American Journal of Medical Genetics 42:61-67 (1992)
Head Circumference of Children With Down Syndrome (0-36 Months) Christina G.S. Palmer, Christine Cronk, Siegfried M.Pueschel, Krystyna E. Wisniewski, Renata Laxova, Allen C. Crocker, and Richard M. Pauli Departments of Industrial Engineering (C.G.S.P.) and Pediatrics and Medical Genetics (R.L.,R.M.P.), University of Wisconsin-Madison; Department of Anthropology, Southern Illinois University, Carbondale (C.C.); Child Development Center, Rhode Island Hospital, Providence (S.M.P.);Institute for Basic Research in Developmental Disabilities, Staten Island, New York (K.E.W.);Developmental Evaluation Center, Children’s Hospital, Boston (A.C.C.) This study provides statistically appropriate head circumference reference curves for males and females with Down syndrome (DS) from birth to 36 months of age. A total of 239 males and 182females from five study populations, yielding a combination of cross-sectional and longitudinal data, were used for the analysis. The method of least squares was used to test the fit of the growth model y = a + bx + c[log(x + l)],where x is age in months. These standardized curves should provide information of value in the medical, physical, and developmental management of children with DS.
KEY WORDS growth standards,head growth, occipital-frontalcircumference, trisomy 21 INTRODUCTION Head circumference (occipito-frontal circumference) measurement during infancy and childhood is one of several useful indices of a child’s medical, physical, and developmental status. Reference head circumference curves for males and females in the general population have been published [Meredith, 1946; Silver and Deamer, 1948;Westropp and Barber, 1956; Eichorn and Bayley, 1962; Nellhaus, 1967; Hamill et al., 1979; Ounsted et al., 1985;Roche et al., 1987;Guo et al., 19881, but there is very little information on individuals in whom such comparisons with general norms may be inappropriate [Horton et al., 19781.One such population for which specific norms have been unavailable is children with Down syndrome (DS).
Received for publication February 5, 1991; revision received April 4, 1991. Address reprint requests to Richard M. Pauli, M.D., Ph.D., University of Wisconsin-Madison, Clinical Genetics Center, 1500 Highland Avenue, Madison, WI 53705.
0 1992 Wiley-Liss, Inc.
Approximately 1 in every 800-1,000 babies is born with DS [Mikkelsen, 19771. Improved medical care has increased their life span [Baird and Sadovnick, 19881 and a change in societal values has resulted in virtually all children with DS being raised at home and integrated into the community. As for any population, children with DS are not immune to other medical complications. Therefore, specific, standardized information regarding their growth is useful. Height and weight reference curves for children with DS have recently been published [Cronk et al., 19881. While several other published studies concerning DS include head circumference measurements [Mosier et al., 1965; Thelander and Pryor, 1966; Pryor and Thelander, 1967; Pueschel, 1984; Ershow, 1986; Wisniewski et al., 1987; Sharav et al., 1988; Wisniewski, 19901, none had generated head circumference reference curves either appropriate for use by or widely available to physicians and other health care professionals following children with DS. We present standard reference curves for head circumference in males and females with DS from birth to 36 months of age. METHODS AND ANALYSIS In order to generate samples of sufficient size head circumference measurements from five different centers (coded as groups), taken between birth and 36 months of age, were utilized. Group 1consisted of children referred for evaluation to the Clinical Genetics Center a t the University of Wisconsin-Madison and the Down Syndrome Clinic a t the Waisman Center on Mental Retardation and Human Development in Madison, Wisconsin. These children were primarily Caucasian, born between 1975 and 1988, and residing in Wisconsin, Illinois, or Michigan. All measurements were taken by physician geneticists. Measurements in Group 2 were collected in the course of comprehensive evaluations in the Developmental Evaluation Center at Boston Children’s Hospital from 1967 to 1980. All measurements were taken by physical anthropologists. Group 3 was made up of children, born between 1967
62
Palmer et d.
and 1970, who were enrolled in an early intervention program at the Child Development Center at the Rhode Island Hospital. All measurements were taken in 1971 by a physical anthropologist. Group 4 were children followed at the Child Development Center a t the Rhode Island Hospital. These measurements were taken by a physician geneticist. Group 5 consisted of children who participated in a study at the Institute for Basic Research in Developmental Disabilities in New York during the period from 1975 to 1985. All the children were Caucasian. The measurements were taken by a nurse and physician. Since the data were from different areas of the country, with different measurers using different measuring devices, it was not possible t o control for either potential measurement error (resulting in outliers) or potential sampling bias. Thus, prior to an analysis of combined sample data, several steps were taken to ensure that such pooling would result in a relatively homogeneous and representative population. Similar procedures were used in Cronk et al. [1988]. First, the data from the five groups were combined and means and standard deviations were calculated at each monthly age interval from birth to 36 months of age. Observations exceeding 2 2.5 standard deviations from the mean a t each monthly interval were excluded as outliers. Second, to reduce the possibility of outliers in cases of longitudinal measures, the data were interpolated. Observations which deviated more than 0.5 cm from the predicted internally generated expected value were excluded as outliers. Finally, one male subject (Group 41, on whom there were 9 measurements, was excluded because it was felt that problems with serial correlation would arise in the analysis. In these ways, a total of 15 observations was discarded. Analysis of variance of the five groups by age and sex demonstrated a statistically significant difference between the sexes. However, no statistically significant differences were demonstrated between the groups in head circumference at any age. Thus, the remaining observations from the five groups were (1)combined and (2) separated by sex for the subsequent analyses. The final data set consisted of 304 observations from 239 males with DS and 236 observations from 182 females with DS. A total of 72 measures in 50 males and 59 measures in 44 females came from Group 1.Group 2 contained single observations on 17 males and 14 females. Group 3 contained single measurements on 11 males and 13 females. Measurements in Group 4 came from 62 males and 47 females, some of whom were followed longitudinally, resulting in a combination of single and multiple observations. Thus, there were 105 male observations and 86 females observations. Group 5 was comprised of single observations on 99 males and 64 females. Table I shows by sex the sample sizes by threemonthly intervals and Table I1lists the number of observations per subject used in the final analysis. Availability of karyotypic information varied from group to group. No child was excluded from the study based on karyotype or lack of available karyotypic confirmation (see Table I11 for the combined distribution of standard trisomy 21, translocation, mosaicism, and clinically confirmed instances from the five groups).
