A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency.

AIMS: To determine the effectiveness of different doses of r-hGH therapy during puberty in children with growth hormone deficiency (GHD). METHODS: Randomized controlled trial of different doses of r-hGH therapy administered during puberty in 49 children with GHD. The patients were allocated randomly using a random number table to one of two groups: group 1 (15 IU/m(2)/week) or group 2 (30 IU/m(2)/week). Patients were included if they had received r-hGH daily at a dose of 15 IU/m(2)/week (0.7 mg/m(2)/day) for at least 1 year before randomization. RESULTS: Height increase standard deviation scores (SDS) were similar between the two groups (group 1: 1.1; group 2: 1.2; p = 0.81). CONCLUSION: A higher dose of r-hGH administered during puberty does not appear to have a significant effect on final height of children with GH deficiency. Altering pubertal tempo or intensifying prepubertal r-hGH therapy may be a more promising approach to improving final height in children with GH deficiency.

Hypoglycaemia and Russell-Silver syndrome.

AIM: To determine both the incidence and aetiology of chronic hypoglycaemia in symptomatic children with Russell-Silver syndrome (RSS) during the first four years of life. STUDY DESIGN: Twenty-four children with RSS under the age of 4 years, who had either clinical symptoms of hypoglycaemia or previous evidence of biochemically documented hypoglycaemia, were admitted to hospital for 48 hours to perform a 24-h cortisol/glucose profile and a diagnostic fast in those who did not develop spontaneous hypoglycaemia. A dietary assessment was also performed. Glucose profile was assessed in 20 children and cortisol profile in 16; combined glucose and cortisol profile in 15 children. Eight children had a diagnostic fast. Mean chronological age at time of assessment was 2.2 +/- 0.8 years (range 1.1-3.9 years). RESULTS: Ten of 24 children had previously been documented as having hypoglycaemia. Seven of 12 patients were growth hormone (GH) insufficient after a glucagon test. Their feeding pattern was described as 'poor and picky eaters' in all, seven requiring nasogastric tube feeding. The mean spontaneous energy intake (n = 8) was 56 +/- 19.6 kcal/kg/day (range 38-90). Nocturnal sweating was the commonest symptom (23.96%), followed by irritability (11.46%), tantrums (7.29%), pallor and shakiness (3.13%). The glucose profile in seven children showed hypoglycaemia but only four were symptomatic. None of the children was cortisol deficient. The mean period of fasting was 11.8 +/- 4 hours (range 3-18 h). No metabolic/hormonal abnormality, with the exception of GH insufficiency, was detected at the time of hypoglycaemia. CONCLUSION: Children with RSS are prone to develop spontaneous hypoglycaemia especially if they are not fed both frequently and regularly. The most likely explanation is accelerated starvation and/or GH insufficiency. We suggest guidelines to minimise hypoglycaemia in these children.

Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism.

It has recently been shown that loss-of-function mutations of the G protein-coupled receptor (GPR)54 lead to isolated hypogonadotropic hypogonadism (IHH) in mice and humans. Such mutations are thought to be rare, even within the clinical IHH population, and only a handful of alleles have been described, making further screening of IHH populations imperative. We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty. One subject with HH, of mixed Turkish-Cypriot and Afro-Caribbean ancestry, was found to be a compound heterozygote for two previously undescribed missense mutations in GPR54: cysteine 223 to arginine (C223R) in the fifth transmembrane helix and arginine 297 to leucine (R297L) in the third extracellular loop. Assessed in vitro using a previously described sensitive signaling assay in cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, whereas the R297L variant showed a mild reduction in ligand-stimulated activity across the ligand dose range. These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54.

Efficacy and safety of Valtropin in the treatment of short stature in girls with Turner's syndrome.

Valtropin (somatropin, BioPartners and LG Life Sciences [LGLS]) is a recombinant human growth hormone (GH) preparation produced using a yeast expression system. An open single-arm phase III study was conducted to evaluate efficacy and safety at a dose of 0.16 IU/kg/day (0.053 mg/kg/day) s.c. for 12 months in the treatment of short stature in girls (n = 30, aged 2-9 years) with Turner's syndrome. The primary efficacy variable was height velocity (HV) at 12 months. Secondary efficacy variables included serum GH dependent growth factors. HV increased from 3.8 +/- 1.8 cm/yr at baseline to 9.7 +/- 1.6 cm/yr (mean +/- SD) after 12 months of treatment. Marked treatment effects were also observed on other growth parameters, serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). Treatment was well tolerated with no significant adverse events. It is concluded that Valtropin is as safe and effective as other human GH preparations for the treatment of growth failure in girls with Turner's syndrome.

