Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake.

Cytosolic PEPCK deficiency (PCKDC) is a rare autosomal recessive inborn error of metabolism, which can present with hypoglycemia, lactic acidosis, and liver failure. It is caused by biallelic pathogenic variants in the PCK1 gene. Only four PCK1 variants have been previously reported in seven patients with PCKDC, and their clinical course of this condition has not been well characterized. Here, we report a Hispanic male with novel biallelic PCK1 variants, p.(Gly430Asp) and p.(His496Gln), who had a unique clinical presentation. He presented with a new onset of growth failure, elevated blood lactate, transaminitis, and abnormal urine metabolites profile, but he has not had documented hypoglycemia. Growth restriction happened due to insufficient caloric intake, and it was improved with nutritional intervention. PCKDC is a manageable disorder and therefore appropriate nutritional and clinical suspicion from typical lab abnormalities which lead to molecular confirmation tests are essential to prevent poor clinical outcomes.

Iodine status and associations with feeding practices and psychomotor milestone development in six-month-old South African infants.

Iodine is important for normal growth and psychomotor development. While infants below 6 months of age receive iodine from breast milk or fortified infant formula, the introduction of complementary foods poses a serious risk for deteriorating iodine status. This cross-sectional analysis assessed the iodine status of six-month-old South African infants and explored its associations with feeding practices and psychomotor milestone development. Iodine concentrations were measured in infant (n = 386) and maternal (n = 371) urine (urinary iodine concentration [UIC]), and in breast milk (n = 257 [breast milk iodine concentrations]). Feeding practices and psychomotor milestone development were assessed in all infants. The median (25th-75th percentile) UIC in infants was 345 (213-596) µg/L and was significantly lower in stunted (302 [195-504] µg/L) than non-stunted (366 [225-641] µg/L) infants. Only 6.7% of infants were deficient. Maternal UIC (128 [81-216] µg/L; rs  = 0.218, p < 0.001) and breast milk iodine concentrations (170 [110-270] µg/kg; rs  = 0.447, p < 0.0001) were associated with infant UIC. Most infants (72%) were breastfed and tended to have higher UIC than non-breastfed infants (p = 0.074). Almost all infants (95%) consumed semi-solid or solid foods, with commercial infant cereals (60%) and jarred infant foods (20%) being the most common solid foods first introduced. Infants who reported to consume commercial infant cereals ≥4 days weekly had significantly higher UIC (372 [225-637] µg/L) than those reported to consume commercial infant cereals seldom or never (308 [200-517] µg/L; p = 0.023). No associations between infant UIC and psychomotor developmental scores were observed. Our results suggest that iodine intake in the studied six-month-old infants was adequate. Iodine in breast milk and commercial infant cereals potentially contributed to this adequate intake.

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study.

This work assesses the urinary metabolite signature of prematurity in newborns by nuclear magnetic resonance (NMR) spectroscopy, while establishing the role of possible confounders and signature specificity, through comparison to other disorders. Gender and delivery mode are shown to impact importantly on newborn urine composition, their analysis pointing out at specific metabolite variations requiring consideration in unmatched subject groups. Premature newborns are, however, characterized by a stronger signature of varying metabolites, suggestive of disturbances in nucleotide metabolism, lung surfactants biosynthesis and renal function, along with enhancement of tricarboxylic acid (TCA) cycle activity, fatty acids oxidation, and oxidative stress. Comparison with other abnormal conditions (respiratory depression episode, large for gestational age, malformations, jaundice and premature rupture of membranes) reveals that such signature seems to be largely specific of preterm newborns, showing that NMR metabolomics can retrieve particular disorder effects, as well as general stress effects. These results provide valuable novel information on the metabolic impact of prematurity, contributing to the better understanding of its effects on the newborn's state of health.

[Significance of the urine strip test in case of stunted growth]. / Intérêt de l'examen des urines à la bandelette en cas de retard de croissance.