TABLE I. Sample Size Groupings of the Analyzed Population Total sample size Number of Observations Age (months) 0-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27-29 30-32 33-36
Females 182 236
Males 239 304
44 42 23 21 20 16 10 6 21 7 7 22
77 41 32 24 27 17 20 5 23 7 10 16
An accurate head circumference measurement is produced by placing a measuring device around the midforehead and the most prominent portion of the occiput in such a way that a maximal circumference is obtained. Measurements in Group 1 and Group 5 were taken primarily with reinforced cloth measuring tapes; no significant variation of measures with tapes of different age could be demonstrated. Measurements in Group 2 and Group 3 followed the methods discussed in Cameron [1986], using a fiberglass tape measure, while measurements in Group 4 were obtained with a plastic reinforced cloth tape measure. All measurements were rounded to the nearest tenth centimeter. In all groups, each child's age a t the time of measurement was converted into months and rounded down to the nearest monthly increment. Each measurement was counted as one data point and the method of least squares [Draper and Smith, 19811 was performed to test the fit of the growth model, described in Hecht et al. 119891: Y = a + bx + c[log(x + 111 (1) where a = estimated head circumference measurement at birth (y-intercept), b and c are estimated constants which determine the shape of the fitted curve (estimate linear growth and acceleratioddeceleration of growth, respectively), x = age in months, Y = estimated mean head circumference measurement at a specific monthly age interval. Several models, varying in the types and numbers of TABLE 11. Number of Observations Per Subject in the Analyzed Population Number of observations 1 2 3 4 5
Females
Males
145 24 10 2 1
190 35 12 2
Head Circumference in Down Syndrome TABLE 111. Karyotypic Information of the Subjects of the Analyzed Populations Cytogenetic information Standard trisomy 21 Translocation Mosaicism Karyotype information unavailable (clinically confirmed)
Female 103 3 2 74
Male 143 4
92
terms, have been developed to describe growth [Draper and Smith, 1981;Berkey and Reed, 19871. Model (1)was adopted for this analysis because linear parameters are easier to fit, it offered high explanatory ability, and it required only 3 constants. The method of least squares was performed separately on male and female data. The amount of variation explained by growth model (1) was very high in each case (R2= 86.4%for males; R2= 86.2%for females).The fit of model (1)was statistically significant (P < 0.001) for both sexes. Male and female data were combined for further analysis of the differences between them. A statistically difference (P < 0.001) was demonstrated by the y-intercept term, a, in model (1)between males and females; there were no statistically significant differences in parameters b and c between them. The method of least squares was justified by demonstrating that the conditionsof independenceand normality were satisfied by our sample data. Since our sample included cases of longitudinal observations,tests for serial correlation, or
55
,
45
4
independence, among the residuals [Draper and Smith, 19811were performed. No significant serial correlation was demonstrated. Additional residuals checking validated the normality assumptions required by the use of the method of least squares, thereby confirming the appropriate use of this method in our study.
RESULTS The equation derived for estimated mean head circumference values for females with DS was: Y = 31.894 - 0.041~+ 9.844[10g(x + 111, with a standard error, SD = 1.689. The equation derived for estimated mean head circumference values for females with DS was: Y = 31.8940 - 0 . 0 4 1 ~+ 9.844[10g(x + 111, with a standard error, SD = 1.626. (The standard error estimates the standard deviation, SD, of the distribution of head circumferences at any age. In fitting the model, it is assumed that the standard error is constant over the range of age, an assumption which was confirmed by residuals checking.) Figures 1 and 2 display for males and females with DS, respectively, the estimated head circumference means f 2 SD. Based on a f 2 SD criterion, 95%of the study population have head circumference measurements which fall within the range of values in Figures 1 and 2. Males and females with DS demonstrate parallel
Males
I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4
8
12
63
16
20
24
28
32
Age (months) Fig. 1. Head circumference growth curves for males with Down syndrome (shaded) compared with males from a general population [Roche et al., 19873.
55
Females
6
Age (months) Fig. 2. Head circumferences growth curves for females with Down syndrome (shaded) compared with females from a general population [Roehe et al., 19871.
