R. Kauli

Premature Thelarche–Natural History and Sex Hormone Secretion in 68 Girls

ABSTRACT. Data obtained during long‐term follow‐up of 68 girls with premature thelarche were analysed. In 85 % onset was before the age of 2 years, in 30.8 % being present at birth. In 44.1 % there was a regression after 32/12±28/12 12years (SD). Basal levels of plasma FSH and response to LH‐RH were significantly higher than prepubertal controls (1.93± 1.56 vs. 0.8±0.1 mU/ml and peaks 12.3±5.4 vs. 7.9±1.0 mU/ml respectively; p<0.001). Twenty‐seven of 52 patients tested had increased plasma estradiol and in 27 of 40 patients tested, urocytograms or vaginal smear showed estrogenization. Basal levels of LH and response to LH‐RH were prepubertal. The girls with premature thelarche were significantly taller than normal controls of the same age (p<0.001). These results suggest that premature thelarche is an incomplete form of precocious sexual development probably due to derangement in the maturation of the hypothalamo‐pituitary‐gonadal axis which results in a higher than normal secretion of FSH, as well as a defect in the peripheral sensitivity to the sex hormones.

Ectopic thyroid gland. A clinical study of 30 children and review.

Of 108 children being treated at our Institute for primary (nongoitrous) hypothyroidism, tests with radioactive iodine 131I uptake showed that 26 of them (24%) had an ectopic thyroid gland. Four euthyroid children also had anterior swellings of the neck which, in each case, proved to be an ectopic thyroid gland. Of the 30 children studied, 20 were girls and 10 were boys. Nine patients were diagnosed within the first year of life. Growth retardation, manifest in 20 patients, was the most common clinical finding at the time of diagnosis. Delayed bone age was a feature in all of them. Growth, after diagnosis was within normal limits in 83% of the infants who were treated within the first two years of life; only 50% of the children diagnosed later grew within normal limits. Similarly, mental function was best preserved in those patients in whom treatment was initiated within the first two years of life.

EFFECT OF HUMAN GROWTH HORMONE THERAPY ON HEAD CIRCUMFERENCE IN CHILDREN WITH HYPOPITUITARISM

Head circumference was measured before and during hGH therapy in fourteen children with isolated growth hormone deficiency (IGHD) and in twenty‐one children with multiple pituitary hormone deficiencies (MPHD).

PUBERTAL DEVELOPMENT IN THE PRADER‐LABHART‐WILLI SYNDROME

ABSTRACT. The sexual maturation in the Prader‐Labhart‐Willi (PLW) syndrome was investigated in 14 patients, 10 females and 4 males. A wide variability in the pattern of pubertal development was found including delayed puberty in 5 patients and normal puberty in 4 patients; sexual precocity was also observed in 5 patients, true precocious puberty in one patient and incomplete sexual precocity in the form of precocious pubarche in 4 patients. In 5 patients, 3 of them with precocious pubarche, the appearance of the pubertal signs was followed by a delay or arrest in their future development. An LH‐RH stimulation test was performed in 11 patients. In the 6 patients who eventually developed normal puberty, the basal levels and the peak responses of both LH and FSH were within the range of those observed in normal controls of the same pubertal stage. In 4 patients showing marked delay or arrest of puberty, the basal levels were normal or low and the responses of LH and FSH to LH‐RH were blunted. Priming with repeated LH‐RH stimulation in one of the male patients led to an augmented LH response, suggesting a hypothalamic hypogonadotrophism. It is concluded that the lack of uniformity in the pattern of sexual maturation in the PLW syndrome is due to a variability in the location and extent of a hypothalamic lesion, which may comprise an active process continuing beyond the perinatal period.

GONADAL FUNCTION IN BLOOM'S SYNDROME

Five patients with Blooms syndrome aged from 2 8/12 to 27 years, all of whom had hypogonadism, were subjected to an i.v. LHRH test and two of them to an i.m. HCG test. There was increased responsiveness of plasma LH and FSH, indicating that the hypogonadism is primary in nature and of early development. The tubular element of the testis seems to be mainly affected, as indicated by the particularly high FSH response to LHRH stimulation, a history of sterility in the two adult patients and documented azoospermia in one of them. The Leydig cells seem to be less affected and secrete sufficient androgens to enable puberty within acceptable normal limits. Hypogonadism seems to be a major characteristic of Blooms syndrome.

