Multiple endocrine neoplasia syndromes 1 and 2: manifestations and management in childhood and adolescence.

The identification of the genetic causes of the multiple endocrine neoplasia (MEN) syndromes 1 and 2, and associated genotype-phenotype relationships, has revolutionised the clinical care of affected patients. A genetic diagnosis can be made during infancy and careful clinical surveillance, coupled with early intervention, has the potential to improve both morbidity and mortality. These developments have seen the management of patients with MEN move into the arena of paediatric medicine. In this review article, we consider the genetic causes of MEN together with the clinical manifestations and management of these syndromes.

A preliminary trial of the effect of recombinant human growth hormone on short-term linear growth and glucose homeostasis in children with Crohn's disease.

BACKGROUND: It is unclear whether recombinant human growth hormone (rhGH) improves linear growth in children with Crohn's disease (CD). AIMS: To investigate the effects of rhGH on height velocity (HV) and glucose homeostasis over a 6-month period. DESIGN AND SETTING: Randomized controlled trial in two tertiary children's hospitals in 22 children with inflammatory bowel disease amongst whom 21 had CD. Duration of disease from diagnosis and number of acute relapses requiring either exclusive enteral nutrition or therapeutic dose of oral prednisolone were similar in the treatment and control groups. INTERVENTION: Either rhGH (0·067 mg/kg per day) as daily subcutaneous injections (rhGH group; n, 11) or no rhGH, (Ctrl; n, 11) for 6 months. MAIN OUTCOME MEASURE: Percentage change in HV after 6 months in the two groups. Auxology, puberty, skeletal age, disease factors, treatment and glucose homeostasis were also assessed. RESULTS: Median HV increased from 4·5 (range, 0·6, 8·9) at baseline to 10·8 (6·1, 15·0) cm/year at 6 month (P = 0·003) in the rhGH group, whereas in the Ctrl group, it was 3·8 (1·4, 6·7) and 3·5 cm/year (2·0, 9·6), respectively (P = 0·58). Median percentage increase in HV after 6 months in the rhGH group was 140% (16·7, 916·7) compared with 17·4% (-42·1%, 97·7%) in the Ctrl group (P < 0·001). There were no significant differences in disease activity and proinflammatory cytokines at baseline and 6 months in both groups and change in bone age for chronological age was also similar in the two groups. In the rhGH group, fasting insulin increased from 4·0 (2·0, 11·0) to 7·0 mU/l (2·0, 16·0) (P = 0·02), whereas in the Ctrl group, it was 3·0 (1·2, 12·7) and 3·8 mU/l (2·1, 7·0) (P = 0·72), respectively. CONCLUSIONS: Although this pilot trial shows that rhGH can improve short-term linear growth in children with CD, the clinical efficacy of this therapy needs to be further studied in longer-term studies of growth, glucose homeostasis and disease status.

Growth monitoring still has a place in selected populations of children.

In 1998, a multiprofessional group developed a consensus on growth monitoring in the UK. While routine serial measurements were not recommended in healthy children, it is clear that there is a subset of children at increased risk of growth-modifying disease who may benefit from growth monitoring. This subset includes children with genetic disorders at increased risk of thyroid dysfunction. Symptoms and signs of thyroid dysfunction are non-specific in the early stages of disease and are easily mistaken for features of an underlying genetic disorder. In this article, we report the case of a 2.8-year-old girl with 18q deletion syndrome who was profoundly weak, hypotonic and poorly responsive at diagnosis of Grave's disease. She was tall and her bone age was 2 years advanced, indicating long-standing disease. Growth monitoring of this patient should have enabled earlier diagnosis and avoided a serious and potentially fatal episode.

The d3/fl-GH receptor gene polymorphism does not influence quality of life and body composition in GH-deficient adults receiving GH replacement therapy.

CONTEXT: The growth response to recombinant human growth hormone (rhGH) in GH deficient (GHD) patients may be influenced by polymorphisms in the growth hormone receptor (GHR) gene. OBJECTIVES: To investigate adults with GHD who have been treated with rhGH for more than 1 year to determine the relationship between genomic deletion of exon 3 in the GHR gene and quality of life (QoL), body composition (BC) and serum IGF1 levels, and to compare these variables to a healthy adult control population. DESIGN: Cross-sectional study. METHODS: A total of 100 healthy adult controls and 131 patients were studied. Deletion of exon 3 in the GHR gene was determined in DNA that was isolated from peripheral blood. QoL was determined using the adult GHD assessment scale and three other validated QoL instruments. RESULTS: In the control population, the frequency of the genotypes was 53% fl/fl, 40% d3/fl and 7% d3/d3, and in the patient population, 55, 39 and 6% respectively. There was no significant difference in QoL scores and BC in control subjects with the fl/fl genotype compared with those with the d3/d3 or fl/d3 genotype. There was no difference in the rhGH dose required to optimize serum IGF1, QoL or BC in patients with the fl/fl genotype compared with those with the d3/d3 or d3/fl genotype. CONCLUSION: Deletion of exon 3 in the GHR gene does not influence adult height, QoL or BC of the normal adult population nor does it influence rhGH dose, QoL and BC in GHD adults treated with rhGH for more than 1 year.

