John D. Bailey

Growth and maturation of patients with Turner's syndrome.

Summary: The effects of sex chromosome constitution and estrogen treatment on increase in height and on skeletal and sexual maturation were studied in 116 patients with female phenotype and at least one major feature of Turners syndrome associated with an abnormality of an X chromosome. Seventy-one patients had a pure 45X karyotype (XO group) and the remainder comprised 33 with X chromosome mosaicism and 12 with a structurally abnormal X (non-XO group).Birth weight at all durations of gestation was similar for XO and non-XO but significantly lower than normal. Correlations of birth weight with adult height and weight were unexpectedly high, 0.96 and 0.92 respectively. Patients were significantly shorter than normal (P < 0.05) at all ages tested from 2–17 years, but increasingly more so after age 10. Mean adult height was 142.0 ± 7.60 cm (n = 28). Unlike most other reports there was no consistent pattern of significant differences in height between XO and non-XO or between Xp monosomic and Xp disomic patients.The 13 patients (2 XO, 11 non-XO) who experienced spontaneous menarche evidenced a slight premenarcheal growth spurt. In 11 of these 13 patients, the average growth rate increased from 3.00–4.83 cm/year in the year before menarche; however, this is far below the mean pubertal growth velocity of 9 ± 1.03 cm/year. This observation indicates that endocrine mechanisms associated with more normal pubertal sexual development also produce a more normal pattern of growth. The estrogen-treated group grew at a lower, fairly constant rate in the 2 years before and 1 year after treatment, and total increase in height after estrogen treatment averaged only 3.6 cm.Rate of skeletal maturation was less than normal (0.53 bone-age year/chronologic year) in the 2 years before treatment, and greater than normal (1.47 bone-age year/chronologic year) in the two years after treatment, suggesting that these patients may be hypersensitive to the skeletal maturing effects of estrogen.Pretreatment breast development: absent or more delayed than pubic hair development, but the delay in both secondary sex characters was greater than the delay in skeletal maturation. At age 12, the average normal girl has moderate breast development, but at bone-age 12, only 5.4% of our patients had moderate breast development and only 10.8% had moderate pubic hair.Significantly but not unexpectedly more. non-XO than XO patients experienced spontaneous menarche. Even the non-XO patients who require estrogen treatment may have a more normal level of ovarian function than do XO patients, who have significantly less pretreatment breast development and later epiphyseal fusion.Speculation: In normal subjects the correlation of birth weight with adult weight is around 0.4; however, in 116 patients with Turners syndrome, correlation with adult weight and height averaged 0.92 and 0.96 respectively, indieating that the short stature characteristie of this syndrome appears to be a consequence of intrauterine event(s). Patients treated with estrogens grew fairly constantly until an average age of 16.4 years. Those in whom menarche occurred spontaneously had experienced a slight growth spurt by then, but stopped growing at an average age of 16.0 years and were not taller as adults than the treated patients. Thus, in patients with this syndrome, sex steroids may merely speed the attainment of the predetermined growth potential.

The Psychoeducational Profile of Boys with Klinefelter Syndrome

Klinefelter syndrome (KS) affects about 1 in 900 males due to an extra X chromosome. Although there are no obvious physical features associated with childhood KS, many boys demonstrate a cognitive deficit in verbal processing. The first section of this article integrates the extant literature on intelligence and achievement outcomes in boys with KS. The second section presents our findings from a 20-year study involving one of the largest unselected cohorts of boys with KS. We followed 36 boys with KS and 33 sibling controls from 6 until 20 years of age. Boys with KS are shown to demonstrate a verbal cognitive deficit and significant underachievement in reading and spelling, as well as in arithmetic. These problems, which are evident from early school years, increase with age such that by late adolescence, boys with KS are four to five grade levels behind. In addition, we also found that they were most likely to have a generalized type of learning disability, with very few boys indicating a pure reading or pure arithmetic problem. They also showed deficits in written language skills and acquisition of knowledge-based subject material were also problematic. Despite significant underachievment and frequent grade failure, many boys with KS had completed high school, and a few were also pursuing postsecondary educations. The discussion section examines how their language-based disability affects comprehension and learning, leading to underachievement.

