Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome.

It is well established that insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and insulin are low in growth hormone deficiency, but due to their dependence on nutrition, they are elevated in healthy obese children. As the presence of growth hormone deficiency in Prader-Labhart-Willi syndrome (PWS) is still controversial, we studied insulin, IGF-I and IGFBP-3 levels in 19 children with PWS (age range 0.5-14.6 years). Serum concentrations of insulin (SDS: -0.7+/-0.9, P = 0.01) and IGF-I (SDS: -0.7+/-0.8, P = 0.002) were low, but IGFBP-3 (SDS: -0.3+/-1.2, P = 0.2) was normal compared to normal weight age-matched children. Since children with PWS are typically obese, insulin, IGF-I and IGFBP-3 levels should be compared to normal obese children who present increased levels of these hormones. In comparison to data of healthy obese children reported in the literature, not only IGF-I, but also IGFBP-3 levels are low and fasting insulin levels even very low, suggesting a growth hormone deficiency.

Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance.

UNLABELLED: Twelve children with documented Prader-Labhart-Willi syndrome were treated with human growth hormone (24 U/m2/week) during 1 year. The children were divided into three groups: group 1: overweight and prepubertal (n=6, age 3.8-7.0 years); group 2: underweight and prepubertal (n=3, age 0.6-4.1 years); group 3: pubertal (n=3, age 9.2-14.6 years). In group 1, height increased from -1.7 SD to -0.6 SD, while weight decreased from 1.1 SD to 0.4 SD, with a dramatic drop in weight for height from 3.8 SD to 1.2 SD. Hand length increased from -1.5 SD to -0.4 SD and foot length from -2.5 SD to -1.4 SD. Body fat, measured by dual X-ray energy absorptiometry, dropped by a third, whereas muscle mass increased by a fourth. Physical capability (Wingate test) improved considerably. The children were reported to be much more active and capable. In group 2, similar changes were seen, but weight for height increased, probably because muscle mass increase exceeded fat mass decrease. Changes in group 3 were similar as in group 1, even though far less distinct. CONCLUSION: Growth hormone treatment in Prader-Labhart-Willi syndrome led to dramatic changes: distinct increase in growth velocity, height and muscle mass, as well as an improvement in physical performance. Fat mass and weight for height decreased in the initially overweight children, and weight for height increased in underweight children.

Prediction of adult skinfolds and body mass from infancy through adolescence.

In this paper age-to-age correlations for the body mass index and for skinfolds are evaluated for a sample of normal children studied from birth to adulthood. While correlations over larger age spans are modest, they become appreciable from childhood to adolescence and from adolescence to adulthood. Correlations are consistently higher for boys compared to girls, and only for the former does the body mass index correlate better than skinfolds. Significant correlations between weight increase in the first year and the adult body mass index were found, as well as between the age of 'adiposity rebound' and the adult body mass index. However, the small size of the correlations forbids any predictive applications. As it turns out, the individual prediction of the adult size of the body mass index or of skinfolds is a thorny problem, whatever variables and methods are chosen. The precision of such a prediction is very low up to late childhood and becomes somewhat better in adolescence. From a positive side, this leaves much room for overweight children to improve their state. On the other hand, the relative risk for becoming a heavy adult is much increased for those who are already heavy as children and adolescents. This underlines the dangers of early overweight from an epidemiological viewpoint.

Replacement of growth hormone (GH) in normally growing GH-deficient patients operated for craniopharyngioma.

Removal of a craniopharyngioma usually results in panhypopituitarism. Some children, however, grow normally or even excessively after extirpation of the tumor despite a proven lack of GH and have so far not been treated with hGH. We studied the effects of short (2-day) and long term (1-yr) administration of hGH on metabolism and growth in six patients receiving regular hormonal replacement therapy. During short term human (h) GH treatment, 15N retention was not significantly increased (mean +/- SEM, 115.4 +/- 9.6% of basal balance) and was not different from the control value. In contrast, 15N retention was 210.3 +/- 20.7% in children with GH deficiency from other causes. Long term administration of hGH (2 IU/m2.day, sc, for 12 months) did not influence growth velocity, but increased the calf circumference and decreased the body mass index and skinfold thickness in prepubertal patients. Insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the 150-kilodalton IGFBP complex were decreased before and restored to normal during treatment. The reverse was observed for the 50-kilodalton IGFBP complex. Growth (velocity) in these patients did not correlate with any of the usual indicators of the growth status and remains unexplained. Although hGH did not affect growth, it had other beneficial effects and is recommended for these patients.

A longitudinal study of lean and fat areas at the arm.