5
Age (months) Fig. 3. Previously published mean head circumference values for males with Down syndrome (open squares from Thelander and Pryor [19661,open triangles from Pryor and Thelander [ 19671,open circles for data in blacks and closed squares for whites both from Ershow [19861, and closed triangles from F'ueschel [19841) with estimated growth curves.
Head Circumference in Down Syndrome
254
0
. . .
, . 4
. .
, . . . , .
a
,
. , . . . , .
I2
16
20
. .
, 24
. . .
, . 28
. .
,
65
.. .
32
Age (months) Fig. 4. Previously published mean head circumference values for females with Down syndrome (open squares from Thelander and Pryor [19661, open triangles from Pryor and Thelander [19671,open circles for data in blacks and closed sauares for whites both from Ershow [19861, and closed triangles from Pueschel [19841) with estimated growth curves.
growth to each other, a finding confirmed by the statistical difference between the constant terms in model (1)and no statistical difference in the remaining coefficients. Similar curves for a general population [Roche et al., 19871are shown for comparison. Head growth velocity appears to be similar to that seen in the general population until about age 5-6 months. At all ages, the + 2 SD and mean head circumference values for both males (Fig.1)and females (Fig. 2) with DS approximate the mean head circumference measurements and - 2 SD, respectively, for the general population [Roche et al., 19871. In order to validate the use of model (11, data from several other studies [Pryor and Thelander, 1967; Thelander and Pryor, 1966; Pueschel, 1984; Ershow et al. 19861 was plotted against the generated reference curves (Figs. 3,4).Because the previous studies calculated averages at specific intervals with few observations, it is not surprising that some of the values do not fall precisely on the mean values predicted by our analysis, which are based on simultaneous use of all data points. However, it is apparent that these data, particularly Pueschel[19841which provides the largest longitudinal sample, support the validity of our reference curves, since all of the outside averages fall within the mean & 2 SD range derived from this study. The data sets used in those previous studies are summarized in Table IV.
DISCUSSION There are two major impediments to the construction of statistically appropriate reference growth curves: 1)sample size (at specific age intervals and across many age intervals), and 2) choice of methodology.Sample size can present difficulties for populations composed of individuals for whom comparison with the general norms may be inappropriate (e.g., children with DS). Difficulty in generating an adequate sample size in such populations may be secondary to the overall smaller number of individuals within each population, as well as the tendency for such individuals to be more intensively evaluated by specialists (e.g., clinical geneticists or other researchers trained in measurement methodologies) within the first year of life, and then more routinely followed by other health care professionals (e.g., pediatricians) for much of the remainder of their lives. The first of these results in an absolute reduction in available sample size at all age intervals, while the second results in a substantial number of observations easily available to most researchers within the first year of life, followed by a rather drastic reduction a t subsequent age intervals. Thus, limited sample sizes can pose a barrier to the construction of reference curves for children outside of the norm. In addition, as clinically important as growth curves are in the medical assessment of individuals, no single
66
Palmer et al. TABLE IV. Population Characteristics in Previous Studies of Head Circumference in Children With Down Syndrome
Type of study Number of individuals (male, female) Total measures, 0-3 y (male, female) Number of observations by monthly age increments (male, female) 0-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27-29 30-32 33-36
Pueschel [19841 Longitudinal 50, 39 463, 307
-
Reference of previous study Ershow et Ershow et al. [1986] al. [1986] (white) (blacks) Longitudinal Longitudinal 20,lO 17,ll 53,21 40,27 20, 9 17, 7
48, 39 46, 38 45,34 45,37
-
-
16, 5
16, 10 12, 9 -
-
12, 8
-
47,35
-
-
-
-
-
44,34 -
-
49, 38 47,34
-
-
-
Thelander and Pryor [19661 Longitudinal 83, 63 33, 27
Pryor and Thelander [19671" Longitudinal 83, 63 22, 24
-
-
5, 7b
-
12, 7b
-
16, 13b
-
-
5, 7b
-
-
4, 4b
-
13, 13b
"It is unclear whether or not the data presented in Thelander and Pryor El9661 and Pryor and Thelander [19671 are independent observations. bData given for 12-month intervals with mean of the intervals used in this tabulation.
specific and generally accepted methodology exists for their construction. Several different methods have been used [Cronk et al., 1988; Guo et al., 1988; Roche et al., 19871; however, each is not without its limitations and assumptions [see Cole, 1988 and subsequent discussion on fitting smoothed centile curves to reference data; see Cook and Ware, 1983 for discussion on analysis of longitudinal data]. The method of least squares to test the fit of a particular growth model is an appropriate methodology where independence of observations and assumptions of normality can be demonstrated [Draper and Smith, 19811. The purpose of this study was to construct statistically appropriate head circumferencegrowth curves for males and females with DS from birth to 36 months of age. The data were elicited from five study populations to maximize the total sample size and number of observations across age intervals (Table I). Several steps were taken to ensure that outliers were removed from the raw data. Analysis of variance demonstrated that 1)there were no statistically significant differences between the head circumference measurements from the five groups at specific age intervals, and 2) that there was a statistically significant difference between the sexes. The method of least squares to test the fit of growth model (1) was performed. Use of this method was justified by demonstrating that the conditions of independence and normality were satisfied by our sample data. The fit of growth model (1) was statistically significant (P < 0.001) for both sexes (R2= 86.4%for males; R2 = 86.2% for females), resulting in the head circumference growth curves shown in Figures 1 and 2. The validity of these head circumference reference curves was demonstrated by plotting head circumference measurements from other published studies. All of the mean head circumference measurements from these other studies fell within the mean 2 2 SD range derived in this study (Figs. 3, 4).
