Mutation analysis in the family of a child with 21-hydroxylase deficiency showed that the father and affected child were homozygous for a mutation, A/C655G, believed to activate a cryptic splice site in intron 2 of the 21-hydroxylase gene. The father, who was clinically asymptomatic, showed no biochemical evidence of disease. These results create problems for the management of future pregnancies in such families and for the interpretation of the risk associated with carrier status for this mutation.
Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.There is yet no clear genotype-epigenotype-phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.
OBJECTIVE Hexarelin is a synthetic six‐amino‐acid compound capable of releasing GH in animals and in man. Its mechanism of action is not understood and little is known about the GH response after repeated administration. The aim of this study was to determine the GH response to the administration of two intravenous boluses of hexarelin, growth hormone releasing hormone (GHRH) or hexarelin with GHRH. DESIGN Single boluses of hexarelin (1 μg/kg), GHRH‐(1–29)‐NH 2 (1 μg/kg) or hexarelin with GHRH‐(1–29)‐NH 2 were administered intravenously. Each study was performed on two further occasions, with a second bolus being administered 60 or 120 minutes after the first. A control study was performed giving saline intravenously. Studies were performed in a random order. SUBJECTS Six healthy adult males (25.4–34.1 years) were studied. MEASUREMENTS Serum GH was measured by radioimmunoassay. GH secretion rates were derived from the measured serum GH concentrations using the technique of deconvolution analysis. RESULTS The peak GH secretion rate following the first intravenous bolus of hexarelin was greater than that following the first bolus of GHRH‐(1–29)‐NH 2 ( P < 0.001), and was greatest following the administration of hexarelin with GHRH‐(1–29)‐NH 2 ( P < 0.001). The coadministration of the two secretagogues resulted in peak GH secretion rates significantly greater than the arithmetic sum of those following their isolated administration ( P = 0.001), demonstrating synergism. Compared to saline, the administration of a second bolus of hexarelin, GHRH‐(1–29)‐NH 2 or both resulted in significant further GH secretion ( P = 0.02, P = 0.002, P = 0.03, respectively). The administration of a second bolus of hexarelin or hexarelin with GHRH‐(1–29)‐NH 2 120 minutes after the first bolus resulted in lower peak GH secretion rates ( P = 0.03). The reductions in peak GH secretion rates following the 60‐minute boluses were not statistically significant. The peak GH secretion rates following the first GHRH‐(1–29)‐NH 2 boluses were similar to those following the 60 and 120‐minute GHRH‐(1–29)‐NH 2 boluses ( P = NS). Irrespective of the interval between the boluses of hexarelin with GHRH‐(1–29)‐NH 2 , the peak GH secretion rates following the second boluses were not significantly different from the arithmetic sum of those following the administration of the second boluses of hexarelin or GHRH‐(1–29)‐NH 2 , indicating loss of synergism on repeated administration. CONCLUSIONS This study shows that hexarelin is a potent GH secretagogue active after two successive doses; the magnitude of the GH response to the second dose was influenced by the dosing interval. Hexarelin and GHRH‐(1–29)‐NH 2 are synergistic, a property which is lost after repeated administration. These findings may help our understanding of GHRPs and may have implications for the potential use of hexarelin and other GHRPs as therapeutic agents.
Dose-response data for GH-releasing peptides are limited. We studied the effects of varying doses (0-1.0 microgram/kg) of hexarelin, a novel GH-releasing peptide, administered iv to healthy adult males on GH, PRL, and cortisol release. In addition, we studied the effect of administration of a single dose of GHRH-(1-29)-NH2 (1.0 microgram/kg), alone or in combination with a low dose of hexarelin (0.125 microgram/kg). Dose-response curves for the maximum GH response and maximum percent change in serum PRL and cortisol concentrations from baseline were constructed. The GH dose-response curve reached a plateau of 140 mU/L, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.48 +/- 0.02 microgram/kg (mean +/- SEM). The PRL dose-response curve reached a plateau of 180% for the maximum percent rise from baseline, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.39 +/- 0.02 microgram/kg. The cortisol dose-response curve showed a step increase to approximately 40% at a hexarelin dose of 0.5 microgram/kg. The coadministration of GHRH-(1-29)-NH2 (1.0 microgram/kg) and low dose hexarelin (0.125 microgram/kg) resulted in massive GH release (115 +/- 32.8 mU/L), a moderate rise in serum PRL (84.9 +/- 27.5%), and no rise in serum cortisol. These data show that iv hexarelin was capable of inducing GH, PRL, and cortisol release in a dose-dependent manner. Low dose hexarelin was synergistic with GHRH and potent for GH release with a minimal effect on other hormones.