Observation of stunted growth in children usually leads the general practitioner to refer the patient to endocrinologists or gastroenterologists. In most cases, after a complementary check-up, the diagnosis is made and treatment is initiated. However, certain cases remain undiagnosed, particularly renal etiologies, such as proximal tubulopathy. The urine strip test at the initial check-up would be an easy and inexpensive test to avoid delayed diagnosis. The aim of the present paper is to increase general physicians' and pediatricians' awareness of the significance of questioning the parents and using the urine strip test for any child presenting stunted growth. We report a patient case of a 20-month-old child admitted to the emergency department for severe dehydration. He had displayed stunted growth since the age of 5 months and showed a negative etiologic check-up at 9 months of age. Clinical examination at admission confirmed stunted growth with loss of 2 standard deviations and signs of dehydration with persistent diuresis. Skin paleness, ash-blond hair, and signs of rickets were also observed and the urine strip test showed positive pads for glycosuria and proteinuria. Polyuria and polydipsia were also revealed following parents' questioning, suggesting proximal tubulopathy (Fanconi syndrome). Association of stunted growth, rickets, polyuria and polydipsia, glycosuria (without ketonuria and normal glycemia), and proteinuria suggest nephropathic cystinosis. Ophthalmic examination showed cystine deposits in the cornea. The semiotic diagnosis of nephropathic cystinosis was confirmed by leukocyte cystine concentrations and genetic investigations. This case report clearly illustrates the significance of the urine strip test to easily and quickly concentrate the diagnosis of stunted growth on a renal etiology (glycosuria, proteinuria), especially on proximal tubulopathy for which the most frequent cause is nephropathic cystinosis. Specificity of nephropathic cystinosis treatment is that the age of treatment initiation is crucial and determinant for the prognosis of the disease and the onset of final stage renal failure. Therefore, the urine strip test should be included in the systematic check-up of stunted growth to identify any renal etiology.

Decreased 6-Sulfatoxymelatonin Excretion in Male GH-Deficient Children and Adolescents.

AIM: To evaluate melatonin secretion in a group of untreated and treated male growth hormone (GH)-deficient children and adolescents. METHODS: We studied 44 male subjects: 8 untreated GH-deficient patients (GHDnt), 16 treated GH-deficient patients (GHDt) and 20 healthy children and adolescents as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24-hour samples), nocturnal (18.00-8.00 h) and diurnal samples (8.00-18.00 h). Levels of 6-SM were expressed as micrograms excreted per time interval and x0394; values (difference between nighttime and daytime values). RESULTS: Significant differences were observed among the 3 groups of pediatric subjects studied for total 6-SM (p < 0.0001), nocturnal 6-SM (p < 0.0001) and x0394; values (p < 0.0001). Subsequent analysis showed significantly higher levels for total 6-SM, nocturnal 6-SM and nighttime-daytime x0394; in the CG versus the GHDnt (p < 0.01) and in the CG versus the GHDt group (p < 0.01). No significant correlations were found between 6-SM excretion and insulin-like growth factor-1 values in the children and adolescents studied. CONCLUSIONS: GH-deficient patients showed lower levels of 6-SM. Our findings provide a different insight to a further understanding of some chronobiological disorders involved in GH deficiency in children.

Concentration of Selected Metals in Whole Blood, Plasma, and Urine in Short Stature and Healthy Children.

The short stature in children is defined as height below the third percentile from the mean for age and gender. This problem affects about 3% of young people. More than 20,000 children in Poland have problems with short stature. There is not much information available in the literature on the study of metals in blood, plasma, and urine in children with short stature. The study was conducted on a group of 56 short stature Polish children and 35 healthy children. The content of metals was determined using high-performance ion chromatography and inductively coupled plasma mass spectrometry methods. The study revealed significant differences between the content of selected metals in body fluids between a short stature group and healthy children. There were significant differences in the Fe, Cu, and Ni concentrations between the groups with respect to the hormonal therapy. There were no significant differences between the groups with respect to the area where the children lived. The results showed no statistically significant differences between metal concentration and age, body weight, and height. The study demonstrated statistically significant differences between the content of metals in body fluids in short stature children compared with the healthy children. It seems that the difference in the concentration of certain elements may also be the result of growth hormone therapy and the interaction between various metals. Both the alterations in the content of metals and their mutual interactions may play an important role in the pathogenesis of short stature children.

