Towards evidence based referral criteria for growth monitoring

Aims: To evaluate the performance of growth monitoring in detecting diseases. Turner''s syndrome (TS) is taken as the target disease. Methods: Case-control simulation study. Three archetypal screening rules are applied to longitudinal growth data comparing a group with TS versus a reference group from birth to the age of 10 years. Main outcome measures were sensitivity, specificity, and median referral age. Results: Clear differences in performance of the rules were found. The best rule takes parental height into account. Combining rules could improve diagnostic accuracy. Conclusion: Growth monitoring is useful to screen for TS. A combined rule that takes absolute height SDS, parental height, and deflection in height velocity into account is the best way to do this. Similar research is needed for other diseases, populations, and ages, and the results should be synthesised into evidence based referral criteria.     

Developing evidence-based guidelines for referral for short stature.

OBJECTIVE: To establish evidence-based guidelines for growth monitoring on a population basis. Study DESIGN: Several auxological referral criteria were formulated and applied to longitudinal growth data from four different patient groups, as well as three samples from the general population. RESULTS: Almost 30% of pathology can be detected by height standard deviation score (HSDS) below -3 or at least two observations of HSDS below -2.5 at a low false-positive rate (<1%) in 0-3-year-old infants. For 3-10-year olds, a rule concerning distance to target height of >2 SD in combination with HSDS <-2.0 has the best predictive value. In combination with a rule on severe short stature (<-2.5 SDS) and a minor contribution from a rule on "height deflection", 85.7% of children with Turner syndrome and 76.5% of children who are short because of various disorders are detected at a false-positive rate of 1.5-2%. CONCLUSIONS: The proposed guidelines for growth monitoring show high sensitivity at an acceptably low false-positive rate in 3-10-year-old children. Distance to target height is the most important criterion. Below the age of 3 years, the sensitivity is considerably lower. The resulting algorithm appears to be suitable for industrialised countries, but requires further testing in other populations.     

Growth in patients with isolated gonadotrophin deficiency.

The growth pattern of 66 patients (50 males, 16 females) with isolated gonadotrophin deficiency (IGnD), who had reached their final height with epiphyseal closure, was evaluated. For the purpose of analysis the males were divided into two groups according to age at referral: group 1 less than 16 years (n = 23) and group 2 greater than or equal to 16 years (n = 27). Sex hormone treatment was initiated at a mean (SD) chronological age of 15.8 (1.3) and 18.6 (1.2) years in groups 1 and 2 in the males and at 15.3 (1.3) years in the females. The duration of treatment (until epiphyseal closure) in the males was 3.9 (1.5) years in group 1 and 2.1 (1.0) years in group 2 and 2.8 (1.3) years in the females. There was no significant difference between the mean final height in groups 1 and 2, but it was significantly higher than the mean parental height (mean height SD score (HtSDS): 0.1 (1.1) v -0.8 (0.9)) and they were significantly correlated. For females the mean HtSDS compared with parental height was 0.4 (1.5) v -0.6 (1.2). It is concluded that the timing of induction of puberty by sex hormones in males and females with IGnD has no significant effect on final height provided that moderate doses are used. Furthermore final height was significantly correlated to mid-parental height.     

Quality of life after growth hormone therapy and induced puberty in women with Turner syndrome

OBJECTIVE: To evaluate health-related quality of life (HRQoL) in young women with Turner syndrome (TS) after long-term growth hormone (GH) therapy and induced puberty and to analyze whether HRQoL was influenced by auxologic parameters, pubertal development, or subjective parameters. STUDY DESIGN: The study group comprised 49 women with TS, mean (standard deviation) age 19.6 (+/-3.0) years, all former participants of 2 GH studies, > or =6 months after GH discontinuation. Puberty was induced by estrogen treatment, at mean age 12.9 (+/-1.1) years. HRQoL was measured by self-reports of the 2 generic questionnaires, SF36 and TAAQOL. As an additional source of information on HRQoL, we applied parental proxy reports. RESULTS: HRQoL of the women with TS was normal. Remarkably, the women with TS had higher HRQoL scores on some of the scales, including "social functioning" and "role-emotional." Satisfaction with height and breast development had a positive influence on several HRQoL scales. CONCLUSIONS: The young women with TS who reached normal height and had age-appropriate pubertal development reported normal HRQoL. The relatively high scores on some of the HRQoL scales can be explained by an estrogen effect or by a possible response shift, indicating a different internal reference in women with TS. We hypothesize that GH and estrogen treatment positively influenced HRQoL in young women with TS.     

