The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene. Correlation with CNS abnormalities.

The correlation between the molecular defects of the GH receptor (R), psychosocial development and brain abnormalities were evaluated in 10 patients with Laron syndrome (LS), in whom all data were available. The findings revealed that the intelligence quotient (IQ) and abnormalities in the brain of the patients with LS differ with various molecular defects of the GH-receptor. The most severe mental deficits and brain pathology occurred in patients with 3, 5, 6 exon deletion. Patients with point mutations in exons 2, 4 and 7 presented various degrees of medium to mild CNS abnormalities that correlated with the IQ. Notably, the patient with the E180 splice mutation in exon 6 had a normal IQ, which fits the report on normal IQ in a large Ecuadorian cohort with the same mutation. This is the first report to support a correlation between IQ, brain abnormalities and localization of the molecular defects in the GH-R gene. As all patients with LS are IGF-I-deficient, it must be assumed that other as yet unknown factors related to the molecular defects in the GH-R are the major cause of the differences in intellect and brain abnormalities.

Psychological impact of islet cell antibody screening.

The purpose of this study was to evaluate the psychological impact of autoantibody screening and its results on at-risk individuals and family members. Individuals who were antibody positive (AP) were identified through a large-scale screening program conducted at our institute. The sample consisted of nine families in whom 10 AP youngsters (7 M, 3 F) were identified, ranging in age from 6-18 years (mean 11.8, median 10 yr). Seventeen parents and eight diabetic youngsters (mean age 15.2, median 16 yr) participated in the study. Reaction to autoantibody positivity was assessed with the Impact of Event scale (IES). The IES was answered twice: within a week from the disclosure of the AP status, and 3 months later. Parents scored higher than their diabetic children and AP children on both measures of the IES, Intrusion and Avoidance. Three months later both scores were significantly reduced in both the parents and the AP children; however, parents still scored significantly higher on both scores than the AP children. The results suggest that learning one's AP status induces significant anxiety, especially in parents of AP youngsters. Although this initial anxiety dissipates over time it still remains quite high after 3 months. The results highlight the importance of psychosocial counseling for all members of diabetes mellitus screening and prevention trials.

Delayed growth and puberty in patients with Gaucher disease type 1: natural history and effect of splenectomy and/or enzyme replacement therapy.

BACKGROUND: Growth retardation in childhood was only recently recognized as a prominent feature of Gaucher disease type 1, but there are few data on both the pubertal development and the final outcome of growth and sexual maturation. OBJECTIVE: To investigate the natural pattern of growth and puberty in patients with Gaucher disease type 1 and the effect of splenectomy and enzyme replacement therapy. METHODS: We retrospectively analyzed growth and puberty in 57 patients with Gaucher disease type 1; 52 were followed since childhood and/or prepuberty and 42 have reached sexual maturity and final height. In the analysis we considered severity of disease, time of splenectomy, and start of enzyme replacement therapy. RESULTS: Deceleration of growth at age 3-5 years was observed in 30 of 57 patients followed since early childhood while untreated: height-SDS decreased from -0.34 +/- 0.42 at age 0-3 years to -1.93 +/- 0.95 (P < 0.01) at age 7-10 years and was more pronounced with severe disease. A high prevalence (59.6%) of delayed puberty, which was more frequent with severe disease, was observed in 47 patients followed before and throughout puberty. No primary endocrine pathology was found. All patients, untreated as well as treated, with growth and pubertal delay had a spontaneous catch-up, achieved full sexual maturation, and most (83.3%) reached a final height within the range of parental height-standard deviation score. Splenectomy (partial and/or total) performed in 20 patients while still growing had a beneficial effect on growth, which was temporary in some and did not affect puberty. ERT improved growth in 11 patients who started therapy before puberty, as evidenced by a progressive increase in the height-SDS, and seemed to normalize the onset of puberty. CONCLUSIONS: Growth retardation in childhood and delay of puberty are characteristic of Gaucher disease type 1 and are more frequent with severe disease. There is a spontaneous catch-up later in life and most patients reach a final height within their genetic growth potential. Enzyme replacement therapy apparently normalizes growth and possibly also the onset of puberty.

Non-classical 21-hydroxylase deficiency in infancy and childhood: the effect of time of initiation of therapy on puberty and final height.