Abnormal gut integrity is associated with reduced linear growth in rural Malawian children.

The aim of the present study was to investigate the relation of environmental enteropathy, as measured by the dual sugar absorption test, to linear growth faltering in 2- to 5-year-old Malawian children. Dietary quality, food insecurity, anthropometry, and site-specific sugar testing were measured in 418 children, and anthropometry was reassessed 3 months later. A linear regression model predicting linear growth was created. Better growth was associated with less urinary lactulose excretion, more clean water usage, not sleeping with animals, and no previous history of malnutrition. Eighty-seven percent of children studied demonstrated evidence of environmental enteropathy. In conclusion, abnormal gut integrity is associated with reduced linear growth in a population of rural African preschool-age children.

Bone mineral density and urinary N-acetyl-beta-D-glucosaminidase activity in paediatric patients with idiopathic hypercalciuria.

BACKGROUND: Idiopathic hypercalciuria (IH) is defined as hypercalciuria that persists after correction of dietary inbalances and has no detectable causes. Patients with IH have a higher prevalence of osteoporosis. Defective reabsorption of calcium by the renal tubule is considered a likely mechanism of IH. N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme that is a very sensitive marker of renal tubular impairment. METHODS: Fifteen patients (nine boys and six girls, mean age 12.4 +/- 4.0 years) with IH (urinary calcium excretion >0.1 mmol/kg per 24 h) had their bodyweight, height, body mass index (BMI), urinary NAG/creatinine ratio (U-NAG/Cr) and 24-h urinary calcium excretion (U-Ca/24 h) assessed. L1-L4 bone mineral density (BMD) was measured by dual energy X-ray absorptiometry and volumetric BMD (BMDvol) was calculated. The obtained results were expressed as Z-scores. RESULTS: The values of basic anthropometric parameters did not differ significantly from the values of the reference population and there was a tendency to short stature, which did not reach statistical significance (P = 0.08). The values of calciuria and U-NAG/Cr were significantly higher while BMD was significantly lower when compared to the reference values (P < 0.0006, P < 0.006 and P < 0.001, respectively). Inverse and significant correlations were found between U-Ca/24 h and BMD, U-Ca/24 h and body height, and U-Ca/24 h and BMDvol (r = -0.64 and -0.70, respectively, P < 0.01; r = -0.55, P < 0.05), while there was no correlation between U-NAG/Cr and U-Ca/24 h, nor between BMD and weight or BMD and BMI. CONCLUSION: Tubular impairment is highly probable in children with IH, but there is a poor relationship with the degree of calcium leakage. Idiopathic hypercalciuria should be considered as a risk factor for stunted growth and low bone mass.

Beta-thalassemia major and its effect on amino acid metabolism and growth in patients in the United Arab Emirates.