Our results demonstrate: 1)that males and females with DS have parallel head growth, with males having larger head circumferences by a constant value; and 2) that children with DS appear to have a head growth velocity similar to that seen in the general population until about age 5-6 months (Figs. 1,2). Such changes have been suggested previously by other researchers [see Wisniewski et al., 1987; Pueschel, 19841, although differences exist in the specified time interval. About 50% of children with DS have a head circumference which falls within the general population range (Figs. 1,2),while studies by Wisniewski et al. [19871and Wisniewski [1990],who studied 780 children with DS up to age 60 months, previously suggested that this occurs in about 20% of such children. The presence of DS does not preclude the existence of unrelated intracranial anomalies or other conditions which may result in differences in head growth. Therefore, it is important to have reference head circumference data for this population. The reference graphs published here may be of use to all health professionals involved in monitoring the medical, physical, and developmental aspects of children with DS.
ACKNOWLEDGMENT The authors thank Norman Draper, Ph.D. for statistical assistance and Francois Sainfort for statistical and technical assistance. Some head circumference measurements from Group l were obtained with support from the Down Syndrome Program, Madison, Wisconsin, and those of Groups 2,3, and 4 with support from the March of Dimes grant #6-449.
REFERENCES Baird PA, Sadovnick AD (1988): Life expectancy in Down syndrome adults. Lancet 1:1354-1356. Berkey CS,Reed RB (1987):A model for describing normal and abnormal growth in early childhood. Hum Biol 59:973-987.
Head Circumference in Down Syndrome Cameron N (1986): The methods of auxological anthropometry. In Falkner F, Tanner JM (eds.): “Human Growth,” Vol 3. New York Plenum Press, p 23. Cole TJ (1988):Fitting smoothed centile curves to reference data. J R Statist SOC 151 A:385-418. Cook NR, Ware J H (1983):Design and analysis methods for longitudinal research. Annu Rev Public Health 4:l-23. Cronk C, Crocker AC, Pueschel SM, Shea AM, Zackai E, Pickens G, Reed RB (1988):Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 81:102-110. Draper N, Smith H (1981):“AppliedRegression Analysis,” 2nd edition. New York: John Wiley & Sons, pp. 10, 697-699, 157, 162. Eichorn DH, Bayley N (1962):Growth in head circumferencefrom birth through young adulthood. Child Dev 33:257-271. , Ershow AG (1986): Growth in black and white children with Down syndrome. Am J Ment Defic 90:507-512. Guo S, Roche AF, Moore WM (1988): Reference data for head circumference and 1-month increments from 1 to 12 months of age. J Pediatr 113:490-494. Hamill PV, Drizd TA, Johnson CL, Reed RE, Roche AF, Moore W M (1979):Physical growth National Center for Health Statistics percentiles. Am J Clin Nutr 32507429. Hecht JT, Horton WA, Reid CS, Pyeritz RE, Chakraborty R (1989): Growth of the foramen magnum in achondroplasia. Am J Med Genet 32528-535. Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall J G (1978):Standard growth curves for achondroplasia. J Pediatr 93:435-438. Meredith HV (1946):Physical growth from birth to two years: 11.Head circumference. Part I. A review and synthesis of North American research on groups of infants. Child Dev 17:l-61. Mikkelsen M (1977): Down syndrome: Cytogeneticai epidemiology. Hereditas 86:45-50.
67
Mosier HD, Grossman HJ, Dingman HF (1965): Physical growth in mental defectives. A study in an institutionalized population. Pediatrics 36:465-519. Nellhaus G (1967):Head circumference from birth to eighteen years: Practical composite international and interracial graphs. Pediatrics 41:106-114. Ounsted M, Moar VA, Scott A (1985):Head circumference charts updated. Am J Dis Child 60:936-939. Pryor HB, Thelander HE (1967): Growth deviations in handicapped children. An anthropometric study. Clin Pediatr 6:501-512. Pueschel SM (1984): “The Young Child With Down Syndrome.” New York Human Sciences Press, Inc., pp 39-55, 105-141. Roche AF, Mukherjee D, Guo S, Moore WM (1987):Head circumference reference data: Birth to 18 years. Pediatrics 79:706-712. Sharav T, Collins RM, Baab PJ (1988):Growth studies in infants and children with Down’s syndrome and elevated levels of thyrotropin. Am J Dis Child 142:1302-1306. Silver HK, Deamer WC (1948):Graphs ofthe headcircumference ofthe normal infant. J Pediatr 33:167-171. Thelander HE, Pryor HB (1966): Abnormal patterns of growth and development in mongolism. An anthropometric study. Clin Pediatr 5493-501. Westropp CK, Barber CR (1956):Growth of the skull in young children. Part I: Standards of head circumference. J Neurol Neurosurg Psychiatry 19:52-56. Wisniewski, KE (1990):Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. Am J Med Genet (Supp) 7:274-281. Wisniewski KE, Schmidt-SidorB, Sersen EA (1987):Reduction of head circumference and brain weight of DS cases: Birth to 5 years. Neurology 37:203.