Using biceps and triceps skinfolds and upper arm circumference, areas of fat and lean tissue at the arm can be approximately determined based on a cylindrical assumption. Based on the first Zürich growth study a longitudinal analysis of estimated fat and lean areas is undertaken. Area may often be a more meaningful parameter than width in development, due to the increasing width of the limbs stretching the layer of fat. When comparing these quantities with the body mass index, correlations in boys were higher for lean area than for fat area, and about equally high for both measures in girls (around 0.8 beyond age 10). The primary goal of this investigation was to quantify the development of lean and fat arm areas from birth to adulthood, and to assess sex differences in this respect. The comparison with results obtained earlier from radiographic data is of particular interest, since such data can rarely be obtained any more, and overall this comparison can be considered encouraging. Lean area develops slowly until the onset of puberty, girls showing a slightly smaller value than boys. The pubertal spurt is very impressive in boys and moderate in girls, timed to age of peak height velocity in both sexes. Fat area changes only minimally in boys older than 16 months, and increases steadily in girls until age 16. The respective velocity curve shows a systematic up and down until age 5, when a gradual increase to a prepubertal fat spurt starts. It is interrupted by a trough in velocity--much more accentuated in boys--at puberty, and followed by a postpubertal fat spurt. When studying subgroups of subjects with a relatively high or relatively low adult body mass index, the heavy group differed relatively more in terms of fat area than lean area. Girls heavy as adults increase their fat area consistently more from about 5 years onwards. Boys later heavy show a qualitatively different pattern in puberty, with accentuated pre- and postpubertal fat spurts, but also a strong trough to a negative velocity in between.

Development and outcome of indices of obesity in normal children.

Based on the Zürich longitudinal growth study, differences are analyzed between those children who later became light adults (later light) and those who later became heavy (later heavy) adults. This is of interest to discover how and when overweight develops, and which variables are most affected (weight, body mass index, circumferences and skinfolds are studied). A further question is whether maturation proceeds differently in these children. The principal idea is to split the sample with respect to adult body mass index into three parts, and to analyse the two extreme groups. It is shown that structural average curves for these subgroups lead to a substantial insight into the processes going on in different variables. Whereas maturation is not much different, subjects later heavy gain substantially more in fat and body mass index from about 4 to 5 years onwards. The natural pattern of ups and downs becomes exaggerated in subjects who are to become heavy at adult age. In those phases where it is natural to build up body mass index there is not much of a difference. In phases where later lean subjects hardly increase their body mass index, later heavy subjects continue to build it up substantially.

Measures of body mass and of obesity from infancy to adulthood and their appropriate transformation.

In this paper we investigate first the choice of an appropriate index of body mass. The traditional indices weight/height (W/H), W/H2 and W/H3 are compared, as well as an approach due to Cole (1986) making the index W/Hp age-dependent, i.e. by allowing the power p to depend on age. While there may be no perfect index reflecting over- and underweight--irrespective of height and width--the Quetelet index W/H2 turned out to be a reasonable index from childhood to adulthood. Second, we study the development of the body mass index W/H2 longitudinally from birth onwards, based on structural average distance, velocity and acceleration curves. As a third topic, transformations for obtaining an approximate normal distribution for W/H2, weight and skinfolds are compared. The usual log-transformation turned out to be unsatisfactory. While for height and arm skinfolds a transformation -1/square root of x performs rather well across age and sex, a transformation -1/x is more appropriate for trunk skinfolds and W/H2.

Angel-shaped phalango-epiphyseal dysplasia (ASPED): identification of a new genetic bone marker.

We describe a "new" mild malformation of the phalanx, which we call the "angel-shaped phalanx" (ASP) because of its resemblance to the little angels used for the decoration of Christmas trees. A particular middle phalangeal type of ASPs is found in a distinct variety of multiple epiphyseal dysplasia with marked retardation of bone age and severe coxarthrosis in adult life, previously reported as "hereditary peripheral dysostosis" [Bachman, 1967: Proc R Soc Med 60:21-22; Giedion, 1969: Fortschr Rontgenstr 110:507-524]. However, these authors overlooked the unique configuration of the middle phalanges. We renamed the condition "angel-shaped phalango-epiphyseal dysplasia (ASPED)", which may be transmitted in an autosomal-dominant manner. Six new patients are added, bringing the total to nine patients (two families and two isolated patients). ASPs were seen in five of six children. The ASPs grew into inconspicuous brachydactyly after physeal closure (3/3). The most important additional radiological finding is late and dysplastic development of both femoral heads (5/5), leading to Perthes-like and osteoarthritic changes and severe hip pain in the early thirties (2/2 adults, having reached this age). The marked retardation of carpal bone age may lead to unnecessary clinical evaluation for endocrine disorders. Less frequent clinical manifestations of ASPED are hyperextensibility of the interphalangeal joints (7/9) and hypodontia (4/7). Other types of ASPs are observed in brachyphalangy type C, spondylo-megepiphyseal-metaphyseal dysplasia, and other conditions. The concept of mild bone abnormalities as specific markers for genetic disease, as with cone-shaped epiphyses and now evident in ASPED, may also be useful for ASPs in general.