BACKGROUND: There may be a marked reduction in essential amino acids in the serum of children with thalassemia major and this is related to decreased growth in affected children. METHODS: One hundred patients with beta-thalassemia and 50 control children selected from among those who had presented with minor disorders unrelated to hematological disease were recruited. Urine and heparinized blood were collected from fasting thalassemic patients. After deproteinization and dilution, amino acid concentrations were measured using ion-exchange chromatography. RESULTS: Isoleucine (p<0.0001), phenylalanine (p<0.05), tyrosine (p<0.0001), taurine (p<0.0001) and glutamine (p<0.01) were significantly decreased in the plasma of thalassemic patients compared to the control group. Whereas glutamate (p<0.0001), serine (p<0.05) and proline (p<0.05) were significantly higher in thalassemic patients, threonine, glycine, alanine, valine, methionine, leucine, ornithine, lysine, histidine and arginine values were not different. The essential amino acids taurine (p<0.0001), methionine (p<0.01), valine (p<0.01), phenylalanine (p<0.01) and leucine (p<0.05) were significantly decreased in urine of thalassemic patients vs. controls, but threonine and ornithine were not different. The mean urinary excretion rate of beta-aminoisobutyric acid was not different (69+/-96 in thalassemics vs. 41+/-52 in controls). However, most plasma and urinary essential amino acids were found to be lower in thalassemics. Thalassemic patients were also found to be significantly growth impaired for age, both in height and weight compared to controls. CONCLUSION: Lower plasma values of essential amino acids and a decrease in urinary amino acids occur in thalassemic patients. Growth impairment both in height and weight also occurs in thalassemic patients compared to a control population.

Urinary excretion of pyridinium crosslinks in short children treated with growth hormone.

The aim of this study was to evaluate the effect of growth hormone (GH) treatment on bone resorption in children with GH deficiency and those with idiopathic short stature. The study population included seven children with subnormal spontaneous GH secretion and 13 children with idiopathic short stature, all of them pre-pubertal. Anthropometric measurements, free, protein-bound and total urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd), serum GH, and serum immunoreactive PTH were measured at baseline and months 1, 3, 6 and 12 of GH treatment. The urinary excretion of total Pyd and Dpd, standardized by the cube of height (m3) in overnight, 24-hour urine collections was not different from age-matched healthy controls at baseline in either group of patients. During treatment with human recombinant GH, both pyridinium crosslinks increased above normal values, reaching a peak after one month in children with GH deficiency and later (after 3-6 months) in children with short stature. Free and total crosslink forms were correlated, and GH treatment did not affect the proportion of free to bound crosslinks. Serum concentrations of iPTH showed a moderate but not statistically significant increase. This study provides no evidence of reduced bone resorption in untreated GH deficiency or in idiopathic short stature. GH treatment induced a marked, but temporary, increase of bone resorption in both groups of patients.

Dietary cyanide from insufficiently processed cassava and growth retardation in children in the Democratic Republic of Congo (formerly Zaire).

Dietary cyanide exposure from cyanogenic glucosides in insufficiently processed cassava has been advanced as a contributing factor in child growth retardation. Whether cyanide exposure aggravates children's growth retardation was studied by comparing two populations of children from the northern and the southern zones of the Bandundu region, Democratic Republic of Congo (former Zaire), using dietary interviews, anthropometry and urine analyses. Both populations consumed cassava as their staple diet, but whereas in the north the cassava was well processed, in the south it was inadequately processed. The mean urinary thiocyanate was much higher in the south, whereas mean urinary sulphate excretion was equally low in the two areas. However, the mean urinary SCN/SO4 molar ratio was higher in the south (0.20), indicating that 10-20% of sulphur amino-acids were used for cyanide detoxication. No significant differences were found between the two populations in weight-for-height and weight-for-age indices but the height-for-age index was significantly lower in children from the south, indicating more severe growth retardation in children exposed to dietary cyanide. Because of the preferential use of sulphur amino-acids for cyanide detoxification in the human body, dietary cyanide exposure from cassava may be a factor aggravating growth retardation in Bandundu.

Relationship between serum and urinary insulin-like growth factor-I through childhood and adolescence: their use in the assessment of disordered growth.

