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There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3–4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03–0.05 mg/kg/day starting from the age of 8–10 years onward scan be considered., (© 2014 S. Karger AG, Basel.)

Background: Congenital isolated growth hormone deficiency (IGHD) is a rare endocrine disorder that presents with severe proportionate growth failure. Dominant (type II) IGHD is usually caused by heterozygous mutations of GH1. The presentation of newly affected family members in 3 families with dominant IGHD in whom previous genetic testing had not demonstrated a GH1 mutation or had not been performed, prompted us to identify the underlying genetic cause., Methods: GH1 was sequenced in 3 Caucasian families with a clinical autosomal dominant IGHD., Results: All affected family members had severe growth hormone (GH) deficiency that became apparent in the first 2 years of life. GH treatment led to a marked increase in height SDS. So far, no other pituitary dysfunctions have become apparent. In the first family a novel splice site mutation in GH1 was identified (c.172-1G>C, IVS2-1G>C). In two other families a previously reported splice site mutation (c.291+1G>A, IVS3+1G>A) was found., Conclusion: These data show that several years after negative genetic testing it was now possible to make a genetic diagnosis in these families with a well-defined, clearly heritable, autosomal dominant IGHD. This underscores the importance of clinical and genetic follow-up in a multidisciplinary setting. It also shows that even without a positive family history, genetic testing should be considered if the phenotype is strongly suggestive for a genetic syndrome. Identification of pathogenic mutations, like these GH1 mutations, has important clinical implications for the surveillance and genetic counseling of patients and expands our knowledge on the genotype-phenotype correlation., (© 2013 S. Karger AG, Basel.)

Growth failure in Noonan syndrome is mainly postnatal of character and is dominated by slow maturation and late puberty. The postnatal early decline seems to be an intrinsic part of the syndrome. Reported adult heights are about -2 SD and are indicative of a secular trend., (2009 S. Karger AG, Basel.)

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., (Copyright 2006 S. Karger AG, Basel)

Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. The symptoms and signs of CAH depend on the degree of enzyme deficiency; severe salt-wasting (SW) form, less severe simple virilizing (SV) form and mild nonclassic (NC) form. In this paper, puberty and fertility in CAH are discussed. The time of onset of puberty and progress of pubertal development is quite normal, except in NC patients (earlier). Also the age of menarche in CAH girls is normal, but it can depend on the level of therapeutic control. In prepuberty, bone age is advanced. In puberty, peak height velocity is normal but occurs at a younger age and can therefore be considered to be low (compared to healthy early maturers). In puberty there seems to be an increased sensitivity for glucocorticoids leading to growth inhibition. All three above factors can play a role in reducing adult height. Subfertility is frequently found in both female and male CAH patients. In females, the pregnancy rate depends on the severity of 21-hydroxylase deficiency (SW

Noonan syndrome is a well-known clinical entity comprising multiple congenital anomalies characterized by typical facial features, short stature and congenital heart defect. Approximately 50% of cases are sporadic. Familial cases are generally autosomal dominant. In 2001 a gene responsible for Noonan syndrome, PTPN11, encoding for the non-receptor protein tyrosine phosphatase SHP-2, was identified. Mutation analysis of the PTPN11 gene was carried out in Nijmegen in 150 patients with Noonan syndrome. Mutations were found in 68 patients (45%), the most common being A922G in exon 8. In exon 4 a mutation was found that encoded the C-SH2 domain of the PTPN11 gene in two unique patients who shared some uncommon features. A 218C-->T mutation was found in exon 3 in one patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia., (2004 S. Karger AG, Basel.)

Objective: To study the effects of long-term growth hormone (GH) treatment on left ventricular (LV) dimensions in children with Noonan's syndrome (NS)., Methods: Echocardiographic measurements of LV dimensions were performed before and during GH treatment in 27 participants (21 boys, 6 girls) in a partly controlled 3-year trial of high-dose GH treatment (0.15 IU/kg/day). Nineteen children had a congenital heart defect, 1 of them had hypertrophic obstructive cardiomyopathy. In the first 3 years, the children were assigned to 1 of 2 groups: group A with discontinuation of GH treatment in the 3rd year, or group B without GH treatment in the 1st year. After the 3rd year, 12 of the 27 children were followed up for 2 additional years to evaluate the long-term effects of GH treatment on the heart., Results: At baseline, LV internal diameters were smaller, while posterior wall thickness were thicker than normal. Over the 1st year, changes in LV dimensions were comparable between the 2 groups. No significant differences were found in LV dimensions between the situation at baseline and after 4 years of GH treatment., Conclusion: Long-term high-dose GH treatment does not have clinically significant adverse effects on LV dimensions in children with NS., (Copyright 2002 S. Karger AG, Basel)