Relief of severe retro-orbital pain and vision improvement after optic-nerve decompression in polyostotic fibrous dysplasia: case report and review of the literature.

INTRODUCTION: We describe a case of a 9-year-old girl who developed progressive severe retro-orbital pain and partial visual loss in association with left optic-nerve compression due to polyostotic fibrous dysplasia of the skull. MATERIALS AND METHODS: Intradural decompression of the optic nerve resulted in immediate and complete resolution of the pain as well as a vast visual improvement. CONCLUSION: In cases of fibrous dysplasia of the skull with evidence of optic-nerve compression, relief of retro-orbital pain should be an additional consideration when deciding to proceed with surgical management.

Clinical and endocrine features and long-term outcome of Graves' disease in early childhood.

Hyperthyroidism is rare in early childhood and most commonly caused by Graves' disease. We report 14 children (4 boys, 10 girls) aged 3.4-7.5 yr. At diagnosis, all patients had weight loss, hyperkinetic activity, tachycardia, difficulty sleeping, and poor concentration and 11 presented with proptosis. Four patients developed long-term neuropsychological problems. There was a family history in 7 cases. All patients had goiters, clinically assessed to be large and diffuse in 21%, medium-sized in 43%, and small in 36%. At diagnosis, height was increased with median (range) height; 1.25 standard deviation score (SDS) (-0.2-5.24) and body mass index (BMI) was decreased; -0.48 SDS (-1.65-1.26). Height and BMI SDS values were statistically different (p<0.032) Bone age was advanced in 4 of 5 children, who had assessments. Total or free T4 levels were elevated and TSH was undetectable. Ninety percent of patients (12/14) had positive thyroid peroxidase autoantibodies, mean level 680 IU/ml (range 50-1347). Initial treatment was with antithyroid medication using carbimazole; median dose 0.75 mg/kg/day (no.=13) or propylthiouracyl 15 mg/kg/day (no.=1). T4 was added in 6 patients. Normalisation of serum T4 occurred at 4 months (1- 9) and TSH at 7 months (3-24) after start of therapy. Treatment was discontinued after a minimum of 2 yr in 11 patients, relapse occurring in 9. Median duration of total therapy was 58 months (18-132). During adolescence, 4 patients had curative therapy by surgery (no.=2) or radioiodine (no.=2). In conclusion, disturbance of growth, behavioral difficulties and infrequent spontaneous remission are key features of Graves' disease in early childhood.

IGFs and IGFBPs in GH insensitivity.

IGF-I, IGFBP-3 and ALS are GH-dependent peptides and their production is disturbed in states of GH insensitivity. This chapter explores the relative degrees of IGF-I, IGFBP-3 and ALS deficiency across the spectrum of GH insensitivity. In classical GH insensitivity syndrome (GHIS), known as Laron syndrome, due to GH receptor (GHR) deficiency, serum IGF-I, IGFBP-3 and ALS are severely reduced with inability to produce these peptides during an IGF-I generation test. Across the spectrum of severity of GHR defects, some patients have short stature and normal facial appearance, so-called partial or non-classical GH insensitivity. In these cases the IGF-I, IGFBP-3 deficiency is less severe. A positive relationship exists between height SDS and IGFBP-3 SDS (r2 = 0.45, p < 0.001) in patients from the European series with GHIS. In a new series of GHIS cases (n = 36) there was a significant difference in IGFBP-3 and ALS (p < 0.05) between classical (n = 25) and non-classical cases (n = 11). IGF-I, IGFBP-3 and ALS were significantly higher (p < 0.05) in pubertal compared with pre-pubertal subjects in the same series. In idiopathic short stature (ISS), heterozygous mutations of the GHR may have a dominant negative effect. ISS patients have lower IGF-I levels than the normal population. In 21 cases, mean IGF-I SDS was -1.39 (-2.4 to -1.16) and IGFBP-3; -0.45 (-1.13 to 0.38). However, IGF-I and IGFBP-3 responses in the IGF-I generation test were generally normal. In acquired GHI due to chronic illness such as Crohn's disease, juvenile arthritis and cystic fibrosis, IGF-I deficiency is present, although IGFBP-3 is usually normal. In summary, assessment of IGF-I, IGFBP-3 and ALS contributes to diagnosis in GH insensitivity states. In our experience, IGF-I is more sensitive to disturbance of GH action that IGFBP-3, however in severe GHIS cases, IGF-I is usually undetectable and measurement of IGFBP-3 is valuable as a guide to the severity of the biological defect.