253例中国Turner综合征患者的自然生长曲线

目的制作中国人Turner综合征（TS）自然生长曲线。研究Turner综合征患儿自然生长规律。方法对全国5省市8所医院确诊的253例TS患者治疗前的身高、体重和骨龄进行观测。同一患者的2次测量值间隔至少超过1年才作为2例次参数计,共取得289个身高值和106个骨龄值。身高值经曲线参数估计法绘制曲线并与正常女孩生长曲线进行比较。结果患儿平均出生身长为(47.2±2.5)cm,身长标准差得分（HtSDS）为-1.52。3岁至13岁各年龄组患儿平均身高及其HtSDS值随年龄增大与正常值差距增大,HtSDS从3岁的-2.11降至13岁的-4.83,患儿平均身高与同年龄正常身高均数之差由3岁的8.03cm增加至13岁的27.89cm,从13岁起逐渐减少至20岁的18.87cm。成年身高为(140.0±7.9)cm。8岁前TS患儿生长曲线     

Foetal size to final height

It is well known that some adult diseases, such as cardiovascular diseases, may be programmed during foetal life. It is not clear, however, whether final height may be predicted from foetal growth. A longitudinal cohort of full-term healthy Swedish babies (n = 3650) was followed up from birth to maturity in a population-based growth study. Length or height and its changes were analysed from birth to 18 y of age; 2807 children, with data available on birth length, final height and parental height, were included in this analysis. The result clearly shows that length at birth relates to final height. In terms of standard deviation scores (SDS), the mean difference in length at birth from the mean was greatly decreased in final height, but retained the same order as was seen at birth. In terms of centimeter difference from the reference mean values, the difference in length at birth remained roughly stable into final height. For instance, babies 5 cm above or below the mean birth length will end up approximately 5 cm above or below the mean in final height. Parental height-a surrogate value of the genetic final height potential of an individual-is shown to influence postnatal growth in height strongly. However, the difference from the mean in length at birth remained into adulthood within the same midparental height group. Conclusion: This study reveals that trends in foetal linear growth continue into maturity. Foetal growth is a significant predictor of postnatal growth. Final height is dependent on both the magnitude of foetal growth and the genetic potential in stature, and appears to some extent to be programmed from foetal growth.     

Final height of patients who underwent bone marrow transplantation during childhood

OBJECTIVE: To determine the impact on final adult height of bone marrow transplantation. METHODS: The final height of 28 long term survivors (18 males; 10 females), allografted before or at the onset of puberty, at a median age of 10.8 years (range 6.3 to 14.6) and who did not receive growth hormone (GH) treatment or other growth promoting agents, was evaluated. Median follow up period after bone marrow transplantation was 7.9 years (range 3.2 to 11.4), and age at the most recent evaluation 18.1 years (range 15.6 to 24.5). Height values were expressed in standard deviation score (SDS) from the mean of the normal population. Height at bone marrow transplantation was compared with final height as well as with parental genetic height. Patients were divided into three groups: severe aplastic anaemia (SAA): three patients given no radiotherapy; leukaemia-total body irradiation (TBI): 14 patients with acute or chronic leukaemia conditioned with chemotherapy and TBI; leukaemia-TBI with previous cranial radiation therapy (CRT): 11 patients. None of the patients had solid tumour. RESULTS: There was a decrease in final height SDS compared to pre-transplantation height SDS (paired t test, p < 0.0001). All patients except one reached an adult height above -2.0 SDS. A significant decrease in height SDS was found in the TBI and the CRT groups (paired t test, p = 0.02 and p = 0.0002, respectively). Whereas height SDS value at the time of transplant was higher than the genetic height SDS, final height SDS values were lower. CONCLUSIONS: Despite the decrease in height SDS found after bone marrow transplantation, 27 of the 28 patients spontaneously achieved what is considered to be a normal height SDS (above -2.0 SDS). This should be taken into account when considering GH treatment in children who underwent bone marrow transplantation for malignant haematological diseases.     

Growth impairment in very low birthweight children at 12 years: correlation with perinatal and outcome variables.

