Paola Cambiaso

Final height after growth hormone therapy in non-growth-hormone-deficient children with short stature

We report the effect of growth hormone (GH) treatment for 4 to 10 years in 15 prepubertal non-GH-deficient short children (10 boys, 5 girls, aged 7.4 to 13.2 years). In 7 patients, GH was administered at a dosage of 0.5 U/kg per week (group 1: 4 boys, 3 girls) and in 8 patients (group 2: 6 boys, 2 girls) at a dosage of 1.0 U/kg per week. After the first year, mean linear growth velocity had significantly increased in both groups. The increase in growth velocity was sustained during the first 4 years and then declined to pretreatment values in the majority of subjects. Treatment with GH did not induce an earlier onset of puberty, but there was a tendency toward faster skeletal maturation. The mean final height standard deviation score (SDS) was similar in the two groups and was significantly higher than the height SDS for chronologic age before treatment, but it did not differ from mean pretreatment predicted adult height SDS nor from mean target height SDS in both groups. Final height was significantly correlated with target height in both groups. These preliminary observations indicate that GH treatment does not generally increase final height over target height in short non-GH-deficient children.

The natural history of the normal/mild elevated TSH serum levels in children and adolescents with Hashimoto’s thyroiditis and isolated hyperthyrotropinaemia: a 3‐year follow‐up

Objective  The natural history of Hashimoto’s thyroiditis (HT) and isolated hyperthyrotropinaemia (IH) is not well defined. We therefore studied the natural course of patients with HT and IH and looked for possible prognostic factors.

High dose immunoglobulin IV treatment in adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is an inborn error of peroxisomal metabolism characterised by progressive demyelination of the central nervous system and by hypoadrenalism. The biochemical defect of ALD results in an impairment in degradation of very long chain fatty acids (VLCFA) with their accumulation in plasma and tissues. Many therapeutic approaches have been tried. Recently, a restricted diet and glycerol trioleate/erucic (GTOE) supplementation have shown normalisation of VLCFA plasma levels, although they are not effective in altering the clinical course of X-linked ALD. The preliminary results are presented of a twelve month trial of immunomodulation by intravenous high-dose immunoglobulins in six patients, mean (SD) age 10.48 (2.8) affected by X-linked ALD, on VLCFA restricted diet plus GTOE supplementation therapy. Six patients aged 9.30 (1.5) with similar clinical characteristics and on the same restricted VLCFA regime of GTO/GTE therapy were studied as the control group. After two months VLCFA levels fell to normal values and remained so for all patients throughout the study. These data show that immunoglobulins are not able to arrest the progression of the disease. The MRI and clinical symptoms deteriorated to the same extent in both groups.

Auxological evaluation in patients with DiGeorge/velocardiofacial syndrome (deletion 22q11.2 syndrome)

Purpose: Patients with microdeletion of chromosome 22q11.2 (del22q11) were studied, in order to evaluate auxological parameters and to correlate growth patterns with the presence of main clinical characteristics of the syndrome.Methods: Between January 1995 and March 2000, auxological parameters (weight, height, head circumference, and bone age) of 73 patients with del22q11 were collected. Five subgroups of patients were distinguished: Group I (37 patients) included patients aged between 0.3 and 4 years, Group II (20 patients) included patients aged between 5 and 10 years, Group III (16 patients) included patients aged between 11 and 16.3 years. The presence or absence of some clinical features was correlated to growth patterns.Results: Weight: in Group I, 5 of 37 (13.5%) patients were below the 3rd percentile, 29 of 37 (78.3%) were below the mean percentile, none was overweight; in Group II, 13 of 20 (65%) patients were between the 10th and the 50th percentiles; in Group III, weight corresponded to the 97th percentile in 5 of 16 (31.2%) patients, and in 2/16 (12.5%) adolescents, the weight measurements were even above the 97th percentile. Height: short stature was detected in 7 of 73 (9.6%) of the total patients; the patients with short stature were all < 10 years old; the height was within the normal age in all adolescent patients. Head circumference: it was below the 3rd percentile in 7 of 73 (9.6%), between the 3rd and the 25th percentiles in 36 of 73 (49.3%) patients, between the 25th and the 75th percentiles in 20 of 73 (27.3%) patients, and between the 75th and the 97th percentiles in 10 of 73 (13.7%) patients. Bone age: mean ± sd bone age was -0.25 ± 0.78 years. Comparisons: the only statistically significant correlation was that between the presence of feeding difficulties and underweight.Conclusion: Auxological parameters of children with del22q11 are characterized by: (1) weight deficiency in the first years of age, (2) weight normalization in the following years, (3) development of obesity in adolescence, (4) short stature in 10% of the patients, (5) normal height in adolescents, (6) slight delay in bone age in infancy, (7) microcephaly in 10% of the patients.

