C. G. D. Brook

THE RELATIONSHIP BETWEEN HEIGHT VELOCITY AND GROWTH HORMONE SECRETION IN SHORT PREPUBERTAL CHILDREN

We have performed 24 h growth hormone (GH) profiles in 50 short prepubertal children aged between 5.2 and 12‐9 years, growing with height velocity standard deviation scores (SDS) between 0.4 and ‐3.9. There was an asymptotic relationship between height velocity and spontaneous G H secretion described by the equation: height velocity SDS = A – B(e cx), where A B and C are constants and x is a measure of spontaneous G H secretion. We considered G H pulse amplitude to be the better description of spontaneous G H secretion as duration of the G H pulse (the time component of area under the curve) contributed little to the relationship between height velocity and area under the pulse. The distribution of G H secretion was continuous and there was no dividing point between G H insufficiency and sufficiency. Similar overlap was observed when the results of G H responses to insulin induced hypoglycaemia were considered; 14% of slowly growing children (height velocity S D S < –0‐8), had a response >15mU/l. Likewise serum I G F‐I concentrations could not clearly separate slowly growing children from normal individuals. We conclude that height velocity, which ultimately determines height achieved, is controlled predominately by G H pulse amplitude. The findings suggest that short normal children growing along or parallel to the third height centile could be made to grow faster by the administration of exogenous G H.

Sexual precocity: sex incidence and aetiology.

The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.

Blood pressure and Turner syndrome

Elevated blood pressure (BP) is an important predictor of morbidity and mortality from cardiovascular disease. Patients with Turner syndrome (TS) have a higher morbidity and mortality in middle age than the normal population. As BP in childhood or early adulthood is predictive of BP later in adult life, we assessed manual and 24u2003h ambulatory BP in patients with TS to determine whether the BP pattern is altered at an early stage in these patients who are known to be at risk of cardiovascular disease.

Tests of adrenal insufficiency

AIM In suspected adrenal insufficiency, the ideal test for assessing the hypothalamo–pituitary–adrenal axis is controversial. Therefore, three tests were compared in patients presenting with symptoms suggestive of adrenal insufficiency. METHOD Responses to the standard short Synacthen test (SSST), the low dose Synacthen test (LDST), and the 08:00 hour serum cortisol concentration were measured in 32 patients. A normal response to the synacthen test was defined as a peak serum cortisol of ⩾u2009500u2009nmol/l and/or incremental concentration of ⩾u2009200u2009nmol/l. The sensitivity and specificity of the 08:00 hour serum cortisol concentration compared with other tests was calculated. RESULTS Three patients had neither an adequate peak nor increment after the SSST and LDST. All had a serum 08:00 hour cortisol concentration of <u2009200u2009nmol/l. Eight patients had abnormal responses by both criteria to the LDST but had normal responses to the SSST. Three reported amelioration of their symptoms on hydrocortisone replacement. Twenty one patients had a normal response to both tests (of these, 14 achieved adequate peak and increment after both tests and seven did not have an adequate peak after the LDST but had a normal increment). The lowest 08:00 hour serum cortisol concentration above which patients achieved normal responses to both the LDST and SSST was 500u2009nmol/l. At this cut off value (compared with the LDST), the serum 08:00 hour cortisol concentration had a sensitivity of 100% but specificity was only 33%. CONCLUSION The LDST revealed mild degrees of adrenal insufficiency not detected by the SSST. The value of a single 08:00 hour serum cortisol concentration is limited.

Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency.

BACKGROUND Growth hormone insufficiency (GHI) is diagnosed conventionally by short stature and slow growth, and is confirmed by diminished peak GH response to a provocation test. Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) have previously been considered individually OBJECTIVE To test the hypothesis that the combined analysis of IGF-I and IGFBP-3 could act as a surrogate marker for the diagnosis of GHI. DESIGN Reference ranges for IGF-I and IGFBP-3 were calculated using 521 normal individuals. A retrospective analysis was performed on 318 children referred for investigation of short stature. RESULTS No significant difference was found between either the IGF-I or IGFBP-3 standard deviation scores (SDSs) in children with and without GHI. If the requirement were for both tests to be positive (<u2009−2u2009SDS) for a diagnosis of GHI, then 99% of children without GHI would be correctly identified; however, the sensitivity of the test was only 15%. CONCLUSIONS Neither IGF-I nor IGFBP-3 alone is a marker for GHI. In addition, they cannot be used as an effective screening test in combination.