Standard and low-dose IGF-I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature.

OBJECTIVE: Abnormalities in the GH-IGF-I axis, consistent with GH insensitivity (GHI), have been reported in some patients with idiopathic short stature (ISS). The standard IGF-I generation test (IGFGT) has not demonstrated mild GHI in subjects with ISS. The aim of this study was to investigate the GH-IGF-I axis in ISS by performing standard and novel low-dose IGFGTs together with determination of spontaneous GH secretion. PATIENTS AND METHODS: Twenty-one (17 male) prepubertal children with ISS, mean age 8.3 years (4.5-12.2), mean height -3.48 SD (-5.40 to -1.79), mean peak GH to provocation with glucagon/clonidine 32.3 mU/l (14.1-66.0) were studied. Serum IGF-I and IGFBP-3 levels were measured during standard (GH 0.033 mg/kg/day x 4) and low (GH 0.011 mg/kg/day x 4) dose IGFGTs at 0, 12, 36 and 84 h. The low-dose IGFGT was performed in seven naive GH-deficient patients (4 male), mean age 8.5 years (range 4.1-11.1). Determination of spontaneous 24-h GH secretion was performed in the 21 ISS patients. RESULTS: Basal IGF-I and IGFBP-3 standard deviation scores (SDS) in ISS patients were -1.39 (-2.4-1.16) and -0.45 (-1.13-0.38), respectively, IGF-I being lower than IGFBP-3 (P < 0.0001). IGF-I increased in the standard IGFGT at 12 h (P < 0.005), 36 h (P < 0.001) and 84 h (P < 0.001); maximal increment 1.54 (-0.32-3.48), and in the low-dose test at 12 h (P < 0.005), 36 h (P < 0.001) and 84 h (P < 0.005); maximal increment 0.53 (0.08 to -1.23). IGFBP-3 SDS increased in the standard IGFGT at 36 h (P < 0.01) and 84 h (P < 0.001); maximal increment 0.72 (-0.44-1.96), and in the low-dose test at 84 h (P < 0.005); maximal increment 0.33 (-0.08-0.87). Five/19 patients with an IGF-I response > 2 x coefficient of variation (CV) of assay in the standard test failed to respond in the low-dose test, suggestive of mild GHI. In GH-deficient patients, IGF-I increased at each time point (P < 0.05) and IGFBP-3 at 36 h (P < 0.05). Mean GH secretion, expressed in SDS, compared with 66 normal stature controls was: basal GH -0.48 (-0.84-0.93), height of GH peaks compared with zero -0.36 (-1.26-1.51) (both P < 0.05), total GH secretion -0.76 (-1.22-0.42), total GH secretion above baseline -0.67 (-1.21-0.94) (both P < 0.01). CONCLUSIONS: In children with ISS, basal IGF-I and IGFBP-3 SDS values were below the mean, IGF-I showing a greater response in both IGFGTs. In the standard IGFGT, the IGF-I increase at 36 h was equal to that at 84 h. The low-dose IGFGT, in combination with the standard test, may identify patients with mild GHI.

Neonatal thyrotoxicosis and maternal infertility in thyroid hormone resistance due to a mutation in the TRbeta gene (M313T).

We report two unusual cases of resistance to thyroid hormone (RTH) in one family. The first case, a male infant, had clinical features of thyrotoxicosis in the neonatal period. In the fourth week of life weight gain was poor despite a daily intake of standard infant formula almost double the infant's estimated requirements. At this time serum free T4 (fT4) was 60.7 pmol/l (Normal range [NR] 11-25 pmol/l) and TSH was inappropriately normal at 1.8 mU/l (NR 0.3-4.0 mU/l). The infant responded clinically and biochemically to propylthiouracil (PTU) at a dose of 10 mg/kg/day. Following 27 days of treatment serum fT4 was 22.6 pmol/l and TSH had risen to 24.9 mU/l. As the infant was thriving treatment was discontinued. The infant, now aged 6 months old, remains clinically euthyroid and developmentally normal off treatment. The infant's mother, from whom he had inherited a mutation of the thyroid receptor beta (TRbeta) gene (M313T), presented earlier with secondary infertility and clinical features of thyrotoxicosis. Treatment with PTU restored her fertility and she spontaneously conceived. In the subsequent pregnancy, clinical and biochemical features of RTH improved, and she gave birth to a small but healthy female infant. In the next pregnancy, resulting in the birth of the affected male infant, clinical and biochemical features of RTH worsened, and high doses of PTU were required to maintain a clinically euthyroid state. To our knowledge, these are the first case reports of RTH associated with added features of a hypermetabolic state in infancy and secondary infertility.

