Can the TW3 bone age determination method provide additional criteria for growth hormone treatment in adopted girls with early puberty? A comparison of the Tanner-Whitehouse 3 method with the Greulich-Pyle and the Tanner-Whitehouse 2 methods.

BACKGROUND/AIMS: Gonadotropin-releasing hormone analogues (GnRHa) are the accepted treatment of idiopathic central precocious puberty. As it has been found that growth velocity may be decreased with GnRHa treatment, clinical trials with GnRHa combined with growth hormone (GH) have been carried out. In a recent study 46 adopted girls with early or precocious puberty were randomly assigned to treatment with either GnRHa or GnRHa combined with GH, and followed to final height (FH). It was found that FH was significantly higher in the combined treatment group, 158.9 compared with 155.8 cm in the GnRHa treated group. In order to select the patients who could benefit from added GH, predictions of FH at the start of treatment according to the methods of bone age determination of Greulich-Pyle (GP) and Tanner-Whitehouse 2 (TW2) were compared. It was found that the GP method was the most useful method for patient selection. Recently, a revision of the Tanner-Whitehouse method, named Tanner-Whitehouse 3 (TW3), has been developed. The present study examined the usefulness of the TW3 method in selecting suitable patients for combined treatment. METHOD: The TW3 method bone age determinations of the 46 girls were compared to the GP and TW2 method determinations, using the differences between actual FH and predicted adult height (PAH). Beside accuracy of prediction of FH, the criteria of efficiency of selection and replicability were applied in the comparison. RESULTS: We found that the GP method, also when compared to the TW3 method, gave the most accurate prediction of the FH on only GnRHa treatment. This gives the best ground for selection of patients who can benefit from combined treatment. The GP method was also the most efficient in selecting patients, i.e., it could select the least number of patients that needed the combined treatment. The only drawback of the GP method was that it requires an experienced pediatric radiologist. Automated methods are being developed and may soon facilitate the use of the GP method for those less experienced. The FH after combined treatment could be predicted with an equation including PAH GP as well as PAH TW3 as variables. CONCLUSION: The GP method remains the most useful method for selection of those patients who will benefit most from the addition of GH to GnRHa in the treatment of idiopathic central precocious or early puberty. FH prediction after combined treatment requires PAH GP as well as PAH TW3.

Can bone age determination provide criteria for growth hormone treatment in adopted girls with early puberty?

In treatment of idiopathic central precocious puberty, GnRH analogues (GnRHa) have been accepted as the treatment of choice. Since growth velocity may be impaired with GnRHa treatment growth hormone (GH) treatment has been added in clinical trials. Recently, a study followed adopted girls with early or precocious puberty on GnRHa or combined GnRHa and GH treatment to final height. It was found that final height was significantly higher in the combined treatment group, although the difference was small. It was seen that patients that were extremely short at arrival and short at start of treatment seemed to be candidates for combined treatment. We have now analysed the data in order to define criteria for the sub-group in need of combined GnRHa-GH treatment in order to achieve normal final height, i.e. above -2 SDS. Bone ages of 46 patients at start of treatment, randomized to either GnRHa treatment or GnRHa treatment combined with GH, were examined blindly by the same radiologist and the PAH calculated. The methods according to Greulich-Pyle / Bayley-Pinneau (GP/BP) and Tanner-Whitehouse (TW2) were used. Predictions versus final height data were analysed. The accuracy of FH prediction was greatest for GnRHa treated group using the GP/BP method. The GP/BP method gave useful cut off limits for when combined treatment was necessary to possibly achieve normal height. If pre-treatment GP/PAH was > 157cm, the patients attained normal height with GnRHa treatment only. Ten out of 13 (77%) such girls could be correctly identified. Using TW2 with a cut off of 164 cm, 9 out of 13 could be selected. Using a multi regression equation of best fit the number of correctly selected cases for GnRHa treatment only, could not be further increased in this group. We conclude that bone age determination and adult height prediction with the Greulich-Pyle/Bayley-Pinneau method, provides useful criteria for selecting the subgroup of adopted girls with early puberty where combined treatment with GnRHa and GH is not necessary to reach normal final height.

Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty.

BACKGROUND: Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotrophin-releasing hormone (GnRH) analogues. During such treatment, decreased growth velocity is frequent. AIM: To study whether the addition of growth hormone (GH) to GnRH analogue treatment improves final height in girls with early or precocious puberty. METHODS: Forty-six girls with early or precocious puberty (age < or =9.5 y) adopted from developing countries were randomized for treatment for 2-4 y with GnRH analogue, or with a combination of GH and GnRH analogue. RESULTS: During treatment, the mean growth velocity in the GH/GnRH analogue group was significantly higher compared to the control group. Combined GH/GnRH analogue treatment resulted in a higher final height: 158.9 cm compared to 155.8 cm in the GnRH analogue-treated group. Three out of 24 girls (13%) in the combined group and nine of the 22 girls (41%) treated with GnRH analogue alone attained a final height below -2 standard deviation scores (SDS). CONCLUSION: The difference between the two groups is statistically significant, and possibly of clinical importance. A future challenge is to identify a subgroup with clinically significant advantage of GH addition to GnRH analogue treatment. Being very short on arrival in Sweden and being short and young at start of treatment are possible indicators.