This work describes physiological studies of the growth hormone releasing peptide (GHRP) hexarelin. Four groups of studies were conducted on young, healthy, adult male volunteers, as follows; 1. Studies which demonstrated that hexarelin is a potent growth hormone (GH) secretagogue, capable of inducing GH release after two successive administrations. GHRP acts synergistically with growth hormone releasing hormone (GHRH) to induce massive GH release. However, this synergistic action is lost on repeated administration. 2. Studies which showed that GH itself attenuates the GH response to GHRP. 3. Studies which showed that the GH-releasing activity of GHRP, alone or in combination with GHRH, is attenuated but not abolished by increasing somatostatin (SS) tone. The large GH release induced by GHRP plus GHRH despite the presence of high SS tone suggests that combined therapy may be utilised to produce GH release in conditions where SS tone is unknown. 4. Studies which established GH dose-response curves for hexarelin. This group of studies also showed that hexarelin is non-specific for GH release, inducing prolactin (PRL) and cortisol release in a dose-related manner. These studies showed that at low doses of hexarelin it is possible to induce adequate GH release with minimum concomitant rise in PRL and cortisol. Moreover, combined GHRH plus low dose hexarelin is synergistic for GH release with no additive effect on PRL and cortisol release. The actions of GHRPs and their interaction with the two main endogenous regulators of GH secretion, namely, GHRH and SS, strongly suggests that an endogenous GHRP ligand exists and plays an important role in the regulation of GH release. The specific GH release induced by low doses of GHRP, alone or in combination with GHRH, together with the oral activity of these peptides, holds a great promise for future therapeutic use.
This study evaluated the effect of corticotrophin-releasing hormone (CRH) on growth hormone releasing hormone (GHRH)-stimulated growth hormone (GH) release in man.Six healthy adult volunteers (age 20-35 years) were studied. On different occasions they each received an intravenous bolus of saline, CRH(1-41) (100 micrograms), adrenocorticotrophic hormone (ACTH) [Synacthen (500 ng/m2)] or hydrocortisone (50 mg), followed 30 minutes later by an intravenous bolus of either GHRH-(1-29)-NH2 (1.0 microgram/kg) or saline.Serum GH concentrations were measured using an immunoradiometric assay, and cortisol concentrations were measured by commercial radioimmunoassay. TSH concentrations were measured using a solid phase immunoradiometric assay kit.Pretreatment with CRH(1-41) attenuated the GH response to GHRH [saline/GHRH-(1-29)-NH2 20.2 +/- 6.2 mU/l; CRH(1-41)/GHRH-(1-29)-NH2 10.9 +/- 2.8 mU/l (P = 0.01)]. This effect was not due to the rise in ACTH or cortisol induced by CRH(1-41), since pretreatment with either ACTH or hydrocortisone significantly augmented the GH response to GHRH-(1-29)-NH2 in the same subjects [ACTH/GHRH-(1-29)-NH2 30.3 +/- 8.8 mU/l (P = 0.01); hydrocortisone/GHRH-(1-29)-NH2 36.4 +/- 11.2 mU/l (P = 0.02)].Our data suggest that the inhibitory effect of CRH(1-41) on GHRH-(1-29)-NH2-induced GH release is not a result of ACTH or cortisol release but reflects a direct action of CRH on GH secretion, possibly via stimulation of somatostatin release. The acute rise in GH following glucocorticoid administration could be explained in part by a rapid suppression of endogenous CRH.
Abstract Both general paediatricians and healthcare professionals in primary care often think of paediatric endocrine disorders as being rare and rather esoteric. While there is an element of truth in this, it remains a fact that, collectively, paediatric endocrine disorders are common, though, individually, many are rare and may not ever be encountered within the practising lifetime of a primary care health professional.
In our study of surface markers of Iranian children affected by acute lymphocytic leukemia, the majority(80 %)had non-T, non-B, or null cell leukemia. The null- cell l e ukemia had a better p r ogno s l s as was conf irmed by o t h ers. Twe l v e of our patie nts who had null cell l e ukem i a are a live and well 18 mont hs to 20 mont hs a f t e r initiat i on of the r a py. Three of t he patients who had l e s s than 27' null c e l l s in t he i nitial study died i n a pe r i od o f less than o ne year after d i agnosis. Af t e r therapy while on remission , there was a decrease i n the percentage o f nu l l c e l ls ( i n nul l c e l l l e ukemi a ) a nd an i ncre ase i n t h e p e r centage of T a nd B lymphocyt e s i n the pe r i phe r a l b lood which approachta o n the a ge and sex-matched norma l control s ubjects .
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