OBJECTIVE: Serum insulin-like growth factor-I (sIGF-I) measurement as an index of growth hormone status has become a common test in the investigation of disordered growth. IGF-I may also be measured in the urine. The aims of this study were to investigate the correlation between serum and urinary IGF-I in normal children and compare their use in the evaluation of growth disorders. DESIGN: Normal ranges for serum and urinary IGF-I were devised from a cross-sectional study of normal schoolchildren. These were then used to assess the sensitivity and specificity of serum and urinary IGF-I in the diagnosis of childhood GH deficiency. PATIENTS: A cohort of 333 (M = 156, F = 177) healthy schoolchildren aged 5-19 years were recruited and data previously collected from 22 growth hormone deficient (GHD) and 47 short normal (SN) children were compared with those of the normal children. MEASUREMENTS: Height, weight and pubertal status were assessed in all children. Serum IGF-I (sIGF-I) (n = 305) and total amount of urinary IGF-I excreted overnight (TuIGF-I) (n = 205) were measured by RIA using excess IGF-II to block the interference of IGFBPs. RESULTS: Serum IGF-I was loge transformed and overall levels (geometric mean +/- 1 tolerance factor) were higher in females than males (F: 569 (329, 985) micrograms/l; M: 398 (227, 696) micrograms/l). LogeIGF-I correlated with age (F: r = +0.76, P < 0.001, M: r = +0.71, P < 0.001) and was significantly affected by both sex and Tanner stage of puberty (TS) (both P < 0.001). The distribution of TuIGF-I was normalized by performing a square root transformation (square root of TuIGF-I). square root of TuIGF-I was correlated with age (F: r = +0.36, P < 0.001; M: r = +0.5, P < 0.001) and was significantly affected by TS (P < 0.001). In both sexes there was a highly significant correlation between logeIGF-I and square root of TuIGF-I (F: r = +0.39, P < 0.001; M: r = +0.41, P < 0.001). Using the third centile of our normal ranges as a cut off to identify GHD, sIGF-I had a sensitivity of 82% and specificity of 62%, whereas TuIGF-I had a sensitivity of 18% and specificity of 79%. CONCLUSIONS: This study demonstrates that although urinary IGF-I has no place in the diagnosis of growth disorders, in normal children there is a highly significant relationship between serum and urinary IGF-I with levels of each changing in a similar manner through childhood and adolescence. Thus, TuIGF-I could be used as a valid surrogate for sIGF-I in the physiological assessment of the relationship between IGF-I status and the normal growth process.

Sleep, respiratory rate, and growth hormone in chronic neonatal lung disease.

This study assessed whether respiratory rates (RRs) correlate with urinary growth hormone (U-GH) excretion and sleep architecture in infants with chronic neonatal lung disease (CNLD) in early (1 month), middle (6 months), and late (10 months) infancy. Twenty-three preterm infants (CNLD=16, controls=7) were studied on 51 occasions. CNLD infants were stratified according to mean non-REM sleep respiratory rate (NREM RR) in early infancy into "High RR CNLD" infants (mean NREM RR >2 SD higher than controls) and "Normal RR CNLD" infants (mean NREM RR within 2 SD of controls' mean). "High RR CNLD" infants (RR >45) had a lower mean birthweight (P=0.015), current weight (P=0.042), current length (P=0.02), and growth velocity in early infancy (grams/week gained: P=0.042) than "Normal RR CNLD" and control infants. Mean (95% CI) U-GH excretion (ng U-GH/g urinary creatinine) was higher in "High RR CNLD" infants in air or their usual O2 (1,932 [459, 3,406]) than "Normal RR CNLD" (394 [147, 642]) and controls (320 [147, 492]) (P=0.024). With resolution of tachypnea by mid-infancy, hemoglobin oxygen saturation (SaO2) >93%, mean growth parameters and U-GH excretion for the "High RR CNLD" group were not significantly different from "Normal RR CNLD" and control groups. CNLD infants demonstrated increased sleep efficiency (P=0.016), whereas controls had similar sleep efficiency between early and middle infancy (P=0.452). Mean percent time in REM sleep (REM%) and slow wave sleep (SWS%) were not significantly different between early and middle infancy and did not vary in relation to respiratory rate. We conclude that tachypneic infants with CNLD have slower growth and elevated U-GH excretion in early infancy. With resolution of tachypnea, growth improved, U-GH excretion decreased, and sleep consolidation occurred. An elevated U-GH in tachypneic CNLD infants may reflect stress, compromised nutrition (GH resistance), or a feedback loop involving a direct effect of GH on lung growth and repair.