OBJECTIVE: To review the characteristics of children with non-classical 21-hydroxylase deficiency (NC-21-OHD) diagnosed during infancy and childhood, and to evaluate the relationship of pubertal and bone age maturation at initiation of glucocorticoid therapy with the course of puberty and final height. DESIGN: We retrospectively compared the course of puberty, growth pattern and final height in two groups of patients: group A (two males, six females), hydrocortisone (HC) treatment 7.5-15 mg/m2 per 24 h, initiated > or = 1 year before onset of true puberty and group B (seven females), treatment started with the first signs of true puberty present. PARTICIPANTS: Thirteen girls and two boys with NC-21-OHD diagnosed at age range 0.5-10.6 years were followed-up for 9.0 +/- 3.8 years (mean +/- S.D). Therapy with HC was initiated because of signs of hyperandrogenism, accelerated growth and bone maturation, or true precocious puberty. The HC dose was adjusted according to linear growth and basal plasma androgen levels. RESULTS: Puberty and peak height velocity developed significantly earlier in the girls of group B: gonadarche at 7.9 +/- 1.4 years and peak height velocity at 9.2 +/- 1.4 years vs 10.2 +/- 0.4 years (P = 0.002) and 11.5 +/- 0.7 years (P = 0.006) in group A. Menarche, however, occurred only slightly earlier in group B (12.0 +/- 1.1 vs 12.8 +/- 0.5 years, P = 0.068). All eight children in group A achieved a final height within the range of their mean parental height standard deviation scores (SDS) in comparison with only 1/7 in group B (P = 0.0014). Seven of eight patients who started therapy before a bone age of 9 years achieved a final height within the parental height SDS range, compared with 2/7 who started therapy later (P = 0.041). The final height SDS was significantly better for group A (0.05 +/- 0.19, mean +/- S.E.M.) than group B (-1.63 +/- 0.23, P = 0.0007), even when adjusted for a significant effect of the mean parental height SDS (A. -0.63 +/- 0.28; B, -0.89 +/- 0.31, P = 0.0245, ANCOVA). CONCLUSION: Every child with signs of excess androgen activity or early puberty should be studied for the possibility of NC-21-OHD. Screening programs for populations with a high frequency of the gene for NC-21-OHD would facilitate early diagnosis and treatment. Pubertal stage and bone age at the introduction of therapy dictate height prognosis. Initiation of therapy before puberty with careful follow-up and HC dose adjustment can assure the achievement of genetic adult height.

Final height of girls with central precocious puberty, untreated versus treated with cyproterone acetate or GnRH analogue. A comparative study with re-evaluation of predictions by the Bayley-Pinneau method.

This study was designed to determine the benefit of therapy on final height (FHt) in girls with central precocious puberty (CPP). A total of 102 patients were evaluated--28 untreated, 26 treated with cyproterone acetate (CyA), and 48 treated with GnRH analogue (GnRHA)-and their achieved FHt was compared to the respective target height (THt). Of the untreated girls, half (14/28) had a slow course of puberty and reached THt +/- 0.5 SD (FHt 160.2 +/- 7.1, THt 159.5 +/- 6.6 cm); the other half (14/28) had an accelerated course of puberty with a FHt well below THt (FHt 150.8 +/- 4.3, THt, 159.2 +/- 5.9 cm) and in most cases (14/28) below the height-SDS of both parents. The treated girls (both regimens) reached THt above (CyA group: FHt 157.8 +/- 5.1, THt 156.8 +/- 5.1 cm; GnRHA group: 159.6 +/- 6.3, THt 157.7 +/- 5.7 cm). We conclude that without treatment the FHt of girls with CPP may be significantly compromised and that therapy is more beneficial if started before bone age exceeds 12 years. Our data also showed that for final height predictions in CPP the Bayley and Pinneau tables for average children should be used, regardless of the advanced bone age of the patients.

Early polycystic ovary-like syndrome in girls with central precocious puberty and exaggerated adrenal response.