AIM: To compare the growth of very low birthweight (VLBW) children in early adolescence with that of their normal birthweight peers; to examine the role of factors contributing to growth-parental height, perinatal variables, bone maturity and sexual maturation; to examine the correlation between head growth and cognitive and educational outcome. METHODS: Standing and sitting heights, weight, occipito-frontal circumference (OFC), skinfold thicknesses and pubertal staging were assessed in 137 VLBW children and 160 controls at 11-13.5 years of age. Ninety six (70%) of the VLBW children had their bone age assessed using the TW2 method. Reported parental heights were obtained by questionnaire. All children had standardised tests of cognitive and educational ability. Perinatal data had been collected prospectively as part of a longitudinal study. RESULTS: VLBW children had lower heights, weight, and OFC. Skinfold thicknesses were no different. The children's short stature was not accounted for by difference in parental height, degree of pubertal development, or by retarded bone age. Indeed, the TW2 RUS score was significantly advanced in the VLBW children. Using the bone ages to predict final adult height, 17% have a predicted height below the third centile and 33% below the tenth. Weight was appropriate for height, but there was a residual deficiency in OFC measurements after taking height into account. In the VLBW group smaller head size was associated with lower IQ and mathematics and reading scores. CONCLUSIONS: Growth problems persist in VLBW children and final heights may be even more abnormal than present heights suggest. VLBW children have smaller OFCs than expected from their short stature alone and this may be associated with poorer educational and cognitive outcomes.     

Final height of patients who underwent bone marrow transplantation during childhood.

OBJECTIVE: To determine the impact on final adult height of bone marrow transplantation. METHODS: The final height of 28 long term survivors (18 males; 10 females), allografted before or at the onset of puberty, at a median age of 10.8 years (range 6.3 to 14.6) and who did not receive growth hormone (GH) treatment or other growth promoting agents, was evaluated. Median follow up period after bone marrow transplantation was 7.9 years (range 3.2 to 11.4), and age at the most recent evaluation 18.1 years (range 15.6 to 24.5). Height values were expressed in standard deviation score (SDS) from the mean of the normal population. Height at bone marrow transplantation was compared with final height as well as with parental genetic height. Patients were divided into three groups: severe aplastic anaemia (SAA): three patients given no radiotherapy; leukaemia-total body irradiation (TBI): 14 patients with acute or chronic leukaemia conditioned with chemotherapy and TBI; leukaemia-TBI with previous cranial radiation therapy (CRT): 11 patients. None of the patients had solid tumour. RESULTS: There was a decrease in final height SDS compared to pre-transplantation height SDS (paired t test, p < 0.0001). All patients except one reached an adult height above -2.0 SDS. A significant decrease in height SDS was found in the TBI and the CRT groups (paired t test, p = 0.02 and p = 0.0002, respectively). Whereas height SDS value at the time of transplant was higher than the genetic height SDS, final height SDS values were lower. CONCLUSIONS: Despite the decrease in height SDS found after bone marrow transplantation, 27 of the 28 patients spontaneously achieved what is considered to be a normal height SDS (above -2.0 SDS). This should be taken into account when considering GH treatment in children who underwent bone marrow transplantation for malignant haematological diseases.     

Linear growth and skeletal maturation in subjects with treated celiac disease.

BACKGROUND: The aim of this study was to report on the long-term growth and development in a group of treated patients with celiac disease. METHODS: The study includes 26 patients (11 boys and 15 girls) with typical celiac disease who were younger than 2.5 at diagnosis and were followed by means of a growth longitudinal monitoring from the introduction of a gluten-free diet (mean age, 1.7 +/- 0.5 years) until adulthood, over a median period of 15.3 years. Growth indicators used were: height, skeletal age, weight and BMI. RESULTS: At the time of admission, the patients had a general tendency to short stature, underweight and retarded skeletal maturation. They did not catch up completely in height and skeletal age after a dietary treatment period of 3 years. Most of them were seen to be slightly below average height for age during childhood and adolescence with skeletal maturity retardation, even if a fairly large interindividual variation of height profiles was evident. CONCLUSIONS: Notwithstanding the early treatment, the careful follow-up, and the good adhesion to the dietary rules of the patients under study, slight negative effects of the disease on growth were not avoided.     