Growth hormone treatment during suppression of early puberty in adopted girls. Swedish Growth Hormone Advisory Group.

Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotropin-releasing hormone (GnRH) analogues. During such treatment decreased growth velocity is frequent. The aim of this investigation was to study whether the addition of growth hormone (GH) to GnRH analogue treatment improves height velocity and final height in girls with early or precocious puberty. Forty-six girls with early or precocious puberty adopted from developing countries were randomized for treatment with GnRH analogue or a combination of GH and GnRH analogue. After 2 y of treatment the mean growth in the GH/GnRH analogue group was significantly higher, 14.6 cm, compared to 10.9 cm in the control group. The increase in bone age did not differ, while the difference in predicted adult height increased by 2.7 cm in favour of the combination group. Although data on final height are not yet available, combined GH/GnRH analogue treatment for 2 y resulted in a higher growth velocity and predicted final height compared to GnRH analogue treatment alone.

Growth and subcutaneous fat during the first five years of insulin-dependent diabetes in children.

Thirty-four children were observed prospectively during a period of 5 years from the onset of diabetes regarding height, weight and subcutaneous fat in relation to treatment and diabetes control. Height, weight and body mass index (BMI) did not differ from those in a control group. The girls with diabetes increased their triceps and subscapular fat significantly despite a normal BMI. This increase in relation to control girls was most pronounced during late adolescence. Triceps skinfold and BMI after 5 years were both negatively correlated to insulin dose per kilogram body weight in the diabetic girls. We conclude that girls with diabetes accumulate subcutaneous fat in certain areas rapidly during adolescence in a completely different way from healthy girls.

Serum magnesium and protein concentrations during the first five years of insulin-dependent diabetes in children.

Thirty-four children were followed up prospectively for 5 years from the onset of diabetes regarding serum magnesium, zinc and some proteins. Serum magnesium decreased to significantly lower values (0.76 +/- 0.05 mmol l-1) than those in matched controls after 2 and 5 years, with the lowest mean values in diabetic girls. Serum zinc concentration was higher in the diabetic group than in the control children, and again the diabetic girls differed most from the controls. Serum prealbumin was significantly lower in the diabetic patients after 2 and 5 years than in the controls. Serum albumin was also slightly reduced in the diabetic patients, while orosomucoid was normal. These data indicate chronic magnesium deficiency and insufficient liver synthesis of certain serum proteins in diabetic children.

Clinical characteristics of insulin-dependent diabetes mellitus in children at diagnosis.

The clinical characteristics of 60 consecutive children < 16 years in a Swedish county with newly diagnosed diabetes mellitus, are described. Twenty-four of them were 5.0-9.9 years old. The fathers of 12% had diabetes. There was no seasonal variation in the onset of diabetes. Presenting symptoms were polyuria and polydipsia in more than 90% of the cases. School children had a longer duration of symptoms than pre-school children. Most of the children were in a good state of health, and none were unconscious on admission. HbA1C was a good indicator of diabetes duration (R2 = 0.32). Patients with Coxsackie B IgM antibodies had lower blood glucose than those without such detectable antibodies.

Increased perinatal intracranial pressure and prediction of early puberty in girls with myelomeningocele.

An increased risk of developing precocious puberty has been reported in children with myelomeningocele. In order to evaluate this further and to study factors associated with early or precocious puberty the medical records of all girls with myelomeningocele, born from 1970 onwards (n = 64), who were admitted to our unit were reviewed. Early/precocious puberty (E/PP) was defined as breast development or pubic hair corresponding to Tanner stage 2 before the age of 9.2 years. In 32 out of 62 cases data were sufficient for evaluation of the timing of puberty. Twenty girls had E/PP and 12 girls normal timing of puberty. In the girls who had reached the age of 9.2 years the incidence of E/PP was at least 52%. Girls with E/PP had a higher incidence of hydrocephalus, were treated with intraventricular shunts more often, and had significantly higher frequency of increased intracranial pressure during the perinatal period (p < 0.05, p < 0.01, and p < 0.001, respectively). The group of girls developing E/PP was also more severely disabled with respect to motor and urological function and had more shunt revisions. In conclusion, E/PP in girls with myelomeningocele is strongly associated with increased intracranial pressure particularly during the perinatal period.

Pubertal linear growth of Indian girls adopted in Sweden.

Pubertal linear growth in 66 adopted Indian girls was studied. The infancy-childhood-puberty standard was used, since it is applicable to Indian girls, and enables determination of the onset and height gain of the pubertal growth phase in an individual. At arrival in Sweden, mean height was -2.8 SDS. Despite rapid catch-up growth, the girls were still below the reference mean (-0.8 SDS) at the onset of the pubertal growth spurt, which occurred approximately 1.5 years earlier than in Swedish girls and also earlier than in Indian girls. The pubertal height gain, however, was equivalent to that in Swedish girls with similar timing of puberty. The short final height found in some of these girls appears to be related to shortness prior to puberty and to very early onset of an otherwise normal pubertal growth component.