Head Circumference of Children With Down Syndrome (0-36 Months) Christina G.S. Palmer, Christine Cronk, Siegfried M.Pueschel, Krystyna E. Wisniewski, Renata Laxova, Allen C. Crocker, and Richard M. Pauli Departments of Industrial Engineering (C.G.S.P.) and Pediatrics and Medical Genetics (R.L.,R.M.P.), University of Wisconsin-Madison; Department of Anthropology, Southern Illinois University, Carbondale (C.C.); Child Development Center, Rhode Island Hospital, Providence (S.M.P.);Institute for Basic Research in Developmental Disabilities, Staten Island, New York (K.E.W.);Developmental Evaluation Center, Children’s Hospital, Boston (A.C.C.) This study provides statistically appropriate head circumference reference curves for males and females with Down syndrome (DS) from birth to 36 months of age. A total of 239 males and 182females from five study populations, yielding a combination of cross-sectional and longitudinal data, were used for the analysis. The method of least squares was used to test the fit of the growth model y = a + bx + c[log(x + l)],where x is age in months. These standardized curves should provide information of value in the medical, physical, and developmental management of children with DS.
KEY WORDS growth standards,head growth, occipital-frontalcircumference, trisomy 21 INTRODUCTION Head circumference (occipito-frontal circumference) measurement during infancy and childhood is one of several useful indices of a child’s medical, physical, and developmental status. Reference head circumference curves for males and females in the general population have been published [Meredith, 1946; Silver and Deamer, 1948;Westropp and Barber, 1956; Eichorn and Bayley, 1962; Nellhaus, 1967; Hamill et al., 1979; Ounsted et al., 1985;Roche et al., 1987;Guo et al., 19881, but there is very little information on individuals in whom such comparisons with general norms may be inappropriate [Horton et al., 19781.One such population for which specific norms have been unavailable is children with Down syndrome (DS).
Received for publication February 5, 1991; revision received April 4, 1991. Address reprint requests to Richard M. Pauli, M.D., Ph.D., University of Wisconsin-Madison, Clinical Genetics Center, 1500 Highland Avenue, Madison, WI 53705.
0 1992 Wiley-Liss, Inc.
Approximately 1 in every 800-1,000 babies is born with DS [Mikkelsen, 19771. Improved medical care has increased their life span [Baird and Sadovnick, 19881 and a change in societal values has resulted in virtually all children with DS being raised at home and integrated into the community. As for any population, children with DS are not immune to other medical complications. Therefore, specific, standardized information regarding their growth is useful. Height and weight reference curves for children with DS have recently been published [Cronk et al., 19881. While several other published studies concerning DS include head circumference measurements [Mosier et al., 1965; Thelander and Pryor, 1966; Pryor and Thelander, 1967; Pueschel, 1984; Ershow, 1986; Wisniewski et al., 1987; Sharav et al., 1988; Wisniewski, 19901, none had generated head circumference reference curves either appropriate for use by or widely available to physicians and other health care professionals following children with DS. We present standard reference curves for head circumference in males and females with DS from birth to 36 months of age. METHODS AND ANALYSIS In order to generate samples of sufficient size head circumference measurements from five different centers (coded as groups), taken between birth and 36 months of age, were utilized. Group 1consisted of children referred for evaluation to the Clinical Genetics Center a t the University of Wisconsin-Madison and the Down Syndrome Clinic a t the Waisman Center on Mental Retardation and Human Development in Madison, Wisconsin. These children were primarily Caucasian, born between 1975 and 1988, and residing in Wisconsin, Illinois, or Michigan. All measurements were taken by physician geneticists. Measurements in Group 2 were collected in the course of comprehensive evaluations in the Developmental Evaluation Center at Boston Children’s Hospital from 1967 to 1980. All measurements were taken by physical anthropologists. Group 3 was made up of children, born between 1967
62
Palmer et d.
and 1970, who were enrolled in an early intervention program at the Child Development Center at the Rhode Island Hospital. All measurements were taken in 1971 by a physical anthropologist. Group 4 were children followed at the Child Development Center a t the Rhode Island Hospital. These measurements were taken by a physician geneticist. Group 5 consisted of children who participated in a study at the Institute for Basic Research in Developmental Disabilities in New York during the period from 1975 to 1985. All the children were Caucasian. The measurements were taken by a nurse and physician. Since the data were from different areas of the country, with different measurers using different measuring devices, it was not possible t o control for either potential measurement error (resulting in outliers) or potential sampling bias. Thus, prior to an analysis of combined sample data, several steps were taken to ensure that such pooling would result in a relatively homogeneous and representative population. Similar procedures were used in Cronk et al. [1988]. First, the data from the five groups were combined and means and standard deviations were calculated at each monthly age interval from birth to 36 months of age. Observations exceeding 2 2.5 standard deviations from the mean a t each monthly interval were excluded as outliers. Second, to reduce the possibility of outliers in cases of longitudinal measures, the data were interpolated. Observations which deviated more than 0.5 cm from the predicted internally generated expected value were excluded as outliers. Finally, one male subject (Group 41, on whom there were 9 measurements, was excluded because it was felt that problems with serial correlation would arise in the analysis. In these ways, a total of 15 observations was discarded. Analysis of variance of the five groups by age and sex demonstrated a statistically significant difference between the sexes. However, no statistically significant differences were demonstrated between the groups in head circumference at any age. Thus, the remaining observations from the five groups were (1)combined and (2) separated by sex for the subsequent analyses. The final data set consisted of 304 observations from 239 males with DS and 236 observations from 182 females with DS. A total of 72 measures in 50 males and 59 measures in 44 females came from Group 1.Group 2 contained single observations on 17 males and 14 females. Group 3 contained single measurements on 11 males and 13 females. Measurements in Group 4 came from 62 males and 47 females, some of whom were followed longitudinally, resulting in a combination of single and multiple observations. Thus, there were 105 male observations and 86 females observations. Group 5 was comprised of single observations on 99 males and 64 females. Table I shows by sex the sample sizes by threemonthly intervals and Table I1lists the number of observations per subject used in the final analysis. Availability of karyotypic information varied from group to group. No child was excluded from the study based on karyotype or lack of available karyotypic confirmation (see Table I11 for the combined distribution of standard trisomy 21, translocation, mosaicism, and clinically confirmed instances from the five groups).