Growth in children with congenital hypothyroidism detected by neonatal screening

A prospective analysis of physical growth in 56 children with congenital hypothyroidism compared the childrens height, weight, and head circumference with population percentiles. Two measures of skeletal maturation and predictions of adult height were also compared with population standards. The mean percentiles for the childrens height and head circumference were higher than population means. Although mean bone age scores were slightly higher, predictions of adult height did not differ significantly from midparental height (arithmetic mean of sum of parental heights) and population means. The duration of intrauterine hypothyroidism as measured by gestational bone age and the duration of postnatal hypothyroidism were inversely correlated with heights attained up to 9 years. This association suggests a possible long-term influence of early hypothyroidism on growth. In children with congenital hypothyroidism, maintenance of serum thyroxine levels in the upper half of the normal range results in normal growth patterns.

Regulation of the androgen receptor by androgen in normal and androgen-resistant genital skin fibroblasts

Normal genital skin fibroblast (GSF) monolayers incubated with serum-free medium containing 3 nM [3H]-5 alpha-dihydrotestosterone (DHT) at 37 degrees C for 20 h have about 35% more specific DHT-binding than replicates incubated in serum-free medium with [3H]-DHT for only 1 h to saturate basal specific androgen-receptor activity. If, after 19 h, spent medium is replaced by fresh medium with 3 nM [3H]-DHT for 1 h, specific DHT binding is 85% more than basal. The acquisition of increased binding is temperature dependent (37 greater than 27 degrees C) and cycloheximide (2 microM) suppressible. The increased binding activity is considered to represent an augmentation of androgen receptor concentration because it has the same equilibrium dissociation constant (KD approximately 0.5 nM), rate constant of dissociation (k-1 approximately 6 x 10(-3) min-1) and ligand specificity as basal androgen-receptor activity, and because basal DHT-binding activity is stable in cells preincubated in androgen-free or serum-free medium alone for up to 72 h before assay. Prolonged incubation with methyltrienolone (R1881), a nonmetabolizable synthetic androgen, causes a greater, more persistent increment of androgen receptor activity than does equimolar DHT. The fibroblasts from two subjects with receptor-positive, partial androgen resistance lose their basal receptor activity during prolonged incubation with DHT, but augment it normally with R1881. This suggests that defective DHT metabolism is somehow involved in the pathogenesis of their androgen resistance.

Psychologic and psychoeducational consequences of thyroxine therapy for juvenile acquired hypothyroidism

The observation of severe behavioral reactions or learning problems in three teenagers treated with L-thyroxine for juvenile acquired hypothyroidism prompted us to conduct a prospective study of achievement and behavioral characteristics of patients with newly diagnosed juvenile acquired hypothyroidism. On diagnosis of juvenile acquired hypothyroidism and before treatment with L-thyroxine, 23 children and adolescents underwent a comprehensive battery of psychoeducational tests, which was repeated after 3, 12, and 24 months of replacement therapy. Results revealed that adverse behavioral reactions and learning problems were relatively rare in these children, although symptoms of juvenile acquired hypothyroidism were associated with increased distractibility, hyperactivity, and poorer achievement. The least gain in achievement was made by children with more severe hypothyroidism at diagnosis; children with the best psychologic outcome were those who achieved euthyroidism more slowly. We conclude that severe behavioral manifestations of L-thyroxine therapy for juvenile acquired hypothyroidism are uncommon, but mild behavioral symptoms and poorer school achievement may occur in about 25% of patients, who represent the most severe cases at diagnosis.

Clinical and physiological assessment of asthmatic children treated with beclomethasone dipropionate

Forty-two perennial asthmatic children were selected for a 12-wk study using beclomethasone dipropionate. The groups included 21 steroid-dependent children (Group I) and 21 patients (Group II) whose disease was of sufficient severity that corticosteroid therapy was contemplated. All children received the drug in a dose of 100 mug 4 times daily. During the study, oral prednisone was withdrawn from the steroid-dependent children while other therapy was essentially unchanged. Group II children underwent a double-blind trial, receiving beclomethasone for 6 wk and placebo for 6 wk. Objective assessment of adrenal and pulmonary function was obtained at regular intervals. For the latter, total lung capacity and its subdivisions, airways resistance, maximum expiratory flow volume, and oxygen tension, were measured in both groups. In Group II static elastic recoil was measured also. For most tests the results were statistically significant. In both groups, 18 of 21 patients demonstrated an excellent clinical response, no evidence of adrenal suppression, and improvement in pulmonary function. Forty of 42 patients were followed for another 12 wk, and 19 of each group did well. After 20-24 wk of therapy, 16% of patients harbored monilia in their oropharynx, and 1 patient had clinical monilial stomatitis. Within the limits of the time of the study, beclomethasone dipropionate appeared to provide adequate clinical control in many chronic, severe, steroid-dependent and nonsteroid-dependent asthmatic children.