ADRENOCORTICAL FUNCTION IN CHILDREN WITH PRECOCIOUS SEXUAL DEVELOPMENT DURING TREATMENT WITH CYPROTERONE ACETATE

Adrenal function was studied in thirty‐two children with precocious sexual development who were being treated with cyproterone acetate (CPA) at doses ranging from 68 to 175 mg.m2. day for periods lasting from 2 to 79 months. In eighteen children the adrenocortical function evaluation was made before and during CPA treatment. In these eighteen patients, the mean basal plasma cortisol level during the morning hours was 11·2±4·6 μg/dl (m±SD) before treatment and fell significantly to 7·2±4·1 μg/dl (P < 0·02) during therapy. In fifteen patients tested during insulin hypoglycaemia the cortisol peak fell from 21·6±5·5 μg/dl before treatment to 16·7±6·8 μg/dl (P < 0·05) during CPA therapy. There was a significant inverse correlation between this peak and the dose of CPA but no correlation was found between the cortisol response and duration of treatment. In eight of twenty patients tested, urinary free cortisol levels were undetectable during treatment. No change in basal plasma ACTH levels was demonstrated using standard radioimmunoassay techniques. In the patient receiving the highest dose of CPA and showing complete suppression of the adrenal axis, prolonged stimulation with ACTH‐Depot demonstrated a responsive adrenal gland. Addition of a replacement dose of cortisol to the CPA treatment led to the rapid development of the typical signs of Cushings syndrome. It was concluded that despite the evidence of adrenal suppression by CPA, cortisol supplementation is not necessary and may even be contra‐indicated.

Final height of girls with Turner's syndrome: correlation with karyotype and parental height

Final height of 75 adults with Turners syndrome (45 Israeli, 30 Italian), never treated with GH, was examined to see if a relationship with karyotype patterns and parental height existed. Patients were divided into five groups according to their chromosome pattern, as follows: group A = 45,X karyotype (34 patients); group B = mosaicism (11 with karyotype 45,X/46,XX and 7 with karyotype 45,X/ 46,XY); group C = deletion of all or part of Xp (19 patients); subgroup CI = 6 with complete deletion of Xp; subgroup C2 = 9 with mosaicism 45,X/46,X,i(Xq); subgroup C3 = 4 with 45,X/46,X,ring(X); group D = deletion of Xq (4 patients); pure gonadal dysgenesis (PGD) group = 9 patients with pure 46,XX gonadal dysgenesis. No statistical difference was noted between the mean height of the two national populations studied (Italian 142.2 ±5.7 and Israeli 143.0 ±7.2 cm). The mean heights of group D (148.9 cm; range 147–166.2) and the PGD group (156.0 cm; 141–171.5) were found to be significantly higher than those observed in groups A, B and C (p <0.03, p < 0.02 and p <0.02, respectively), even though gonadal distinction existed in all five groups. Subgroup CI, where a deletion of the entire Xp segment [46,X,i(Xq)] was present, was found to be the shortest group (median height 134.5; range 131.9–138 cm). No fixed pattern of correlation between final height and parental height was found within any of the groups studied but if we consider the mean final height of all Turner patients studied, without division into groups, it correlates well, but only with mothers’height and not with fathers’height. These data provide further confirmation that short stature in Turners syndrome is multifactorial and depends on the deletion of the distal portion of the short arm of chromosome X, on the lack of sex hormone secretion and, in part, on parental height.

A COMPARATIVE STUDY OF THE EFFECT OF OESTROGEN SUBSTITUTION THERAPY ON BREAST DEVELOPMENT IN GIRLS WITH HYPO—AND HYPERGONADOTROPHIC HYPOGONADISM

During treatment of girls with oestrogen deficiency we observed different patterns of breast development in response to therapy.

THE LH RESPONSE TO LH-RELEASING HORMONE IN CHILDREN WITH TRUE ISOSEXUAL PRECOCIOUS PUBERTY TREATED WITH CYPROTERONE ACETATE

Fourteen girls and one boy with isosexual precocious puberty were submitted to LHRH stimulation tests, during and without therapy with cyproterone acetate. In addition, fourteen girls with isosexual precocious puberty not receiving any therapy were tested and served as controls.

Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients—From discovery to treatment

Clinical and laboratory investigations of dwarfed children newly Jewish immigrants from Yemen and Middle East and who resembled patients with isolated growth hormone deficiency were started by our group in 1958. In 1963 when we found that they have high serum levels of hGH, we knew that we had discovered a new disease of primary GH insensitivity. It was subsequently coined Laron Syndrome (LS, OMIM #262500). The etiopathogenesis was disclosed by 2 liver biopsies demonstrating a defect in the GH receptor. Subsequent investigations demonstrated deletions or mutations in the GHR gene. The defect lead to an inability of IGF-I generation, resulting in severe dwarfism, obesity, and other morphologic and biochemical pathologies due to IGF-I deficiency. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Following closely our cohort of 69 patients with LS enabled us to study its features in untreated and IGF-I treated patients. This syndrome proved to be a unique model to investigate the effects of IGF-I dissociated from GH stimulation. In recent studies we found that homozygous patients for the GHR mutations are protected lifelong from developing malignancies, opening new directions of research.