Urinary growth hormone: a screening test for growth hormone sufficiency.

OBJECTIVES: The majority of short statured children referred for serum GH testing prove to be GH sufficient. The purpose of our study was to evaluate urinary growth hormone (uGH) as a screening test for GH sufficiency. PATIENTS: We studied (i) short statured children previously diagnosed as GH sufficient (n = 44) or GH deficient (n = 41) (peak serum GH > or = 8 micrograms/l or < 8 micrograms/l, respectively); (ii) short children undergoing serum GH stimulation tests (n = 23, test group); (iii) normal statured children (n = 45, control group). DESIGN: Three separate overnight urine collections were obtained in all groups. GH injections in GH deficient subjects were discontinued 4 days prior to urine collection. MEASUREMENTS: uGH concentrations were measured using a chemiluminescence immunoassay. Overnight uGH was expressed in several ways (overnight excretion and overnight excretion corrected for body surface area, time and creatinine). Receiver operator curves (ROC) were constructed from the data obtained in the GH sufficient and deficient subjects. Sensitivity and specificity were then determined for various urinary cut-offs. These cutoffs were validated in turn in the test group by comparison of the predicted with the observed GH status. RESULTS: The GH deficient group had the lowest GH output with respect to overnight uGH, overnight uGH/m2, overnight uGH/h and overnight uGH/creatinine when compared with the GH sufficient and control groups (P = 0.0001). Overnight uGH/m2 data gave the greatest area under the ROC curve. At 100% specificity (no GH deficient subjects), it had the highest sensitivity, 63.6% (49.2-78.0% CI) at a cut-off of 2.3 ng/m2 (63.6% of GH sufficient subjects had uGH levels > 2.3 ng/m2). When this and other cut-offs were applied to the test group, we found consistency between the observed and predicted numbers of GH sufficient and deficient subjects. CONCLUSIONS: We conclude that urinary GH is a useful test for the diagnosis of GH sufficiency as defined by serum criteria and can be used to reduce significantly the number of serum stimulation tests.

Urinary IGF and IGF binding protein-3 in children with disordered growth. The North West Paediatric Endocrine Group.

OBJECTIVE: Both IGF-I and IGFBP-3 reflect spontaneous GH secretion in healthy individuals. We have evaluated the clinical usefulness of urinary IGF-I and IGFBP-3 measurements in the diagnosis of children with disordered growth. DESIGN: Serum IGF-I and IGFBP-3 radioimmunoassays (RIA) were developed, and modified for quantitation in urine. The relationship between serum and urine levels, and the performance of these tests in the diagnosis of GH deficiency (GHD) were examined. PATIENTS: Sixty-nine children (age 9.5 +/- 3.6 years; 37 boys, 32 girls) provided a timed overnight urine collection and a serum sample collected on the same morning. Subjects were defined as GHD (n = 22) or short normal (SN; n = 47) on the basis of medical history, clinical examination, auxology and peak response to a GH stimulation test (< 20 mU/L in GHD patients). MEASUREMENTS: IGF-I and IGFBP-3 in serum and urine were measured by RIA, urinary GH (uGH) by immunoradiometric assay (IRMA) after dialysis and urinary creatinine by the alkaline picrate method. Urine results were expressed as total amount excreted (tulGFBP-3 (microgram), tulGF-1 (ng), tuGH (ng), tuCrt (mmol). RESULTS: Urine IGF-I and IGFBP-3 excretion correlated significantly to serum levels of IGF-I and IGFBP-3 and also to tuGH excretion. There was a strong positive relationship between both urinary peptides and tuCrt, which suggested that renal filtration was the source of these peptides in urine. In addition, there were significant correlations with age, bone age and height SD score, of similar magnitude to those for tuGH. In prepubertal children, serum IGF-I and IGFBP-3 were significantly lower in GHD compared with SN children, while in puberty only serum IGFBP-3 was significantly lower in GHD. There was no difference however, in tulGF-I or tulGFBP-3 between GHD and SN children either prepubertally or in puberty with near complete overlap of the values between groups. CONCLUSIONS: Measurements of tulGF-I and tulGFBP-3 have no place in the diagnosis of childhood GHD. Nonetheless, the significant correlations between serum and urinary IGF-I and IGFBP-3 levels and their correlation to uGH indicate that these peptides could be used as non-invasive physiological markers of the GH-IGF axis.