Growth hormone secretion and long-term growth data in children with psychosocial short stature treated by different changes in environment.

OBJECTIVES: We assessed auxological and endocrine data of 65 children (32 girls) from 51 families with an average age of 6.6 years (range, 0.9 to 16.5 years, all but five prepubertal) with psychosocial short stature. METHODS: Fifty-one patients had an assessment of growth hormone (GH) secretion. Thirty-four were subjected to repeated testing with the first test being performed when the child was still in the adverse environment and the next testing after the child was removed. Twenty-five out of those 34 were repeatedly tested during one uninterrupted hospital admission with limited parental access. Thirty patients had a definite, long-term change in their environment (13 were separated from their families) and were assessed concerning their auxological data. RESULTS: Of the 34 patients who had repeated endocrine testing, 11 (32%) showed reversible GH deficiency (GHD), nine (26%) increased their previously normal peak GH concentration, and six (18%) had apparently irreversible GHD. Patients who had a change in environment increased their mean height velocity SDS from -0.9 (SD 1.5) to +1.5 (2.3) (p < 0.0001). Accordingly, height SDS increased from -2.9 (SD 0.8) before to -2.6 (SD 0.8) after the change (p < 0.001). CONCLUSION: One of the diagnostic features of psychosocial short stature is reversible GH insufficiency, which usually normalises after the child is separated from the adverse environment. Catch-up growth is always found after a positive change in the environment, and may occur within the family. However, if a change in environment is not possible, GH therapy may be an option.

Body mass index and hypothalamic morphology on MRI in children with congenital midline cerebral abnormalities.

Obesity is common in children with congenital midline defects of the brain, due to various endocrine reasons: hypothyroidism, growth hormone deficiency and inappropriate cortisol replacement. However, obesity occurs more often in the absence of an endocrinopathy. We reviewed 31 patients (10 females, 21 males) with midline intracranial defects (holoprosencephaly, absence of septum pellucidum, absence of corpus callosum, optic nerve hypoplasia) and correlated the morphology of the hypothalamus with body mass index (BMI), as BMI SDS. Endocrinopathies were present in 16 out of the 31 patients. We conclude that there was a trend of increasing mean BMI SDS with increasing hypothalamic abnormality, although this was not statistically significant.

Disorders of pubertal development.

Puberty is the period of life during which reproductive capability is acquired. It is characterized clinically by the acquisition of secondary sexual characteristics associated with a growth spurt, and on average takes 3-4 years. Early maturation is defined as the development of sexual characteristics before the age of 8 years in girls and 9 years in boys. Delayed puberty is defined when there are no signs of puberty at the age of 13.4 years in girls and 14 years in boys (2 SD above the mean of chronological age for the onset of puberty). There are many forms of premature sexual maturation: gonadotrophin-dependent (central, or 'idiopathic' or 'true' precocious puberty) and gonadotrophin-independent precocious puberty (McCune-Albright syndrome in girls, testotoxicosis in boys); isolated premature thelarche (in the forms of classical, atypical and variant); premature adrenarche (characterized by the production of significant quantities of androgens between 5 and 8 years of age); premature menarche. The differential diagnosis of delayed puberty is between constitutional delay of growth and puberty, pubertal delay secondary to chronic disease and hypogonadotrophic hypogonadism.

Final height in psychosocial short stature: is there complete catch-up?

AIM: To determine whether children with psychosocial short stature attain their genetic height potential. METHODS: We report on 18 children (10 girls, 8 boys) diagnosed by a multidisciplinary team as having psychosocial short stature. All the children had had some kind of change in their environment (9 were separated from their families), and increased their mean height velocity standard deviation score (SDS) from -0.7 (1.3) to +3.6 (4.8) (p < 0.005) as well as their height SDS from -3.0 (0.3) to -2.6 (0.9) in the first year after the change. All the patients were postpubertal and had reached their near final height (mean age, 20.0 y; range, 16.0-23.3). RESULTS: Only 3 out of 18 had a greater final height than the mid-parental target height, 14 out of 18 had a near final height within the mid-parental target range (95% tolerance limits of the mid-parental height (+/- 2 SD = +/- 10 cm). Nevertheless, mean final height expressed in height SDS for the whole group was significantly shorter with -2.4 SDS compared with the mean of the mid-parental target height of -1.5 SDS (p < 0.001). Surprisingly, initial catch-up growth did not correlate with final height attainment. CONCLUSION: The majority of patients will attain a stature within the range of mid-parental target height, although towards the lower limit of this range.