Longitudinal analysis of growth over the first 3 years of life in Turner's syndrome

OBJECTIVE: To evaluate longitudinal growth in Turner's syndrome (TS) over the first 3 years of life. METHODS: Growth of 47 patients with TS was compared with that of 40 age-matched control girls by using an analysis according to the Infancy-Childhood-Puberty and bi-exponential models. RESULTS: A mean of 1.2 SDs were lost before birth and a total of 3.0 SDs were lost by age 3 years. According to the Infancy-Childhood-Puberty model, intrauterine growth retardation contributed -1.24 SDs, a 5-month delay in childhood growth spurt contributed -0.96 SDs, and slow childhood growth contributed an additional -0.8 SDs by age 3 years. The bi-exponential analysis disclosed a quasi-linear first exponent and a confining second exponent, which merged at age 18 months in control subjects and 24 months in patients with TS. The first exponent confers an average annual growth rate of 8.4 cm/y in control subjects and 6.7 cm/y in patients with TS. CONCLUSIONS: Intrauterine growth retardation and the initial 3 years of life contribute most of the deficit in the final height of patients with TS. These data provide a reference of standards for longitudinal growth in patients with TS at age 3 months to 3 years.     

Study of final height in Turner's syndrome: ethnic and genetic influences

In understanding Turner's syndrome, spontaneous adult height is a prerequisite for an accurate assessment of the therapeutic efficiency of growth hormone treatment. The heights described in the literature reveal significant differences (136–147 cm). Our collaborative study pooled results from 16 pediatrie endocrinology centers and obtained a large number of spontaneous adult heights ( n = 216). The selective criteria were: chronological age (CA) > 18 years, bone age (BA) > 16 years, typical karyotype, no treatment with growth hormone or anabolic steroids. Mean CA was 23.3 ± 5.6 years. Chromosomal anomalies were: monosomy X 56%; mosaicism 37.2%; structural aberration 10.6%. Mean final height in the whole group was 141.5 (129–160) cm. There was no significant difference in height between the three groups: monosomy X( n =121:141.1±6.4 cm); mosaicism ( n = 72: 141.5 ± 7.5 cm); X anomaly ( n = 23: 141.4±5.0 cm). Mean parental height was 170.4 ± 7.1 cm (father) and 160.1 ± 6.2 cm (mother). Parental height and patients' heights correlated significantly, but more so with fathers' heights ( r = 0.50) than with mothers'( r = 0.42). The correlation was still apparent with the target height ( r = 0–55). The results of different series in the literature show the existence of significant variations as mean final heights are between 136 and 147 cm. These differences can be explained by the variations in normal female heights in each country. We have found in these different countries a very strong correlation ( r = 0.9I) between normal height and final height in Turner's syndrome. It is therefore necessary to know the spontaneous final height for Turner's syndrome in different countries in order to judge the efficacy of growth hormone treatment, and also to take into account the target height of each child in order to evaluate individual results.     

Height screening at school: ineffective without high standards and adequate resources

Background: The Coventry Consensus in 1998 recommended a single height measurement of all children at school entry or around the age of 5 years and prompt referral of children with height <0.4th centile for further assessment, in order to identify undetected and treatable asymptomatic growth disorders. Aim: To determine adherence and practicalities of following the Coventry Consensus recommendations in a community setting and the cost implications. Methods: Anthropometric data of all children born between September 1992 and August 1993 in the Rhondda and Taff Ely area and measured in school year September 1998 to August 1999 were obtained from the National Child Health System (NCHS) and analysed in July 2000. Results: Only 1592 (67.6%) of 2354 eligible children had their height measured. The NCHS could only flag up height data <2nd centile. Only five of the 15 children with height <0.4th centile were referred initially. Height measurements were not transcribed onto centiles in 75% of the case notes reviewed. When initially recalled, six of the 15 eligible children failed to attend the referral clinic. No new growth disorder was identified in any of these children. A conservative estimate of the cost to the health authority was £14 550 (US$23 300; €20 500) per annum. Conclusion: The study shows poor coverage and compliance together with a lack of parental awareness that short stature could be a potential health problem even in asymptomatic children. For a low yield programme to be successful and cost effective at the national level, a near 100% coverage is required. Further training of professionals in growth measurement and interpretation along with a campaign to raise both public and professional awareness is needed.     

Testosterone treatment of excessively tall boys.