The dynamics of growth of weight, circumferences and skinfolds in distance, velocity and acceleration.

Based on structural average curves of distance, velocity and acceleration, an analysis of the longitudinally assessed growth of weight, arm and calf circumferences and skinfolds (biceps, triceps, suprailiac, subscapular) was undertaken. The data come from the first Zürich longitudinal growth study and represent a normal sample. In addition to a graphic analysis, timing, intensity and duration of the mid-growth spurt (MS) and of the pubertal spurt (PS) are quantified via descriptive parameters of growth. Mechanisms are different and more complex for these variables, in particular for skinfolds, compared to previously studied somatic variables, such as height. Skinfolds showed a rapid decline to a negative velocity minimum in the first year, recovering to a pre-PS fat spurt, earlier and more pronounced for central (suprailiac, subscapular) than for peripheral skinfolds (biceps, triceps). At age of peak height velocity a drop occurred, stronger for boys, followed by a post-PS spurt. A further analysis demonstrates that these ups and downs in skinfold velocity are mainly due to subjects with thick skinfolds. Weight and circumferences show a distinct MS, with sex-independent characteristics and a strong, sex-dependent PS. Weight and even more arm circumference are delayed compared to height in puberty.

Progressive high frequency hearing loss: an additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency.

In an earlier report, we found that X-linked congenital adrenal hypoplasia may be associated with gonadotrophin deficiency. This combination has since been confirmed by many others. At the last examination, our patients were 22.4, 19.9 and 17.5 years old. They were doing well on replacement therapy with hydrocortisone, fluorohydrocortisone, and long-acting testosterone, but in all of them, a progressive hearing loss had appeared, starting at high frequencies at about 14 years of age. The loss progressed with age to lower frequencies, and the oldest patient had some remaining hearing capacity at 125-500 Hz only with a perceptive hearing loss of -95 dB at frequencies above 500 Hz. It is concluded that patients with this syndrome should be examined for hearing loss. X-linked adrenal hypoplasia may also be associated with glycerol kinase deficiency and myopathy. A molecular XP-deletion has suggested a locus for hypogonadotrophic hypogonadism distal to the glycerol kinase and adrenal hypoplasia loci. The observations in our patients suggest that the locus for at least this type of X-linked deafness may be in the same area.

Molecular, cytogenetic, and clinical investigations of Prader-Willi syndrome patients.

Thirty-seven patients presenting features of the Prader-Willi syndrome (PWS) have been examined using cytogenetic and molecular techniques. Clinical evaluation showed that 29 of these patients fulfilled diagnostic criteria for PWS. A deletion of the 15q11.2-q12 region could be identified molecularly in 21 of these cases, including several cases where the cytogenetics results were inconclusive. One clinically typical patient is deleted at only two of five loci normally included in a PWS deletion. A patient carrying a de novo 13;X translocation was not deleted for the molecular markers tested but was clinically considered to be "atypical" PWS. In addition, five cases of maternal heterodisomy and two of isodisomy for 15q11-q13 were observed. All of the eight patients who did not fulfill clinical diagnosis of PWS showed normal maternal and paternal inheritance of chromosome 15 markers; however, one of these carried a ring-15 chromosome. A comparison of clinical features between deletion patients and disomy patients shows no significant differences between the two groups. The parental ages at birth of disomic patients were significantly higher than those for deletion patients. As all typical PWS cases showed either a deletion or disomy of 15q11.2-q12, molecular examination should provide a reliable diagnostic tool. As the disomy patients do not show either any additional or more severe features than typical deletion patients do, it is likely that there is only one imprinted region on chromosome 15 (within 15q11.2-q12).

The dynamics of growth of width in distance, velocity and acceleration.