Body composition in early onset eating disorders.

BACKGROUND: Body mass index (BMI) or equivalent weight for height indices are the most widely used measures of body composition in early onset and adolescent eating disorders. Although of value as screening instruments the limitation in disease states is their inability to discriminate fat and fat-free components of body weight. OBJECTIVE: To compare height-adjusted fat and fat-free components of body composition in children and young adolescents with different types of eating disorders with those of age matched reference children. DESIGN: Weight, height, triceps and subscapular skinfold thickness were measured in 172 children (aged 7-16 y) with eating disorders receiving specialist treatment. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated using Slaughter's and Deurenberg's equations and normalisation for height. Using data from 157 normal children, representative of the UK 1990 growth reference data, reference curves for FMI and FFMI+/-2 s.d. were derived. Results for patient groups were superimposed on these reference curves. RESULTS: FMI and FFMI were both reduced in eating disorders associated with malnutrition, including anorexia nervosa (AN). AN subjects did not differ from other subjects with comparable degrees of malnutrition. Children with eating disorders of normal weight, such as bulimia nervosa and selective eating, did not differ significantly from reference children in their relative FM and FFM. CONCLUSIONS: FM and FFM merit independent consideration in disorders of malnutrition in children, rather than expressing data as percentage body fat or percentage BMI. The implications of loss of FFM on growth and development merit further investigation.

Retroperitoneal endometriosis causing unilateral hip pain.

BACKGROUND: The usual symptoms of endometriosis are secondary dysmenorrhea, dyspareunia, and infertility, but when located in the retroperitoneal space, it might have atypical symptoms that delay diagnosis and postpone therapy. CASE: A young nulligravida presented with secondary dysmenorrhea and concurrent cyclic hip pain. Recent laparoscopy was reportedly normal. Computed tomography (CT)-directed percutaneous needle biopsy of a retroperitoneal mass showed endometriosis. Laparotomy with retroperitoneal dissection removed the endometriosis, and operative arthroscopy released strictured hip tendons improving her hip pain and limp. CONCLUSION: Retroperitoneal endometriosis presenting as hip pain was diagnosed by CT-guided percutaneous needle biopsy permitting removal by a multidisciplinary surgical approach.

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization.

OBJECTIVE: The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmann's syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X-linked-KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X-linked-KS. DESIGN AND PATIENTS: We conducted a clinical study of 170 male and 45 female IHH patients attending the endocrinology departments of three London University teaching hospitals. Approximately 80% of data were obtained from case records and 20% collected prospectively. Parameters assessed included olfaction, testicular volume, family history of hypogonadism, anosmia or pubertal delay, and history or presence of testicular maldescent, neurological, renal or craniofacial anomalies. Where possible, the clinical information was correlated with published data on genetic analysis of the KAL locus. RESULTS: Olfactory acuity was bimodally distributed with no evidence for a spectrum of olfactory deficit. Testicular volume, a marker of integrated gonadotrophin secretion, did not differ significantly between anosmic and normosmic patients, at 2.0 ml and 2.2 ml, respectively. Nevertheless, the prevalence of cryptorchidism was nearly three times greater in anosmic (70.3%, of which 75.0% bilateral) than in normosmic (23.2%, of which 43.8% bilateral) patients. Individuals with nIHH, eugonadal isolated anosmia and/or KS were observed to coexist within 6/13 autosomal IHH pedigrees. On three occasions, fertility treatment given to an IHH patient had resulted in the condition being transmitted to the resulting offspring. Mirror movements and unilateral renal agenesis were observed in 24/98 and 9/87 IHH patients, respectively, all of whom were identifiable as X-KS males on the basis of pedigree analysis and/or defective KAL coding sequence. Abnormalities of eye movement and unilateral sensorineural deafness were observed in 10/21 and 6/111 KS patients, respectively, but not in nIHH patients. DISCUSSION: Patients with IHH are almost invariably either anosmic (KS) or normosmic (nIHH), rather than exhibiting intermediate degrees of olfactory deficit. Moreover, the prevalence of cryptorchidism is nearly three times greater in KS than in nIHH despite comparable testicular volumes, suggesting a primary defect of testicular descent in KS independent of gonadotrophin deficiency. Disorders of eye movement and hearing appear only to occur in association with KS. Taken together, these findings indicate a clear phenotypic separation between KS and nIHH. However, pedigree studies suggest that autosomal KS is an heterogeneous condition, with incomplete phenotypic penetrance within pedigrees, and that some cases of autosomal KS, nIHH and even isolated anosmia are likely to have a common genetic basis. The prevalences of anosmia, mirror movements and unilateral renal agenesis among X-KS men are estimated to be 100, 85 and 31%, respectively. In sporadic IHH, mirror movements and unilateral renal agenesis are 100% specific phenotypic markers of de novo X-KS. By comparison, only 7/10 X-KS families harboured KAL coding defects. Clinical ascertainment, using mirror movements, renal agenesis and ichthyosis as X-KS-specific phenotypic markers, suggested that de novo X-KS was unlikely to comprise more than 11% of sporadic cases. The majority of sporadic KS cases are therefore presumed to have an autosomal basis and, hence, the preponderance of affected KS males over females remains unexplained, though reduced penetrance in women would be a possibility.