TABLE I. Sample Size Groupings of the Analyzed Population Total sample size Number of Observations Age (months) 0-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27-29 30-32 33-36
Females 182 236
Males 239 304
44 42 23 21 20 16 10 6 21 7 7 22
77 41 32 24 27 17 20 5 23 7 10 16
An accurate head circumference measurement is produced by placing a measuring device around the midforehead and the most prominent portion of the occiput in such a way that a maximal circumference is obtained. Measurements in Group 1 and Group 5 were taken primarily with reinforced cloth measuring tapes; no significant variation of measures with tapes of different age could be demonstrated. Measurements in Group 2 and Group 3 followed the methods discussed in Cameron [1986], using a fiberglass tape measure, while measurements in Group 4 were obtained with a plastic reinforced cloth tape measure. All measurements were rounded to the nearest tenth centimeter. In all groups, each child's age a t the time of measurement was converted into months and rounded down to the nearest monthly increment. Each measurement was counted as one data point and the method of least squares [Draper and Smith, 19811 was performed to test the fit of the growth model, described in Hecht et al. 119891: Y = a + bx + c[log(x + 111 (1) where a = estimated head circumference measurement at birth (y-intercept), b and c are estimated constants which determine the shape of the fitted curve (estimate linear growth and acceleratioddeceleration of growth, respectively), x = age in months, Y = estimated mean head circumference measurement at a specific monthly age interval. Several models, varying in the types and numbers of TABLE 11. Number of Observations Per Subject in the Analyzed Population Number of observations 1 2 3 4 5
Females
Males
145 24 10 2 1
190 35 12 2
Head Circumference in Down Syndrome TABLE 111. Karyotypic Information of the Subjects of the Analyzed Populations Cytogenetic information Standard trisomy 21 Translocation Mosaicism Karyotype information unavailable (clinically confirmed)
Female 103 3 2 74
Male 143 4
92
terms, have been developed to describe growth [Draper and Smith, 1981;Berkey and Reed, 19871. Model (1)was adopted for this analysis because linear parameters are easier to fit, it offered high explanatory ability, and it required only 3 constants. The method of least squares was performed separately on male and female data. The amount of variation explained by growth model (1) was very high in each case (R2= 86.4%for males; R2= 86.2%for females).The fit of model (1)was statistically significant (P < 0.001) for both sexes. Male and female data were combined for further analysis of the differences between them. A statistically difference (P < 0.001) was demonstrated by the y-intercept term, a, in model (1)between males and females; there were no statistically significant differences in parameters b and c between them. The method of least squares was justified by demonstrating that the conditionsof independenceand normality were satisfied by our sample data. Since our sample included cases of longitudinal observations,tests for serial correlation, or
55
,
45
4
independence, among the residuals [Draper and Smith, 19811were performed. No significant serial correlation was demonstrated. Additional residuals checking validated the normality assumptions required by the use of the method of least squares, thereby confirming the appropriate use of this method in our study.
RESULTS The equation derived for estimated mean head circumference values for females with DS was: Y = 31.894 - 0.041~+ 9.844[10g(x + 111, with a standard error, SD = 1.689. The equation derived for estimated mean head circumference values for females with DS was: Y = 31.8940 - 0 . 0 4 1 ~+ 9.844[10g(x + 111, with a standard error, SD = 1.626. (The standard error estimates the standard deviation, SD, of the distribution of head circumferences at any age. In fitting the model, it is assumed that the standard error is constant over the range of age, an assumption which was confirmed by residuals checking.) Figures 1 and 2 display for males and females with DS, respectively, the estimated head circumference means f 2 SD. Based on a f 2 SD criterion, 95%of the study population have head circumference measurements which fall within the range of values in Figures 1 and 2. Males and females with DS demonstrate parallel
Males
I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4
8
12
63
16
20
24
28
32
Age (months) Fig. 1. Head circumference growth curves for males with Down syndrome (shaded) compared with males from a general population [Roche et al., 19873.
55
Females
6
Age (months) Fig. 2. Head circumferences growth curves for females with Down syndrome (shaded) compared with females from a general population [Roehe et al., 19871.
