eating ∼ Dipl. Troph. from Nutricia GmbH, and growth from birth onward, habits are established during early Nutricia Metabolics, for providing leaving them 6 cm shorter than childhood, and a fundamental us with information about their healthy peers. During the change in eating patterns is almost composition of former amino acid last 2 decades, this phenomenon impossible beyond the first years of supplements. 48,49​ attenuated, probably because of life. ‍ the use of modern AAMs and the Abbreviations There was no evidence for a higher broad palette of special low-protein rate of overweight or obesity in the foods. However, patients with PKU entire cohort, which is in contrast remain shorter, suggesting that this – AAM: amino acid mixture to the findings of recent studies phenomenon cannot be explained 50 52 MHPA: mild from various countries. ‍‍ These by nutrition alone. Extended hyperphenylalaninemia heterogeneous results might be longitudinal studies should include Phe: phenylalanine explained by different culturally other potential influencing factors: PKU: phenylketonuria conditioned eating habits as 1 for example, tyrosine supply and SDS: SD score important factor influencing weight. genotypes. Downloaded from www.aappublications.org/news by guest on October 2, 2021 10 Thiele et al

Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF critically reviewed and revised the manuscript; Drs Mohnike and Baerwald supported data collection and interpretation and critically reviewed and revised the manuscript; Dr Pfäffle was responsible for the scientific direction of CrescNet, assisted in the interpretation of data, and critically revised the manuscript; Dr Kiess assisted in data interpretation and critically reviewed and revised the manuscript; Drs Arelin, Mütze, and Rohde performed data collection and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Dr Mütze’s current affiliation is Division of Neuropediatrics and Inherited Metabolic Diseases, Department of General Pediatrics, Heidelberg University Children’s Hospital, Heidelberg, Germany. Dr Weigel’s current affiliation is Outpatient Clinic for Children and Adolescents, Endocrinology and Metabolism, Augsburg, Germany. This trial has been registered with the International Clinical Trials Registry Platform (identifier DRKS00004942). DOI: https://​doi.​org/​10.​1542/​peds.​2017-​0015 Accepted for publication Aug 11, 2017 Address correspondence to Skadi Beblo, MD, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig (CPL), Department of Women and Child Health, University Hospitals, University of Leipzig, Liebigstraße 20 a, D-04103 Leipzig, Germany. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by an unrestricted research grant from Nutricia Metabolics, Nutricia GmbH Germany and Merck Serono GmbH to Dr Beblo and Ms Thiele through the University of Leipzig. POTENTIAL CONFLICT OF INTEREST: This investigator-initiated study was partly supported by an unrestricted research grant from Nutricia Metabolics, Nutricia GmbH, Germany and Merck Serono GmbH to Dr Beblo and Ms Thiele through their employer the University of Leipzig; the other authors have indicated they have no potential conflicts of interest to disclose.

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Thiele et al https://doi.org/10.1542/peds.2017-0015 November 2017 Growth and Final Height Among Children With Phenylketonuria 5 140 Pediatrics 2017 ROUGH GALLEY PROOF Growth and Final Height Among Children With Phenylketonuria Alena G. Thiele, Ruth Gausche, Cornelia Lindenberg, Christoph Beger, Maria Arelin, Carmen Rohde, Ulrike Mütze, Johannes F. Weigel, Klaus Mohnike, Christoph Baerwald, Markus Scholz, Wieland Kiess, Roland Pfäffle and Skadi Beblo Pediatrics 2017;140; DOI: 10.1542/peds.2017-0015 originally published online October 31, 2017;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/140/5/e20170015 References This article cites 46 articles, 7 of which you can access for free at: http://pediatrics.aappublications.org/content/140/5/e20170015#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Endocrinology http://www.aappublications.org/cgi/collection/endocrinology_sub Metabolic Disorders http://www.aappublications.org/cgi/collection/metabolic_disorders_s ub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 2, 2021 Growth and Final Height Among Children With Phenylketonuria Alena G. Thiele, Ruth Gausche, Cornelia Lindenberg, Christoph Beger, Maria Arelin, Carmen Rohde, Ulrike Mütze, Johannes F. Weigel, Klaus Mohnike, Christoph Baerwald, Markus Scholz, Wieland Kiess, Roland Pfäffle and Skadi Beblo Pediatrics 2017;140; DOI: 10.1542/peds.2017-0015 originally published online October 31, 2017;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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