Anthropometry in adolescence--secular trends, adoption, ethnic and environmental differences.

A secular trend towards higher final height and earlier pubertal maturation is seen in countries with favourable socio-economic development and higher social classes in countries are also associated with taller height and earlier maturation. Environmental factors, such as nutrition and infections, appear to be the main causes for differences in growth and maturation between ethnic and social groups. Differences in final height are mainly due to prepubertal growth. Studies on immigrant children and children adopted into privileged conditions from developing countries confirm the influence of early growth on subsequent growth. Catch-up growth in adopted children could only partially compensate for early stunting, and in several cases was cut short by early pubertal development. A minority developed very early puberty and eventually very short final height. The optimal rate of catch-up growth, the trigger mechanism for early puberty, and the effect of various types of nutritional intervention need to be studied. The studies reported here indicate the critical importance of optimal intra-uterine, infant and childhood growth as a basis for satisfactory growth during adolescence.

A longitudinal study on anthropometric and clinical development of Indian children adopted in Sweden. II. Growth, morbidity and development during two years after arrival in Sweden.

One hundred and fourteen consecutively recruited children adopted from India (60% girls) to Sweden were studied during 2 years after arrival, with examinations monthly the first 6 months and thereafter every 3 months. Sixty-two percent were below 1 year of age at arrival. There was a mean increase from -2.2 standard deviation scores (SDS) height/age to -0.7 SDS during the two years, and a similar development for weight/age, with no significant difference between boys and girls. The weight/height remained at around -0.8 throughout the study period. Those who had lowest height/age at arrival had the most marked catch-up, but remained smaller throughout the 2 years. The psychomotor development was initially delayed in nearly 30% of the children, mainly among those stunted and/or with very low weight at arrival. After 2 years the rate was at a level similar to Swedish children. In a sub-sample, birth weight was found to be correlated to subsequent height and weight development. Hepatitis B, salmonella, giardia lamblia, trichuris trichiura, ascaris and hymenolepis nana were still found in a small percentage after 2 years. Other morbidity was at the same level as in Swedish children. Adopted children who are stunted and/or have a very low weight at arrival should be followed up with special care, and infectious diseases found at arrival should be kept in mind for differential diagnosis at subsequent disease episodes.

A longitudinal study on anthropometric and clinical development of Indian children adopted in Sweden. I. Clinical and anthropometric condition at arrival.

One hundred and fourteen children (60% girls) adopted from India through five major adoption organizations, were recruited consecutively. This paper describes the environment of the children in India and in Sweden, discusses the certainty of the ages and reports their condition at arrival in Sweden. The median age at arrival was 9.3 months, 62% being below one year of age (range 3-72 months). Infectious diseases similar in kind and frequency to those noted in child populations in developing countries, were found. Height/age and weight/age mean values were approximately -2 standard deviation scores (SDS) of the NCHS/WHO standard, which is similar to the anthropometric status of Indian average children. There were no significant sex differences. Thirty-seven birth weights were known, the majority below 2,500 g. Psychomotor retardation was found in 29% of the children. In the children with stunting and in those with weight/age less than -3 SDS at arrival there were high percentages of psychomotor retardation, anaemia and combined wasting and stunting. Therefore these children should be regarded as a risk group and be followed up with special care.

Menarcheal age and growth pattern of Indian girls adopted in Sweden. I. Menarcheal age.

The median menarcheal age of 107 girls adopted from India by families in Sweden was 11.6 years, which was significantly lower than in Swedish and most Indian studies. Five girls had menarche before the age of 9 years, the earliest at 7.3 years. Those who arrived at a later age had earlier menarche. No differences in menarcheal age were found with respect to geographic origin. The reasons for the earlier pubertal maturation are not clear. Factors associated with the rapid transition from an underprivileged to a privileged environment are probably involved, besides genetic determinants. The serious medical, social and emotional consequences of very early pubertal development necessitate further clarification of the underlying mechanisms.

Menarcheal age and growth pattern of Indian girls adopted in Sweden. II. Catch-up growth and final height.

Adopted girls (n = 107) previously studied regarding menarcheal age in relation to age at arrival, were analysed as to growth pattern and final height related to nutritional status at arrival and menarcheal age. It was found that most girls had catch-up growth regarding height and half of them regarding weight. Faster catch-up and later arrival age in Sweden were associated with earlier menarche. The catch-up growth was, however, incomplete, and lower the initial height for age, lower was the height for age at the succeeding measurements, and the final height. The mean final height was 154 cm, but 8% of the girls were 145 cm or shorter. The data suggest that linear growth and final height is influenced by the preadoptive nutritional condition, as well as by the degree and timing of subsequent catch-up growth, and the timing of puberty. Pubertal onset is related to the degree and timing of catch-up growth.