5
Age (months) Fig. 3. Previously published mean head circumference values for males with Down syndrome (open squares from Thelander and Pryor [19661,open triangles from Pryor and Thelander [ 19671,open circles for data in blacks and closed squares for whites both from Ershow [19861, and closed triangles from F'ueschel [19841) with estimated growth curves.
Head Circumference in Down Syndrome
254
0
. . .
, . 4
. .
, . . . , .
a
,
. , . . . , .
I2
16
20
. .
, 24
. . .
, . 28
. .
,
65
.. .
32
Age (months) Fig. 4. Previously published mean head circumference values for females with Down syndrome (open squares from Thelander and Pryor [19661, open triangles from Pryor and Thelander [19671,open circles for data in blacks and closed sauares for whites both from Ershow [19861, and closed triangles from Pueschel [19841) with estimated growth curves.
growth to each other, a finding confirmed by the statistical difference between the constant terms in model (1)and no statistical difference in the remaining coefficients. Similar curves for a general population [Roche et al., 19871are shown for comparison. Head growth velocity appears to be similar to that seen in the general population until about age 5-6 months. At all ages, the + 2 SD and mean head circumference values for both males (Fig.1)and females (Fig. 2) with DS approximate the mean head circumference measurements and - 2 SD, respectively, for the general population [Roche et al., 19871. In order to validate the use of model (11, data from several other studies [Pryor and Thelander, 1967; Thelander and Pryor, 1966; Pueschel, 1984; Ershow et al. 19861 was plotted against the generated reference curves (Figs. 3,4).Because the previous studies calculated averages at specific intervals with few observations, it is not surprising that some of the values do not fall precisely on the mean values predicted by our analysis, which are based on simultaneous use of all data points. However, it is apparent that these data, particularly Pueschel[19841which provides the largest longitudinal sample, support the validity of our reference curves, since all of the outside averages fall within the mean & 2 SD range derived from this study. The data sets used in those previous studies are summarized in Table IV.
DISCUSSION There are two major impediments to the construction of statistically appropriate reference growth curves: 1)sample size (at specific age intervals and across many age intervals), and 2) choice of methodology.Sample size can present difficulties for populations composed of individuals for whom comparison with the general norms may be inappropriate (e.g., children with DS). Difficulty in generating an adequate sample size in such populations may be secondary to the overall smaller number of individuals within each population, as well as the tendency for such individuals to be more intensively evaluated by specialists (e.g., clinical geneticists or other researchers trained in measurement methodologies) within the first year of life, and then more routinely followed by other health care professionals (e.g., pediatricians) for much of the remainder of their lives. The first of these results in an absolute reduction in available sample size at all age intervals, while the second results in a substantial number of observations easily available to most researchers within the first year of life, followed by a rather drastic reduction a t subsequent age intervals. Thus, limited sample sizes can pose a barrier to the construction of reference curves for children outside of the norm. In addition, as clinically important as growth curves are in the medical assessment of individuals, no single
66
Palmer et al. TABLE IV. Population Characteristics in Previous Studies of Head Circumference in Children With Down Syndrome
Type of study Number of individuals (male, female) Total measures, 0-3 y (male, female) Number of observations by monthly age increments (male, female) 0-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27-29 30-32 33-36
Pueschel [19841 Longitudinal 50, 39 463, 307
-
Reference of previous study Ershow et Ershow et al. [1986] al. [1986] (white) (blacks) Longitudinal Longitudinal 20,lO 17,ll 53,21 40,27 20, 9 17, 7
48, 39 46, 38 45,34 45,37
-
-
16, 5
16, 10 12, 9 -
-
12, 8
-
47,35
-
-
-
-
-
44,34 -
-
49, 38 47,34
-
-
-
Thelander and Pryor [19661 Longitudinal 83, 63 33, 27
Pryor and Thelander [19671" Longitudinal 83, 63 22, 24
-
-
5, 7b
-
12, 7b
-
16, 13b
-
-
5, 7b
-
-
4, 4b
-
13, 13b
"It is unclear whether or not the data presented in Thelander and Pryor El9661 and Pryor and Thelander [19671 are independent observations. bData given for 12-month intervals with mean of the intervals used in this tabulation.
specific and generally accepted methodology exists for their construction. Several different methods have been used [Cronk et al., 1988; Guo et al., 1988; Roche et al., 19871; however, each is not without its limitations and assumptions [see Cole, 1988 and subsequent discussion on fitting smoothed centile curves to reference data; see Cook and Ware, 1983 for discussion on analysis of longitudinal data]. The method of least squares to test the fit of a particular growth model is an appropriate methodology where independence of observations and assumptions of normality can be demonstrated [Draper and Smith, 19811. The purpose of this study was to construct statistically appropriate head circumferencegrowth curves for males and females with DS from birth to 36 months of age. The data were elicited from five study populations to maximize the total sample size and number of observations across age intervals (Table I). Several steps were taken to ensure that outliers were removed from the raw data. Analysis of variance demonstrated that 1)there were no statistically significant differences between the head circumference measurements from the five groups at specific age intervals, and 2) that there was a statistically significant difference between the sexes. The method of least squares to test the fit of growth model (1) was performed. Use of this method was justified by demonstrating that the conditions of independence and normality were satisfied by our sample data. The fit of growth model (1) was statistically significant (P < 0.001) for both sexes (R2= 86.4%for males; R2 = 86.2% for females), resulting in the head circumference growth curves shown in Figures 1 and 2. The validity of these head circumference reference curves was demonstrated by plotting head circumference measurements from other published studies. All of the mean head circumference measurements from these other studies fell within the mean 2 2 SD range derived in this study (Figs. 3, 4).