Growth hormone insensitivity: pathophysiology, diagnosis, clinical variation and future perspectives.

The study of genetic growth hormone (GH) insensitivity is an evolving field. GH insensitivity syndrome (GHIS), otherwise known as Laron syndrome, is a heterogeneous disorder. Biochemical features consist of severe insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) deficiency and elevated GH secretion. In a heterogeneous 'European' cohort of GHIS patients, features varied from classical to moderate abnormalities of phenotype and endocrine disturbance. A study of facial features within this series showed that a mild subgroup existed with normal facies, mild short stature and moderate biochemical abnormalities. Overlap with idiopathic short stature (ISS) exists, with heterozygous mutations of the GH receptor demonstrated to cause impaired growth. This 'partial' GHIS has not yet been defined endocrinologically. GH sensitivity, measured by IGF-I and IGFBP-3 responses in the IGF-I generation test, may reveal abnormalities in ISS, although it is likely that the dose of recombinant human GH and frequency of sampling in the test need to be modified.

Growth abnormalities associated with adrenal disorders and their management.

Linear growth can be disturbed in paediatric adrenal disease associated with endocrine hypo- or hyperfunction. Tall stature is a feature in some patients with adrenocorticotropic hormone resistance syndromes and short stature is recognized in the IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) association. In autoimmune Addison's disease, growth is usually normal. In congenital adrenal hyperplasia, height may be compromised by advanced skeletal maturation or by suppressed growth, particularly in the neonatal period due to excess glucocorticoid treatment. In virilizing adrenal tumours, height is increased at diagnosis, but after surgical cure final height is usually in the normal range. In Cushing's disease, height was abnormally short in 50% of patients at presentation. After successful treatment, spontaneous catch-up growth was not seen. This led to a diagnosis of growth hormone (GH) deficiency in 80% of patients. With GH replacement, catch-up growth and long-term benefit occurred. Disturbance of linear growth is an important feature of many patients with adrenal disorders in childhood. Assessment of its pathogenesis and careful management are necessary to ensure optimal final adult height.

Autonomy of audiologists in educational settings.

Professional autonomy continues to be an issue of major concern for practicing audiologists. Members of the Educational Audiology Association completed a written survey covering the amount of independence and authority they experience when employed in an educational setting. Four areas were explored: scope of practice; referral procedures; assessment and management activities; and employment conditions. Responses indicated that educational audiologists have a great deal of autonomy in matters relating to the scope of their practice and the implementation of daily activities. Autonomy in the area of employment conditions was much less widespread. This report provides a detailed description of the survey responses, conclusions, and implications for future training needs for audiologists who may be employed in an educational setting.

Screening procedures used to identify children with hearing loss.

This study focused on the hearing-screening procedures used to identify children who have hearing losses who were later enrolled in SKI*HI parent/infant programs throughout the country. Responses to a questionnaire for 1,404 children indicated that although auditory brainstem response (ABR) technology provided the lowest mean identification age, informal hearing-screening procedures (parental suspicion and referral) were the procedure of identification for 80% of the children. The data suggest that formal screening programs are not presently locating the vast majority of infants who have hearing losses. Recommendations for professional and parental education in the area of hearing-loss screening are provided.

Modified assay for true and apparent metabolisable energy based on tube feeding.

1. To improve the accuracy with which true metabolisable energy (TME) values of feedingstuffs are determined, a modification to the assay based on tube-feeding is proposed. 2. To ensure that the gastrointestinal tracts of the experimental birds are as empty as possible at the start of the assay it is recommended that the normal food is withdrawn 48 h before tube-feeding. 3. In order to partly alleviate the effects of starvation, all birds are given two doses of 25 g glucose (as an aqueous solution) about 40 and 16 h before tube-feeding. Birds, from which endogenous energy losses are to be derived, are fed 50 g glucose rather than given no food. 4. All birds are given 50 ml water by tube about 32 h after feeding to overcome any effects induced by low water intake. 5. A comparison of the two procedures with 8 feedingstuffs showed that the mean coefficient of variation was reduced from 5.5% to 1.5% for TME and from 4.7% to 1.8% for TME.