Twenty-nine tall boys with a mean height prediction of 198 cm were treated for serious psychosocial reasons with high doses of a long-acting testosterone preparation (500 mg/m2/month). Their ages at the start of treatment ranged from 9.8 to 16.9 years, and the mean duration of treatment was 1.2 years. Bone age was assessed according to the Tanner-Whitehouse II (RUS) method, and height predictions were calculated using the age-specific regression equations of Tanner and colleagues. On the basis of bone age at the start of treatment, three groups were formed (bone age 12.1 to 14, 14.1 to 15, and greater than 15 years), and the results were assessed separately. In the whole series, adult height was reduced by 5.4 cm; the best results (8cm) were achieved in the youngest bone age group. Under treatment, bone maturation was accelerated (1.8 years per year) and growth velocity increased (youngest bone age group) or was normal (older bone age groups). Testicular volume remained prepubertal in young patients and decreased in older ones. After discontinuation of treatment, testicular volume and sperm count became normal again after a mean period of 1.5 years, but in a few cases recovery was slower. It is concluded that adult height in tall boys may be effectively reduced by testosterone, that the results are best if treatment is started in early puberty, and that the suppressing effects on pituitary and testicular function are fully reversible. Since the indication for treatment is a psychosocial one, the patients should be carefully selected, taking into account not only growth but also psychological and familial factors.     

Height screening at school: ineffective without high standards and adequate resources.

BACKGROUND: The Coventry Consensus in 1998 recommended a single height measurement of all children at school entry or around the age of 5 years and prompt referral of children with height <0.4th centile for further assessment, in order to identify undetected and treatable asymptomatic growth disorders. AIM: To determine adherence and practicalities of following the Coventry Consensus recommendations in a community setting and the cost implications. METHODS: Anthropometric data of all children born between September 1992 and August 1993 in the Rhondda and Taff Ely area and measured in school year September 1998 to August 1999 were obtained from the National Child Health System (NCHS) and analysed in July 2000. RESULTS: Only 1592 (67.6%) of 2354 eligible children had their height measured. The NCHS could only flag up height data <2nd centile. Only five of the 15 children with height <0.4th centile were referred initially. Height measurements were not transcribed onto centiles in 75% of the case notes reviewed. When initially recalled, six of the 15 eligible children failed to attend the referral clinic. No new growth disorder was identified in any of these children. A conservative estimate of the cost to the health authority was pound 14 550 (US23 300 dollars; 20 500 euro) per annum. CONCLUSION: The study shows poor coverage and compliance together with a lack of parental awareness that short stature could be a potential health problem even in asymptomatic children. For a low yield programme to be successful and cost effective at the national level, a near 100% coverage is required. Further training of professionals in growth measurement and interpretation along with a campaign to raise both public and professional awareness is needed.     

Delayed diagnoses of Turner's syndrome: proposed guidelines for change

OBJECTIVE: To measure the delays in diagnosis of Turner's syndrome (TS) and to propose strategies for earlier screening and diagnosis. METHODS: The medical records of 81 girls with TS were reviewed for age at diagnosis, reason(s) for karyotype analysis, and clinical features including growth failure. Delay in diagnosis was calculated as equal to age at diagnosis for children born with lymphedema and/or 2 or more of the following dysmorphic features: webbed neck, nail dysplasia, high palate, and short fourth metacarpal. For all others, delay in diagnosis was calculated as the difference between the age at which height fell below the 5th percentile and the age at which the diagnosis of TS was made. RESULTS: Lymphedema was the key to diagnosis in 97% of the girls diagnosed with TS in infancy, and short stature was the key to diagnosis for 82% of the girls diagnosed in childhood or adolescence. For girls diagnosed in childhood or adolescence, the delay in diagnosis averaged 7.7 +/- 5.4 years. Many had dysmorphic features and/or a history of lymphedema at birth, and diagnosis was made an average of 5.3 years after patients had fallen below the 5th percentile for height. By the time of diagnosis, patients were very short, averaging -2.9 SD in height. CONCLUSIONS: The diagnosis of TS is often delayed. We recommend karyotype analysis for all girls with unexplained short stature, delayed puberty, webbed neck, lymphedema, or coarctation of the aorta. Furthermore, karyotype analysis should be strongly considered for those who remain above the 5th percentile for height but have 2 or more features of TS, including high palate, nail dysplasia, short fourth metacarpal, and strabismus.     