Unilateral cryptorchidism corrected in prepubertal age: Evaluation of sperm parameters, hormones, and antisperm antibodies in adult age

OBJECTIVE To evaluate whether prepubertal orchidopexy for unilateral cryptorchidism can reduce adult dysspermia. DESIGN Patient follow-up comparison with control groups. SETTING Surgical and endocrinologic sections of a childrens hospital and a university infertility-care center. PATIENT(S) Seventy-one patients with unilateral cryptorchidism who underwent orchidopexy in prepubertal age (6.4 +/- 2.8 years) were followed up as adults (20.0 +/- 2.8 years). MAIN OUTCOME MEASURE(S) Patients underwent testicular examination and hormonal evaluation, 49 of these had semen analysis and antisperm antibody tests. Semen results were compared with those of two age-matched control groups: a group of 20 healthy, randomly selected subjects and a group of 20 patients operated on in postpubertal age for cryptorchidism. RESULT(S) Unilateral reduced testis size was found in 30.1% of patients, eight patients had a low LH level, eight had a low T level, and none had abnormal FSH values. Antisperm antibodies were found in 1 of 49 cases. Cluster analysis of sperm parameters showed that the mean values of patients were worse than those of the healthy controls but better than those of the subjects operated on in postpubertal age. CONCLUSION(S) This study indicates that prepubertal orchidopexy can given better results than postpubertal correction.

A CDKL5 mutated child with precocious puberty

To date, 43 patients have been described with mutations in or involving the CDKL5 gene. The typical phenotype includes early‐onset, often intractable epileptic seizures and severe mental retardation with very limited progress in psychomotor development. Most patients also show impaired social interaction with avoidance of eye‐to‐eye contact, and some clinical features reminiscent of Rett syndrome (RTT), including stereotypic hand movements, lack of purposeful hand use, acquired microcephaly, and generalized hypotonia. We report on the case of a 5‐year‐old girl with a de novo CDKL5 gene mutation who developed early puberty, which has not been described before.

Adrenal steroidogenic defects in children with precocious pubarche

The occurrence of nonclassical congenital adrenal hyperplasia among children with precocious pubarche is still a matter of debate. We studied the adrenal steroid response to ACTH stimulus (Synacthen, 0.25 mg i.v. bolus) in 26 Italian children (5 boys, 21 girls) who had presented pubic hair, without other signs of virilization, at ages ranging between 0.45 and 8.8 years. The control groups comprised 8 prepubertal children (5 boys, 3 girls) and 12 children at Tanner stage 2 for pubic hair development (1 boy, 11 girls). Two patients were diagnosed as having nonclassical congenital adrenal hyperplasia: 1 due to 21-hydroxylase deficiency, the other due to 3 beta-hydroxysteroid-dehydrogenase deficiency. The remainder, classified as having idiopathic precocious pubarche (PP), had adrenal androgens higher than normal prepubertal children and similar levels to those observed in early pubertal controls. In contrast to a recent report, we confirmed that mild adrenal enzymatic defects can occur in PP, and, consequently, the use of ACTH testing in children with PP seems to be recommended.