Height and weight growth before and during treatment with human growth hormone (hGH) was studied in 46 Dutch patients treated for craniopharyngioma. Weight was expressed as body mass index (BMI, weight/height). At the time of tumor treatment mean +/- SD height standard deviation score (SDS) was -1.22 +/- 1.38 and BMI SDS was 0.56 +/- 1.32. The initial height SDS was inversely related to age (r = -0.38; p < 0.02). Before hGH treatment height SDS decreased to - 1.57 +/- 1.08 (p < 0.05) and BMI SDS increased to 1.54 +/- 1.58 (p < 0.005) during the first year after tumor treatment. Changes in height SDS correlated positively with basal prolactin (PRL) levels (r = 0.46; p < 0.05). Neither tumor localization nor treatment mode was related to changes in height SDS and BMI SDS. Forty patients were treated with hGH, started a median interval of 2.0 years after tumor treatment. At the time of the start of hGH treatment height SDS in these patients was -1.70 +/- 1.13, and BMI SDS was 1.44 +/- 1.79. During treatment with hGH, height SDS increased to -1.05 +/- 1.10 (p < 0.001) in the first, and to -0.80 +/- 1.04 (p < 0.001) in the second year. BMI SDS did not change during hGH therapy. In conclusion, there is a large variation in height SDS and BMI SDS at the time of initial presentation as well as during spontaneous growth after tumor treatment. Spontaneous growth is related to serum PRL concentrations. Treatment with hGH significantly increased height SDS during the first 2 years, whereas BMI SDS did not change.

Pit-1 is a transcription factor which is expressed in the somatotrope, lactotrope, and thyrotrope cell population of the anterior pituitary gland from early fetal development throughout life. Mutations in the Pit-1 gene result in insufficient expression of this factor, accounting for a form of combined pituitary hormone deficiency for growth hormone (GH), prolactin, and thyroid-stimulating hormone. Clinical presentation at diagnosis can be variable, although all forms finally result in severe growth retardation due to GH deficiency and hypothyroidism. The clinical variability is due to other factors than the exact location of the mutation; however, the type of inheritance seems to correlate well with the genotype. Early detection of Pit-1 abnormalities might prevent the sequelae associated with some early and severe presentations of this disorder.

In 1987 a multicentre trial of recombinant human growth hormone (GH) was started in girls with Turner syndrome. Fifty-four patients were randomly assigned to receive GH, 8 IU/m2 3 times/week (group 1), or 4 IU/m2 6 times/week (group 2). In addition, the 35 patients older than 12 years received ethinyloestradiol, 100 ng/kg body weight/day, and after 2 years GH therapy was increased to 6 IU/m2 6 times/week. Recombinant human GH treatment was stopped when the height increment during the previous 6 months of treatment was less than 0.5 cm. Treatment has so far been stopped in 48 patients: treatment was stopped early in 2 patients due to lack of motivation, 1 patient died suddenly and the treatment protocol was completed in 45 patients. The last height measurement obtained, which was considered as (near) final height, was 152.3 +/- 5.3 cm (mean +/- SD) in these patients, which is higher (p < 0.001) than the adult height of 147.0 +/- 6.3 cm reported in 63 untreated adult Dutch patients with Turner syndrome. No differences in outcome were found between the two dose regimens.

Girls with Turner syndrome were divided according to age (group A 6-12 years, and group B 12-19 years) and human growth hormone (GH) dose regimen (A1 and B1, three injections/week; A2 and B2, six injections/week). All groups responded to GH, 24 IU/m2/week, with an increase in height velocity, though in the older girls, the response was comparatively poor. Therefore, the dose regimens in groups B1 and B2 were increased to 36 IU/m2/week given as six injections in both groups. This change resulted in an increase in height velocity only in group B1. During the first 2 years only, the height velocity was greater in group A2 than group A1. The conclusion is that a regimen of six injections/week is more effective than one of three injections/week in terms of initial height gain and change in predicted adult height. In girls with Turner syndrome aged over 16 years, GH therapy has no significant effect.

Thirty-four patients (27 girls and 7 boys) with precocious puberty who had reached final height were examined in order to analyze their growth. Thirty patients were diagnosed as having idiopathic precocious puberty, while 4 patients had cerebral organic disorders. Twenty-two patients were treated with cyproterone acetate, 3 with medroxyprogesterone acetate, and 9 patients remained untreated. Growth data of these three groups showed no differences, and final height was not affected by treatment. In patients with precocious puberty, adult height was significantly more often in the lower percentiles (less than or equal to P25, corresponding to an SDS of -0.67) than expected. In both treated and untreated patients, any negative influence of the early onset of puberty on well-being in later life could not be established.

A 19-month-old boy presented with failure to thrive and polydipsia. Low-renin hypertension was diagnosed by the presence of hypertension, hypokalaemic alkalosis, suppressed plasma renin activity and low plasma aldosterone. Plasma levels and urinary excretion of other mineralocorticoids and glucocorticosteroids were low or normal. Urinary tetrahydrocortisol (THF) was increased relative to tetrahydrocortisone (THE) and also the plasma cortisol to cortisone ratio was elevated. These findings are suggestive of a decreased activity of cortisol-11 beta-hydroxysteroid dehydrogenase. Hypertension and hypokalaemia were not influenced by spironolactone and dexamethasone. Triamterene normalised serum potassium, but addition of furosemide was required for lowering blood pressure. With this treatment catch-up growth was observed.

In a double-blind study 12 prepubertal children with idiopathic growth hormone (GH) deficiency were treated with growth hormone releasing factor (GRF) 1-44 in a dosage of 7.5 or 15 micrograms/kg body weight, administered once a day subcutaneously. With 7.5 micrograms/kg the average growth velocity increased from 2.5 to 4.6 cm/year, an insufficient response. With the higher dosage the average growth velocity increased from 2.7 to 7.0 cm/year, a similar increase as observed with GH therapy in subsequent periods. In 3 of the 6 children treated with the higher dose appropriate catch-up growth was observed. The growth response of the lower leg length was not always consistent with the statural growth response.