Rapid decrease of urinary pyridinoline excretion in growth hormone deficient children following discontinuation of growth hormone therapy.

In order to examine the effect of growth hormone on urinary pyridinoline excretion, 32 patients with complete or partial growth hormone deficiency had their urinary pyridinoline excretion measured while receiving growth hormone and for 14 days after it was discontinued. There was a significant positive correlation between increases in growth velocities during the first year of growth hormone administration compared to before it, and the ratio of the urinary pyridinoline excretion levels while receiving growth hormone to those after discontinuation. Therefore, urinary pyridinoline excretion rapidly decreased in patients with growth hormone deficiency when the administration of growth hormone was stopped. Exogenous growth hormone appears to stimulate bone resorption in these patients.

Urinary growth hormone excretion: results of a multicenter study in France.

Urinary growth hormone excretion (uGH), expressed as the average of three consecutive nocturnal measurements, was studied in 324 prepubertal and pubertal children without (n = 188) or with (n = 136) growth disorders. In prepubertal control children (n = 127), the mean uGH was 11.9 +/- 4.9 ng/l without any correlation with sex or age. During puberty, a significant increase of uGH was observed in both sexes (boys: prepubertal 12.3 +/- 4.84 vs. pubertal 16.2 +/- 4.7 ng/l; girls: prepubertal 11.6 +/- 4.99 vs. pubertal 18.3 +/- 8.5 ng/l). In children with growth disorders, the results observed in various categories show a highly significant decrease in organic hypopituitary patients (p < 10(-6)) and obese subjects (p < 10(-6)) when compared to normal prepubertal children. In contrast, a significant increase was observed in 5 Laron-type dwarfisms (p < 10(-6)). However, in 24 children with partial growth hormone deficiency assessed by blood measurements (two pharmacological tests between 5 and 10 ng/ml), the results were not significantly different from the controls (13.6 +/- 6.4 ng/l). In a group of 66 children with short stature and normal blood response to pharmacological tests, uGH concentrations were significantly higher than those of the control group (17.3 +/- 8.71 ng/l, p < 10(-6)). The data suggest that uGH measurements lead to findings comparable to blood measurements, avoiding the disturbance of pharmacological tests, in well-delimited categories of patients. In contrast, uGH measurements are not the best way to detect partial GH-deficient children, but may be used to screen partial peripheral GH resistance in children with nonendocrine short stature.

Urinary pyridinium collagen cross-links predict growth performance in children with idiopathic short stature and with growth hormone (GH) deficiency treated with GH. Skeletal metabolism during GH treatment.