The superior-mesenteric-artery syndrome: cause or complication of anorexia nervosa?

The so-called superior-mesenteric-artery syndrome is not mentioned in psychiatric journals or books. Yet two variations of the condition have been described. In its acute form, it can be mistaken for psychogenic vomiting in anorexic patients, while its chronic intermittent form is readily misdiagnosed as anorexia nervosa. The case report is of a 16-year-old boy admitted for investigation and treatment of severe weight loss. He initially responded to a modified behaviour program, but within days developed an acute small-bowel obstruction. Superior-mesenteric-artery syndrome was diagnosed and he improved with appropriate medical management. This condition needs to be considered by the psychiatrist who otherwise might not differentiate it from the symptoms of anorexia nervosa.

A REPORT OF FOUR CASES, INCLUDING THREE IN ONE SIBSHIP, WITH COMPARATIVE HISTOLOGIC EVALUATION OF THE JUXTAGLOMERULAR APPARATUSES AND GLOMERULI

An electrolyte‐losing syndrome is described in three siblings, including one set of twins, and in an unrelated infant who was the product of incest. In most respects the clinical and laboratory findings in these patients were compatible with the condition which has come to be known as Bartters syndrome. In all four of our patients, however, symptoms were manifested early in life, the disease ran a malignant course and death occurred early. Electron microscopic examination of the kidneys from two of our patients showed characteristic structural changes in the glomeruli including immaturity of the podocytes and extensive loss or fusion of their foot processes. Light microscopy of the kidneys from all four cases showed an unusually large proportion of immature glomeruli that seemed to diminish slowly with age. Some ninety per cent of these small glomeruli were located peripherally. The incidence and size of hypertrophied JGA, also the degree and extent of hyperplastic arterial thickening, appeared to increase with age. These findings are discussed in relation to the hypothesis that the basic abnormality in Bartters syndrome may involve a defect of sodium reabsorption in the proximal tubule, and that this leads to hypertrophy of the JGAs of functioning nephrons with excessive production and release of renin, which causes vasoconstrictive dormancy of the more peripheral glomeruli.

Familial Persistent Mullerian Duct Syndrome

We found persistent müllerian duct structures in 2 phenotypically normal brothers who had undergone an operation for inguinal hernia. The older boy had transverse testicular ectopia and his younger brother had unilateral cryptorchidism. Bilateral orchiopexy was done with excision of the fallopian tubes, uterus and upper vagina. Histological examination showed normal testes in both patients. Since there is a risk of testicular malignancy in such patients, long-term followup is mandatory.

EXTERNAL GENITAL ABNORMALITIES ASSOCIATED WITH WILMS TUMOR

The records of 170 patients with unilateral and 18 patients with bilateral Wilms tumor and 6 patients with congenital mesoblastic nephroma were reviewed for abnormalities of the external genitalia. There were 4 patients with cryptorchism, 1 with hypospadias, 1 with mixed gonadal dysgenesis, and 3 with male pseudohermaphroditism. Of the group, these 9 patients had earlier symptoms; 6 of them were under two years old. Five patients (27.7%) with bilateral Wilms tumors had external genital anomalies in contrast to only 4 (2.3%) of those with unilateral tumors. One of the 9 children with genital anomalies had unilateral congenital mesoblastic nephroma; the others had Wilms tumor. In all cases the histologic subtypes were unusual. These observations substantiate the previously reported association between external genital abnormalities and Wilms tumor and also represent a somewhat higher than expected incidence. The children with this association are remarkable for the high frequency of a particular histologic type of tumor and for the high incidence of bilaterality. The high incidence of Wilms tumors in the male pseudohermaphrodite population presented suggests that such patients should be monitored for development of renal tumors.