Multiple pituitary hormone deficiency: management of puberty for optimal auxological results.

The overview in this paper focuses on ways of achieving optimal auxological results in puberty, principally in idiopathic and congenital multiple pituitary hormone deficiency (MPHD), suggested by the co-authors. We agreed that diagnosing gonadotrophin insufficiency/deficiency is difficult in young children and should be repeated in late prepuberty, but a firm diagnosis of MPHD helps avoid endocrine re-testing at the end of growth. The hypothalamic-pituitary axis must be reassessed periodically in evolving endocrinopathies, though current practice varies widely. Optimum age to induce puberty is 11-12 years in girls and 13-14 boys, and sex steroids are the preferred agents. Short-course testosterone to increase micropenis size is advantageous, but inducing early testicular maturation is not known to improve later fertility. There is also little evidence for increasing the dose of GH during puberty, though therapy should continue to final height, and possibly until peak bone mass is achieved. Delaying puberty is an option in septo-optic dysplasia, and minimising the dose of hydrocortisone is crucial in treating ACTH/cortisol insufficiency. Many unresolved questions remain in this difficult area.

Idiopathic short stature.

Idiopathic short stature (ISS) is a term used to describe the status of children with short stature that cannot be attributed to a specific cause. Many children diagnosed as having ISS have partial GH insensitivity, which can result from disturbances at various points of the GH-IGF-I axis. Several clinical studies on spontaneous growth in ISS showed that adult height was almost in the range of target height. GH treatment led to adult height not significantly higher than the pretreatment predicted adult height in most reports. No metabolic side effects have been observed, even when the dose was higher than in GH deficiency. Manipulation of puberty with gonadotrophin releasing hormone analogues reported by a few authors in a small number of children has shown conflicting results. Long-term psychological benefits of GH therapy for short normal children have not been demonstrated to date.

Morbidity and mortality associated with vasopressin replacement therapy in children.

OBJECTIVE: To assess the incidence and associated risk factors of adverse reactions of DDAVP treatment of children with diabetes insipidus, comparing different routes of administration. DESIGN: We retrospectively studied 103 children (44 females, 59 males) with cranial diabetes insipidus (mean age 6.9 years at diagnosis) treated with intramuscular (59), intranasal (84) and/or oral (64) DDAVP, over a mean follow-up period of 5.2 years. RESULTS: Eight patients died. For at least two children death was related to water intoxication. Major complications (symptomatic water overload with or without seizures) or asymptomatic hyponatraemia were observed in 33 patients. The incidence of total complications was significantly higher in cortisol deficient patients than in those with normal cortisol reserve (36% vs 6%). In patients on concomitant carbamazapine treatment major complications were more frequent in comparison to the remaining patients (33% vs 10%). Although not achieving significance, there were fewer complications using the oral route. CONCLUSIONS: Caution is needed in managing patients with DI, especially if risk factors such as cortisol deficiency or concomitant carbamazepine treatment are present. The oral route of administration seems to be preferred for both convenience and safety. Major changes in dose and formulation should be undertaken in hospital.