GH is able to promote longitudinal growth in children with GH-deficiency (GHD) and in some children with idiopathic short stature (ISS). The objectives of this study were to evaluate the predictive value of bone and collagen markers on the growth response to GH therapy in children with ISS and with GHD, and to characterize the effects of GH treatment on bone and collagen turnover in children with ISS and with GHD. Twenty prepubertal short, slowly growing, children treated with GH, 15 IU/m2 per week, were studied; of them 13 (10 males) had ISS and 7 (5 males) had GHD. An overnight 12-h urinary collection and a fasting morning blood sample were obtained at baseline, 1, 3, 6, and 12 months of treatment. Urinary levels of collagen cross-links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), and circulating levels of osteocalcin, intact PTH, calcitonin, procollagen type III aminoterminal propeptide (PIIINP), insulin-like growth factor-I, and alkaline phosphatase were determined. Urinary collection was also obtained from 127 healthy children (51 males) aged 6-13 yr. In children with ISS, the changes in Dpd over 1 month of GH therapy were related to the changes in height velocity (HV) over 1 yr of therapy (r = 0.67; P < 0.05); the changes in Pyd after 1 month of GH treatment were related to the changes in HV at 6 months of GH treatment (r = 0.57; P < 0.05). All the other markers evaluated were not related to the HV changes in children with ISS. In children with GHD, the changes in Pyd and in Dpd after 1 month of GH treatment were positively related to the changes in HV after 12 months of therapy (r = 0.82; P < 0.05, and r = 0.82; P < 0.05, respectively). The changes in Pyd after 1 month were also related to the HV changes after 6 months of GH (r = 0.77; P < 0.05). Positive relationships between the HV after 6 months of GH and the increases of PIIINP (r = 0.80; P < 0.05) and osteocalcin (r = 0.77; P < 0.05) after 3 months of GH therapy were observed. All patients showed urinary Dpd and Pyd excretions in the normal range. In patients with ISS, Pyd (P < 0.05), Dpd (P < 0.05), osteocalcin (P < 0.01), PIIINP (P < 0.01), and alkaline phosphatase (P < 0.01) increased longitudinally during the GH treatment and the increments reached a maximum after 3-6 months of therapy. Patients with GHD showed an increase of the same markers but the increases occurred earlier, after 1 month of GH therapy. The collagen cross-links, Pyd and Dpd, could be helpful early markers in predicting the responsiveness to GH therapy in children with ISS and with GHD. GH treatment stimulates bone and collagen metabolism.

Concentraçöes urinárias do hormônio de crescimento em crianças normais e com baixa estatura / Urinary concentration of growth hormone in normal children and with low body height

O hormônio de crescimento urinário (U-GH) noturno foi determinado durante três noites consecutivas em 40 crianças normais, voluntárias, com estatura entre os percentis 10 e 90 e em 29 crianças com estatura abaixo do terceiro percentil, diagnosticadas como baixa estatura constitucional e/ou familial (BEC) ou deficientes de GH (DGH) de acordo com os critérios diagnósticos clássicos. O U-GH foi também determinado durante a realizaçäo dos testes farmacológicos (hipoglicemia ou L-dopa) nas crianças com baixa estatura. Observou-se uma grande variabilidade inter e intra-individual (CV=38 por cento) na excreçäo do U-GH, tanto em crianças normais quanto em crianças com BEC e com DGH. Näo houve diferença entre o sexo masculino e o feminino nas concentraçöes do U-GH (3,1 x 3,6 ng/noite, NS). Os púberes apresentaram maior excreçäo que os impúberes (4,1 x 2,3 ng/noite, p<0,01) e observou-se uma correlaçäo positiva do U-GH com idade (r=0,28, p<0,005). As crianças com DGH apresentaram menor excreçäo de U-GH que crianças normais impúberes (1,1 x 2,2 ng/noite, p<0,0005) e que crianças com BEC (1,1 x 2,2 ng/noite, p<0,001), porém näo houve completa discriminaçäo entre os três grupos. A sensibilidade e especificidade diagnósticas foram respectivamente de 81 por cento e 69 por cento para um ponto de corte de 1,6 ng/noite. Houve correlaçäo positiva entre o U-GH noturno e a resposta do GH plasmático aos testes farmacológicos (r=0,67, p<0,0001), porém a determinaçäo do U-GH durante os testes nao auxiliou na discriminaçäo dos grupos. Considerando determinados pontos de corte (1,2 e 2,5 ng/noite) e coleta de três amostras consecutivas, acreditamos que o método pode ser utilizado como "screening" na avaliaçäo da baixa estatura, reduzindo a indicaçäo de testes farmacológicos.