The influence of renal and cardiovascular abnormalities on blood pressure in Turner syndrome

Patients with Turner syndrome (TS) are at an increased risk of morbidity and mortality from cardiovascular disease. This study was undertaken to establish the prevalence of hypertension in patients with TS and to establish to what extent cardiovascular or renal abnormalities contribute to the measured blood pressure.

Growth hormone secretion in children determined by time series analysis.

Mid childhood growth has been studied in 26 short children (18M;8F) aged between 5·2 and 11·9 years growing with height velocity standard deviation score (SDS) between 0 and — 0·8 and 24 short children (17M;7F) growing with height velocity SDS >0·8. Twenty‐four hour GH profiles were analysed by an iterative method of pulse detection and subjected to time series analysis to determine dominant periodicity within the data arrays. Children aged >7 years displayed no dominant periodicity but after this age a periodicity of 200 min emerged. In the whole sample, differences between growth rate could be explained entirely by pulse amplitude. Nevertheless, the normal decline in height velocity over this age period occurred despite a significant shift in periodicity and an increase in GH pulse amplitude. This modulation of childhood growth by GH pulse amplitude perisisted into puberty and the pubertal growth spurt of 14 tall girls was shown to be amplitude modulated with the periodicity unchanged. We conclude that mid childhood and pubertal growth is GH pulse amplitude modulated with a periodicity of approximately 200 min.

THE HALF-LIFE OF EXOGENOUS GROWTH HORMONE AFTER SUPPRESSION OF ENDOGENOUS GROWTH HORMONE SECRETION WITH SOMATOSTATIN

We have estimated the half‐life of serum growth hormone (GH) in six subjects on 14 occasions following an intravenous bolus injection of either 50 or 500 mU of biosynthetic human growth hormone (B‐hGH) while endogenous GH secretion was suppressed by a continuous infusion of somatostatin. The disappearance curve of serum GH was mono‐exponential and the mean half‐life was 8.9 min (SD 1.5). This is less than previously reported and has important implications for the performance of GH profiles, which should be performed with 10–15 min sampling intervals, and the calculation of pituitary GH secretion rates.

Hypoplastic optic nerves and pituitary dysfunction. A spectrum of anatomical and endocrine abnormalities.

Fourteen children with optic nerve hypoplasia associated with either mid-brain abnormalities or pituitary dysfunction, or both, are described. All patients were either partially sighted or blind. One case is reported in detail. The importance of hypoglycaemia in the neonatal period and later in childhood is emphasised in relation to diagnosis and developmental delay. Pituitary dysfunction is variable and may be progressive. Forty percent of the patients had a septum pellucidum and its presence or absence cannot be used as a radiological marker for the condition. Long term endocrine follow up of these patients is required.

Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy?

Dysfunction of the Wilms’Tumour gene (WT1), a transcription factor critical for normal development and function of the urogenital tract, can result in both tumorigenesis and urogenital abnormalities. The association of WT1 gene mutations with most cases of Denys‐Drash syndrome is well described. More recently WT1 mutations have also been described In a related condition, Frasier syndrome. We report a case where genetic analysis showed a WT1 mutation typically associated with Frasier syndrome: a 1228 + 5 guanine to adenine substitution at the 3’alternative splice donor site in intron 9. The case provides a focus for the discussion of recent evidence that Denys Drash and Frasier syndrome form two ends of a spectrum of disorders. In addition, it illustrates the increasing significance of genetic investigation within clinical practice for diagnostic, prognostic and therapeutic purposes and the importance of karyotype analysis in phenotypically normal girls with renal disease.