Exaggerated adrenal response (ExAR), i.e. hypersecretion of both 17-hydroxypregnenolone (170HPreg) and 17-hydroxyprogesterone(17OHP) in response to adrenocorticotropic hormone (ACTH) stimulation, is frequently found in women with polycystic ovary (PCO) syndrome who had precocious adrenarche. In an earlier study we found an abnormal adrenal response in girls with idiopathic true central precocious puberty (CPP) at early stages of puberty. On follow-up it was noted that a significant number of girls with CPP develop PCO-like syndrome at a relatively young age. The aim of the present study was to determine if there is an association between ExAR and early PCO in girls with a history of CPP. Included were 49 girls with a history of CPP, 34 of whom were treated with gonadotropin-releasing hormone (GnRH) analog. All 49 were evaluated at full maturity, at ages 12.5-14 years, 0.5-4 years after menarche or resumption of menses. Of the 49 girls, 20 had at least 3/4 clinical signs of PCO (irregular menses, hirsutism, acne and obesity) and were defined as PCO-like+, whereas 29 did not fulfil the criteria and were considered PCO-like-. Girls with a definite enzyme deficiency were excluded from the study. All participants underwent a combined iv ACTH-GnRH test at early follicular phase. The PCO-like+ girls all revealed ExAR, i.e. an elevated stimulated 17OHPreg of 63.4 +/- 9.6 nmol/l (normal 28.6 +/- 9.2 nmol/l) and a normal stimulated 17OHPreg/17OHP ratio of 7.1 +/- 1.8 (normal 6.2 +/- 2.7), whereas all the PCO-like- had a normal adrenal response (30.0 +/- 8.7 and 5.3 +/- 2.0 nmol/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

High prevalence of abnormal adrenal response in girls with central precocious puberty at early pubertal stages.

Abnormal adrenal response is often observed in girls with precocious adrenarche (1). We studied the adrenal response in 112 girls with idiopathic true central precocious puberty (CPP) at early stages of puberty compared to that in 21 girls with normal puberty (controls). The aims of this study were to determine the prevalence of abnormal adrenal response at early stages of puberty, the possible correlation of abnormal adrenal response with pubertal signs at onset of puberty and with plasma androgen levels, and a possible association with the activity of the hypothalamic-pituitary-gonadal (HPG) axis. All participants underwent a combined i.v. adrenocorticotropic hormone (ACTH)-gonadotropin-releasing hormone (GnRH) test at Tanner stage 2-3: 62 of the CPP girls before and 50 during treatment with GnRH analog. The stimulated levels of 17-hydroxypregnenolone (17OHPreg) and the stimulated 17OHPreg/17-hydroxyprogesterone ratio were analyzed and compared to previously reported norms. The result revealed three patterns of adrenal response: normal (17OHPreg < or = 24 nmol/l and 17OHPreg/17OHP ratio < or = 7) in 50/112 (44.6%) CPP patients and 17/21 (80.9%) controls; exaggerated (17OHPreg > 24 nmol/l, 17OHPreg/17OHP ratio < or = 7) in 50/112 (44.6%) CPP patients and 3/21 (14.3%) controls; and non-classical 3 beta-hydroxysteroid dehydrogenase deficiency (17OHPreg > 24 nmol/l and 17OHPreg/17OHP ratio > 7) in 12/112 (10.8%) CPP patients and 1/21 (4.8%) controls. The clinical features at onset of puberty were comparable in all girls with the CPP in spite of the different adrenal response patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

The young diabetic subjects in the Israel Army.

Between 1978 to 1986, 145 of the Type 1 diabetic patients under our care reached the age of 18 (military service recruitment age). Of the 77 (45 men, 32 women) who decided to volunteer for service, 60 (35 men, 25 women) responded to a questionnaire relating to the conditions of their military service following its completion-these comprised Group A. Of the 68 patients who did not volunteer for service (20 men, 48 women), 44 patients comprised Group B (10 men, 34 women). Group A and Group B were compared in regard to their diabetes history and diabetes management and control during two periods, 17-18 years and 18-20 years. Group A was also evaluated regarding military employment, working and accommodation conditions and diabetes management during army service. The patients in Group A came from a higher socioeconomic level (p < 0.009) and had a significantly higher educational level (p < 0.008). The men in Group A achieved significantly better diabetes control, as evaluated by HbA1, in both periods compared to all the others in both groups. During army service the patients in Group A underwent fewer hospitalizations than the others and only two of them developed complications, whereas among those in Group B 5 patients developed complications. Our data demonstrate that youngsters with Type 1 diabetes can maintain satisfactory diabetes management and control and can function not only adequately, but often far beyond, in the stressful situations with which they are confronted within the rigid authoritative system of military service. Our data also indicated that diabetic patients wishing to volunteer for such service constitute a selected group with a higher socioeconomic background and a higher motivation to prove themselves.