Responses to GHRH plus arginine test are more concordant with IGF-I circulating levels than responses to arginine and clonidine provocative tests

BACKGROUND/OBJECTIVE Although pharmacological GH stimulation tests are still considered the gold standard for GH deficiency (GHD) diagnosis, they are burdened by poor specificity. The majority of children diagnosed as having GHD show normal GH responses when re-tested at the end of growth, thus questioning the initial diagnosis. We evaluated the concordance between IGF-I levels and GH responses to provocative tests. METHODS We analyzed 105 GHRH plus arginine tests, 79 arginine tests, and 124 clonidine tests performed in 192 short children. IGF-I levels ≤-2SD score (SDS) were considered suggestive for high likelihood of GHD. The percentage of positive and negative results for each test was determined and compared with IGF-I levels, clinical follow-up and response to therapy. RESULTS In children with IGF-I>-2SDS the arginine test showed a concordance rate of 6.9%, the clonidine test of 28.6%, and GHRH plus arginine test of 70%. In children with IGF-I≤-2SDS the concordance was 96.1%, 85.7%, and 46.4%, respectively. The overall concordance was 66.7% for GHRH plus arginine, 42.7% for clonidine, and 27.8% for arginine tests. CONCLUSION Our results suggest that GHRH plus arginine test provides the best concordance with the assessment of IGF-I levels thus suggesting that the combination of the two procedures may significantly reduce the need of a second provocative test.

Indirect methods for TSH reference interval: At last fit for purpose?

To the Editor We read with great interest the article by Katayev et al1 and the companion editorial by Horowitz2 that discuss the production of reliable reference intervals for common tests such as calcium, creatinine, mean corpuscular volume, and thyroid-stimulating hormone (TSH). Katayev et al1 used a computerized version of the technique proposed almost 50 years ago by Hoffmann3 in a large number of results stored in the laboratory information system serving 6 laboratories. According to Katayev et al,1 “The computerized Hoffmann method for the indirect determination of RIs [reference intervals] produced intervals that were remarkably similar to peer-reviewed RIs.” Horowitz2 disagrees and states “… the reference intervals generated in this way are strikingly different from the reference intervals in use….” The articles disagree because TSH is being measured more and more precisely, but different assays show a relevant bias; manufacturers, laboratory professionals, and clinicians rarely appreciate the effect of this bias on the cutoffs quoted in guidelines. In some cases, we agree that TSH could indeed be unfit for purpose.4 Katayev et al1 reported upper reference limits in 2 large sets of data using the ADVIA Centaur analyzer (Siemens Medical Solutions Diagnostics, Tarrytown, NY) of 3.05 and 3.19 mIU/L consistent with that proposed by the American Association of Clinical Endocrinologists (3 mIU/L).5 Since 2000, we have been using the same analyzer and the program GraphROC, which implements the “indirect” method proposed by Kairisto and Poola6 based on the Hoffmann method.7 In synthesis, the distribution is split and the mode (rather than the mean) of the hypothesized health-related distribution is forced to be the same as the mode in the original distribution. The health-related distribution consisted of 2 halves of 2 different gaussian distributions, with the same mode and …

Autosomal-dominant isolated growth hormone deficiency (IGHD type II) with normal GH-1 gene.

Background: Autosomal-dominant isolated GH deficiency (IGHD) is a rare disorder that is commonly believed to be due to heterozygous mutations in the GH-1 gene (GH-1). These mutations cause the production of a protein that affects the release of the product of the normal allele. Rarely, heterozygous mutations in the gene encoding for HESX-1 gene (HESX-1) may cause autosomal-dominant IGHD, with penetrance that has been shown to be variable in both humans and mice. Subjects and Methods: We have sequenced the whole GH-1 in the index cases of 30 families with autosomal-dominant IGHD. In all the families other possible causes of GH deficiency and other pituitary hormones deficits were excluded. We here describe the clinical, biochemical and radiological picture of the families without GH-1 mutations. In these families, we also sequenced the HESX-1. Results: The index cases of the five families with autosomal-dominant IGHD had normal GH-1, including the intronic sequences. They had no HESX-1 mutations. Conclusion: This study shows that GH-1 mutations are absent in 5/30 (16.6%) of the families with autosomal-dominant IGHD and raises the possibility that mutations in other gene(s) may be involved in IGHD with this mode of transmission.