Managing expectations in the child of short stature with no underlying cause

Idiopathic short stature is a common reason for referral to the general paediatric or endocrine clinic. It can negatively impact the quality of life for the child and young person, extending into adulthood for some. However, these children are healthy individuals and treatment is not usually indicated. Whilst those with constitutional delay in growth and puberty can be given hormonal supplementation to induce puberty, there is no treatment available in the UK for the remaining children and young people as growth hormone is not approved for idiopathic short stature. It is important to emphasise to the child, young person and family that they are following a normal pattern of growth to reduce the perception that there is a problem. Growth charts plotted with bone age and a target range for family size are useful for predicting adult height and managing patient and parental expectations.     

Final height in Swedish children with idiopathic growth hormone deficiency enrolled in KIGS treated optimally with growth hormone

Aim: To assess final height in children with growth hormone deficiency (GHD) treated with human recombinant growth hormone (GH). Methods: Final height data for 401 Swedish children with idiopathic GHD and treated with GH, included in KIGS (Pfizer International Growth Database) between 1987 and spring 2006, were analysed retrospectively. Data were grouped according to sex, age and severity of GHD. Height at entry into KIGS, at the onset of puberty and near final height were analysed between groups. Results: Groups were heterogeneous for GHD, which ranged from partial to severe. For all groups, mean final height corrected for mid‐parental height was within the normal Swedish height range. In patients with severe GHD, mean final height was almost identical to mean normal Swedish height. About 16% of patients showed disproportionality (short legs) at final height and were significantly shorter than other patients. The parents of these children also demonstrated short stature. Conclusion: Children with idiopathic GHD receiving GH replacement therapy can achieve a final height that as a group is within the normal range and all achieve a height within their genetic potential.     

Efficacy of long-term growth hormone treatment in Turner's syndrome. European Study Group

The efficacy of long-term growth hormone treatment and the optimal treatment modalities in Turner's syndrome are still controversial. Studies have shown widely divergent results. While there is still need for results of randomized controlled trials, large uncontrolled trials remain a valuable source of preliminary information. This study of 136 girls with Turner's syndrome (TS) from the European Lilly Turner Study shows that the treatment regimens followed by girls with TS who start GH treatment at a relatively late age (12.9 +/- 2.2 yr) lead at best to a small average gain in final height. Mean gain over initial projected final height was 3.7-4.7 cm, depending on the chosen Turner-specific height-for-age reference data. There was a considerable variation in gains over initial projected final height (range -10.6 to +17.2 cm), which may be partly explained by the existence of good and bad responders. Whether there is a genetic/molecular basis for this and how responsiveness can best be predicted remains an important challenge.     

Management of diabetes mellitus in children younger than 5 years of age

Optimal treatment for children younger than 5 years of age with insulin-dependent diabetes mellitus is not well defined. Nineteen young children with this disease were treated with a program in which frequent home blood-glucose monitoring was used as the basis for an educational program emphasizing parental adjustment of insulin in response to current glucose levels and anticipated diet and exercise. Eleven children were treated from diagnosis (group I) and another eight (group D) were referred after less intensive treatment. The mean duration of observation of group I children was 13.6 months (range, six to 24 months). For group D, the mean time between diagnosis and referral was 14.9 months (range, seven to 24 months) and 14.6 months (range, six to 24 months) after referral. Before referral, there were 11 hospitalizations in group D. During the intensified program there were two hospitalizations in group D and one in group I. There were 3.3 episodes of severe hypoglycemia per child per 18 months in group D before referral, 1.7 episodes after referral, and 0.4 episodes in group I. Ten of 14 severe hypoglycemic episodes during intensified treatment occurred when there was no or infrequent home blood-glucose monitoring. Only four episodes seemed to have been unpredictable and unpreventable. Mean glycosylated hemoglobin levels were higher in group D patients when compared with both the duration of insulin-dependent diabetes mellitus and the time of initiation of intensified treatment. Mean daily insulin doses increased progressively in group I patients following diagnosis, and were comparable with those in group D patients at 15 and 18 months' duration of illness. Thus, frequency of hospitalization and severe hypoglycemia can be decreased in young children. Frequent home blood-glucose monitoring is required and extensive educational and psychosocial support is necessary for families to implement this intensive approach. The long-term effects on psychoneurological development need evaluation.