Psychological aspects of developmental endocrinopathies in adolescence.

Ninety-six adolescents referred to a pediatric endocrinology clinic were divided into eight groups according to degree of sexual maturity and height. Each adolescent was assessed by a psychiatric interview, a self-concept questionnaire, a human figure drawing test and a cognitive screening battery. The results showed a definite deleterious effect of growth retardation, but not sexual maturity, on self-concept. Sex of the adolescent did not affect the results. Cognitively there was no difference between groups. The psychological impact of short stature should be taken into consideration in the decision to utilize pharmacological or delay of puberty.

Social, educational and vocational status of 48 young adult females with gonadal dysgenesis.

OBJECTIVE: The purpose of this study was to evaluate the educational, vocational and social function of young adults with gonadal dysgenesis. DESIGN: Forty-eight female patients with gonadal dysgenesis (17, 45XO; 26, 45XO/46XX or other mosaics; and five pure gonadal dysgenesis) followed by our multidisciplinary team from childhood, were re-evaluated in adult age. RESULTS: Mean age +/- SD at diagnosis was 11.4 +/- 5.0 years and mean age at the time of survey was 29.6 +/- 6.3 years. The mean final height for the patients was 145.5 +/- 8.3 cm (range 134-170 cm). Mean verbal IQ (WISC-R) for the 39 subjects tested was 101.4 +/- 20.7 and mean performance IQ was 86.8 +/- 17.7. No difference in verbal IQ levels was found between the various karyotype groups. Twenty-five had an academic education. All were employed except for one housewife; 37 work in white collar professions. A significant correlation was found between verbal IQ and education (P = 0.005) and between verbal IQ and profession (P = 0.005). Twenty-three served in the army. Fourteen are married: three have an adopted child and two a child born after in vitro fertilization (IVF); others are waiting for IVF or adoption. Five patients had some form of psychiatric problem that required psychiatric or psychological treatment in the past (two had transitory anorexia nervosa and three behavioural problems). Sixty-three per cent reported having wide and satisfactory social relations but limited to female friends. CONCLUSION: Positive adjustment in the professional area and fair adjustment in the social area were not related to physical stigmata or to any other independent variable tested, but rather to intellectual ability and a high degree of achievement motivation.

Cognitive and behavioral determinants of compliance in diabetics.

The interaction between patient and medical team is especially stressful in cases of diabetes, because of the high potential for critical behaviors by the team and for avoidance or aggressive behaviors by the patient. This study examined some cognitive and behavioral correlates of compliance behaviors in 70 insulin-dependent diabetics. A special scale was developed to evaluate specific cognitions, behaviors, and anxiety during confrontations with the physician, dietitian, nurse, and secretary. Another special scale was developed to evaluate compliance with self-care behaviors in diabetes. Cognitive and behavioral coping skills specific to patient-medical team encounters were found to be significant correlates of various compliance variables in the following order: maintenance of positive self-esteem and efficacy during criticism, positive acceptance of criticism, avoidance of conflict by offering compromise solutions, and assertive request for follow-up with a specific doctor. Each was found to be a significant predictor of compliance behaviors. The findings indicate the importance of positive cognitive and assertive coping skills in specific stressful situations involving the patient and medical team.

Four years experience with the microcomputer system "Diacon" in the treatment and education of diabetes.

The use of a user-friendly microcomputer system "DIACON" which stores, analyses and displays blood glucose, details of the nutrition intake, insulin dose and other details relevant to diabetes management is described. This system tested for over four years in more than 100 diabetic patients has proven to be a useful educational and therapeutic tool.

Psycho-social aspects of children and adolescents with diabetes.

The diagnosis of diabetes mellitus, a life-long disease with many possible complications, has a dramatic impact upon the entire family, precipitating a state of "shock". The psychological problems in diabetes should be divided in 3 periods: at diagnosis (other diseases or tension existing in the family and not related to diabetes, socio-economic state); initial adaptation period (acceptance to be "different", adjustment to rules of control such as daily injection of insulin, self blood glucose monitoring or urine testing, changing of nutritional habits, etc.), and long term coping (self-image, family dynamics, social activities, school achievements, vocational rehabilitation and continuing compliance. Counselling of the psychological problems is an ongoing need and is best delivered when the treating team included psychologists and social workers.