In this paper the dynamics and intensity of the growth of bihumeral and biiliac width and of humerus and femur bicondylar diameter are studied and compared, and sex differences are established. The analysis is based on a newly introduced statistical tool, the structural average curve for distance, velocity and acceleration. It accounts for individual developmental tempo and allows pooling data for a sample of subjects. In all four variables studied, a sharp decline in velocity after birth is followed by a more gradual decline in infancy and childhood. A mid-growth spurt (MS) at about age 7 can be found in all variables, of about equal timing and intensity for the two sexes. The pubertal spurt (PS) is earlier for girls, and less intense except for biiliac width. The study shows a characteristic pattern across variables of width regarding the intensity of growth in different periods. The accentuated MS and PS for bihumeral width, contrasting with relatively early and small PS for the bicondylar width of femur, are remarkable.

The dynamics of linear growth in distance, velocity and acceleration.

Growth of body, leg, trunk and arm length from birth to adulthood is studied in the subjects of the First Zürich Longitudinal Growth Study, using a recently developed technique, the 'structural average curve'. In this way truly longitudinal average curves are obtained for velocity, acceleration and distances, and various phases of growth are analysed not only graphically, but also by descriptive parameters in terms of timing, intensity and duration. These phases consist of the pubertal spurt (PS), the mid-growth spurt (MS) and growth in infancy. The overall pattern is the same in all variables studied: velocity drops sharply after birth, followed by a kink between 7 and 12 months, and a more gradual decrease until the MS, which peaks around 7 years. In girls the PS immediately follows the MS, while in boys a 'latency period' of approximately constant growth velocity precedes the PS, which occurs almost 2 years later, and is more intense than in girls. There are no appreciable sex differences in the MS, but the PS is later and more intense for boys, even when accounting for the smaller adult size of girls. When comparing linear variables the PS turns out to be earlier for the legs than for the trunk, whereas the trunk has an earlier MS. The trunk starts high in relative distance and in velocity after birth, whereas the legs have a high velocity throughout childhood. In adolescence the trunk again shows more intense growth. Surprisingly, the growth of the arms in many ways resembles more that of the trunk and not that of the legs.

Testicular adrenal-like tissue (TALT) in congenital adrenal hyperplasia: detection by ultrasonography.

In a consecutive series of 15 male adolescents and young adults with congenital adrenal hyperplasia (CAH), the size, shape, firmness and echostructure of the testes were assessed. The latter was abnormal in 7 patients under long standing treatment with glucocorticoids (group I). In 8, 5 under and 3 off treatment for several years, ultrasonography (US) was normal (group II). On the basis of the US findings the patients were placed in two groups. In group I, the testes had a heterogeneous ultrasonographic pattern; clinically, most felt hard and irregular, although their volume was normal. Sperm count in 3 patients was 5.0 to 14.4 x 10(6)/ml. Five patients have 21-hydroxylase deficiency that was diagnosed in early infancy and had salt-wasting; two have 11-beta-hydroxylase deficiency that was diagnosed late and had no salt-wasting. In group II, testicular volume, shape, firmness and echostructure were normal. All have 21-hydroxylase deficiency, no history of salt-wasting and were diagnosed late. Sperm counts in 3 patients off treatment were 10.5 to 66.0 x 10(6)/ml. In severe cases with a history of salt loss, TALT with deficient spermiogenesis seems likely despite treatment. In mild cases, TALT is absent and spermiogenesis may be normal even without treatment. US is much more accurate in assessing the testes than palpation.

A physiological mode of puberty induction in hypogonadal girls by low dose transdermal 17 beta-oestradiol.

Transdermal 17 beta-oestradiol administration (17 beta-E2), used mainly in menopausal women, allows a continuous 17 beta-E2 delivery through the skin into the systemic circulation, avoiding intestinal and hepatic passage. In order to explore whether transdermal 17 beta-E2 could be used for the induction of puberty, 17 beta-E2 patches with low dose delivery were administered in nine prepubertal girls with Turner syndrome (bone age greater than 10.5 years) for a mean period of 2.2 years. Treatment schedule: 5 micrograms/day for 6-9 months, 10 micrograms/day for 6-9 months, 25 micrograms/day for long-term substitution; addition of cyclic gestagen p.o. after 18-24 months. Breast development started within 3 months of therapy and menstruation occurred after 2 years. Growth rate increased from 3.2 to 5.0 cm/year during the 1st year of therapy, height prediction did not change. Serum oestradiol (E2) and urinary E2 conjugates increased proportionally with 17 beta-E2 doses, serum oestrone (E1) rose much less. The possibility to imitate time course, clinical events and hormonal changes of normal puberty, the absence of adverse drug reactions and the excellent acceptance and easy mode of application suggest that transdermal 17 beta-E2 is optimally suited for hormonal substitution in girls with hypogonadism.