Our results demonstrate: 1)that males and females with DS have parallel head growth, with males having larger head circumferences by a constant value; and 2) that children with DS appear to have a head growth velocity similar to that seen in the general population until about age 5-6 months (Figs. 1,2). Such changes have been suggested previously by other researchers [see Wisniewski et al., 1987; Pueschel, 19841, although differences exist in the specified time interval. About 50% of children with DS have a head circumference which falls within the general population range (Figs. 1,2),while studies by Wisniewski et al. [19871and Wisniewski [1990],who studied 780 children with DS up to age 60 months, previously suggested that this occurs in about 20% of such children. The presence of DS does not preclude the existence of unrelated intracranial anomalies or other conditions which may result in differences in head growth. Therefore, it is important to have reference head circumference data for this population. The reference graphs published here may be of use to all health professionals involved in monitoring the medical, physical, and developmental aspects of children with DS.
ACKNOWLEDGMENT The authors thank Norman Draper, Ph.D. for statistical assistance and Francois Sainfort for statistical and technical assistance. Some head circumference measurements from Group l were obtained with support from the Down Syndrome Program, Madison, Wisconsin, and those of Groups 2,3, and 4 with support from the March of Dimes grant #6-449.
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Head Circumference in Down Syndrome Cameron N (1986): The methods of auxological anthropometry. In Falkner F, Tanner JM (eds.): “Human Growth,” Vol 3. New York Plenum Press, p 23. Cole TJ (1988):Fitting smoothed centile curves to reference data. J R Statist SOC 151 A:385-418. Cook NR, Ware J H (1983):Design and analysis methods for longitudinal research. Annu Rev Public Health 4:l-23. Cronk C, Crocker AC, Pueschel SM, Shea AM, Zackai E, Pickens G, Reed RB (1988):Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 81:102-110. Draper N, Smith H (1981):“AppliedRegression Analysis,” 2nd edition. New York: John Wiley & Sons, pp. 10, 697-699, 157, 162. Eichorn DH, Bayley N (1962):Growth in head circumferencefrom birth through young adulthood. Child Dev 33:257-271. , Ershow AG (1986): Growth in black and white children with Down syndrome. Am J Ment Defic 90:507-512. Guo S, Roche AF, Moore WM (1988): Reference data for head circumference and 1-month increments from 1 to 12 months of age. J Pediatr 113:490-494. Hamill PV, Drizd TA, Johnson CL, Reed RE, Roche AF, Moore W M (1979):Physical growth National Center for Health Statistics percentiles. Am J Clin Nutr 32507429. Hecht JT, Horton WA, Reid CS, Pyeritz RE, Chakraborty R (1989): Growth of the foramen magnum in achondroplasia. Am J Med Genet 32528-535. Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall J G (1978):Standard growth curves for achondroplasia. J Pediatr 93:435-438. Meredith HV (1946):Physical growth from birth to two years: 11.Head circumference. Part I. A review and synthesis of North American research on groups of infants. Child Dev 17:l-61. Mikkelsen M (1977): Down syndrome: Cytogeneticai epidemiology. Hereditas 86:45-50.
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Mosier HD, Grossman HJ, Dingman HF (1965): Physical growth in mental defectives. A study in an institutionalized population. Pediatrics 36:465-519. Nellhaus G (1967):Head circumference from birth to eighteen years: Practical composite international and interracial graphs. Pediatrics 41:106-114. Ounsted M, Moar VA, Scott A (1985):Head circumference charts updated. Am J Dis Child 60:936-939. Pryor HB, Thelander HE (1967): Growth deviations in handicapped children. An anthropometric study. Clin Pediatr 6:501-512. Pueschel SM (1984): “The Young Child With Down Syndrome.” New York Human Sciences Press, Inc., pp 39-55, 105-141. Roche AF, Mukherjee D, Guo S, Moore WM (1987):Head circumference reference data: Birth to 18 years. Pediatrics 79:706-712. Sharav T, Collins RM, Baab PJ (1988):Growth studies in infants and children with Down’s syndrome and elevated levels of thyrotropin. Am J Dis Child 142:1302-1306. Silver HK, Deamer WC (1948):Graphs ofthe headcircumference ofthe normal infant. J Pediatr 33:167-171. Thelander HE, Pryor HB (1966): Abnormal patterns of growth and development in mongolism. An anthropometric study. Clin Pediatr 5493-501. Westropp CK, Barber CR (1956):Growth of the skull in young children. Part I: Standards of head circumference. J Neurol Neurosurg Psychiatry 19:52-56. Wisniewski, KE (1990):Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. Am J Med Genet (Supp) 7:274-281. Wisniewski KE, Schmidt-SidorB, Sersen EA (1987):Reduction of head circumference and brain weight of DS cases: Birth to 5 years. Neurology 37:203.