The impact of long-term therapy by a multidisciplinary team on the education, occupation and marital status of growth hormone deficient patients after termination of therapy.

Forty-two GH deficient patients (14 isolated GH deficiency (IGHD), 28 multiple pituitary hormone deficiencies (MPHD), 23 males and 19 females) were evaluated after termination of hGH therapy and achievement of final height. IGHD patients were found to score higher in intelligence quotients (IQ) than the MPHD patients. The educational and occupational achievements of all patients positively correlated with their IQ level. Three patients achieved only elementary education, 26 completed high school and 13 had higher education. Thirty patients who had completed their education were employed, whereas 12 continued to study. Seventeen of the male patients and five females served in the Army. Eight patients were married and half of the single patients reported having a stable relationship with the opposite sex. The hypopituitary patients did not differ in five out of seven subscales of the human services rehabilitation scale when compared to a normal control group. These results which vary from those previously reported demonstrate the importance of long-term psychosocial counselling initiated at the time of diagnosis as part of the therapeutic approach in hypopituitary patients.

Recurrent hypothermia, hypersomnolence, central sleep apnea, hypodipsia, hypernatremia, hypothyroidism, hyperprolactinemia and growth hormone deficiency in a boy--treatment with clomipramine.

A boy referred at the age of 4 years because of obesity and under observation for 16 years, was found to be suffering from a hypothalamic syndrome of unknown origin characterized by progressive obesity, polyphagia, deficiency of growth and thyroid hormone, hyperprolactinemia, hypodipsia, hypernatremia and hyperosmolality without diabetes insipidus. At ages 11 and 16 there were 3 day episodes of spontaneous muscular weakness, hypersomnolence and hypothermia associated with central sleep apnea and severe bradycardia. Subsequently, decreased ventilatory responsiveness to carbon dioxide (CO2) was found as a consequence of blunted neural drive. Therapy with clomipramine HCl (Anafranil Ciba-Geigy) for 6 months led to a normalization of serum sodium levels, pulse rate, ventilatory response to dioxide with no recurrence of the central apnea within 4 following years.

Psychosocial aspects of young adult growth hormone deficient patients previously treated with human growth hormone--a preliminary report.

This paper describes a multidisciplinary approach to treating patients with hGH deficiency. The team includes paediatric endocrinologists, social workers and psychologists, and is felt to provide a much better standard of care, producing subjects who are well integrated into society.

Comparison of metabolic and psychological parameters during continuous subcutaneous insulin infusion and intensified conventional insulin treatment in type I diabetic patients.

Two methods of insulin treatment--intensified conventional therapy (ICT) of three to four daily injections and continuous s.c. insulin infusion (CSII)--were compared in nine patients with insulin-dependent diabetes mellitus (mean age +/- SD 29.4 +/- 5.6 years; duration of diabetes 14.6 +/- 2.9 years). Patients followed each regimen for 3 to 4 months. Under both regimens hemoglobin A1 (HbA1) levels were lower than those recorded previously, but under CSII the mean HbA1 and glucose levels were significantly lower than under ICT (7.8 +/- 0.1 vs. 8.9 +/- 0.2% for HbA1 and 136 +/- 40 vs. 155 +/- 60 mg/dl for blood glucose, P less than 0.001). There was no difference in the frequency of blood glucose levels less than 60 mg/dl, but under CSII hypoglycemic symptoms appeared at lower glucose levels. There was no marked difference between the two regimens regarding scores for depression and anxiety and other psychological parameters, but patients who chose to continue treatment with CSII following completion of the study had previously manifested a significantly higher degree of distress symptoms, which had been reduced during the study. CSII was preferred by some patients because of the superior metabolic control achieved and the greater flexibility in time and size of meals permitted, but was rejected by others because of technical failures and bulkiness of the device. It is concluded that metabolic control can be improved by either regimen, but external pumps must be further miniaturized and technical failures eliminated before CSIII is acceptable to larger numbers of patients.