The diagnosis of hypophosphatasia in children as a multidisciplinary effort: an expert opinion.

Hypophosphatasia (HPP) is a rare genetic disorder in which pathogenic variants of the ALPL gene lead to a marked decrease of tissue non-specific alkaline phosphatase (TNSALP) activity. Although HPP is a systemic disorder, its clinical manifestations are more evident on bones, teeth, muscle and central nervous system. The clinical spectrum ranges from severe forms with extreme skeletal deformities, respiratory impairment, seizures, to very mild forms with onset in late adulthood and few clinical signs. The diagnosis can be suspected by measurement of TNSALP activity, but the insufficient awareness among health professionals and the lack of official guidelines are responsible for delayed diagnosis in children with HPP. The purpose of the current document is to provide an expert opinion directed at optimizing the diagnostic pathway of pediatric HPP. From April to December 2022, a multidisciplinary working group of 6 experts including two pediatric endocrinologists, a pediatric neurologist, a pediatric odontologist, a clinical geneticist, and a molecular biologist gathered in a series of periodic meetings to discuss the main issues related to the diagnosis of HPP in children and formalize an Expert Opinion statement. The experts agreed on a diagnostic trail that begins with the recognition of specific clinical signs, leading to biochemical analyses of TNSALP activity and vitamin B6 serum concentration. Very important are the neurological and dental manifestation of the disease that should be thoroughly investigated. The evaluation of TNSALP activity must consider sex and age variability and low activity must be persistent. Repeated blood measurements are thus necessary. The molecular analysis is then mandatory to confirm the diagnosis and for genetic counseling.

Intact FGF23 concentration in healthy infants, children, and adolescents, and diagnostic usefulness in patients with X-linked hypophosphatemic rickets.

OBJECTIVE: FGF23 measurement may have a diagnostic role to investigate patients with phosphate disorders. However, normal values for infants, children, and adolescents have not been defined. METHODS: In a total of 282 (males 145, females 137) healthy infants (n = 30), prepubertal (n = 147), pubertal (n = 59), and postpubertal (n = 46), and in twenty patients with X-linked hypophosphatemic rickets (XLH, age 10.2 ± 5.6 years) serum phosphate (automated analyzer), and plasma intact FGF23 (immunochemiluminescent sandwich assay, DiaSorin) concentrations were measured. RESULTS: Intact FGF23 concentrations were higher in healthy infants than in prepubertal (P < 0.01) and postpubertal subjects (P < 0.05); pubertal subjects showed higher values (P < 0.05) than postpubertal subjects. Serum phosphate concentrations were higher (P < 0.001) in healthy infants than in prepubertal, pubertal, and postpubertal subjects. Pubertal subjects had higher (P < 0.001) serum phosphate concentrations than postpubertal subjects. Intact FGF23 and serum phosphate concentrations did not differ (P = NS) by sex, age of menarche, and time after menarche. In healthy subjects, there was no correlation between intact FGF23 and serum phosphate concentrations. Intact FGF23 concentrations were higher (P < 0.0001) in patients with XLH than in healthy subjects according to chronological age and pubertal development. In all patients, intact FGF23 concentrations were above 40 pg/mL; intact FGF23 concentrations were inversely correlated with serum phosphate concentrations (r = -0.65; P < 0.01). CONCLUSION: In healthy subjects, chronological age and puberty were main determinants of intact FGF23 concentrations. Intact FGF23 concentrations may be a useful marker for the early diagnosis of XLH in pediatric patients.

Vitamin D status and the immune assessment in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is characterized by a heterogeneous phenotype, including alterations in phospho-calcium metabolism and immunodeficiency. We analyzed vitamin D status and the immune assessment, focusing on T cell subpopulations and dendritic cells (DCs) in a cohort of 17 pediatric 22q11.2DS patients and 17 age-matched healthy subjects. As antigen-presenting cells, DCs are the main target of vitamin D, promoting a tolerogenic T cell response. Patients were subdivided into three groups according to the parameters of phospho-calcium metabolism and serum levels of 25OHD: normal values, vitamin D deficiency and hypoparathyroidism. Different degrees of T cell deficiency, ranging from normal to partial T cell numbers, were observed in the cohort of patients. The group with vitamin D deficiency showed a significant reduction of naive T cells and a significant increase of central memory T cells compared to controls. In this group the number of circulating DCs was significantly reduced. DC decrease affected both myeloid and plasmacytoid DC subsets (mDCs and pDCs), with the most relevant reduction involving pDCs. A direct correlation between 25OHD levels and recent thymic emigrant (RTE) and DC number was identified. Despite the limited cohort analyzed, our results show that deficiency of the pDC subset in patients with 22q11.2DS may be included among the causative factors of the progressive increase of risk of autoimmune diseases in these patients. As most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, we suggest a potential role of vitamin D supplementation in preventing autoimmune or proinflammatory diseases in 22q11.2DS.

17ß-hydroxysteroid dehydrogenase type 3 deficiency: female sex assignment and follow-up.

BACKGROUND: Deficiency of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is a rare autosomal recessive 46,XY disorder of sex development (DSD). It is due to pathogenetic variants in the HSD17B3 gene. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Δ4-androstenedione (Δ4-A) to testosterone (T) in the fetal testis. Affected individuals are usually raised as females and diagnosis is made at puberty, when they show virilization. METHODS: A girl with a presumptive diagnosis of complete androgen insensitivity syndrome underwent endocrine and genetic assessment. Long-term follow-up was reported. RESULTS: The diagnosis of 17ß-HSD3 deficiency was made (stimulated T/Δ4-A ratio: 0.15; HSD17B3 gene analysis: c.277+4A>T in intron 3/c.640_645del (p.Glu214_Glu215del) in exon 9. After extensive information, parents decided to maintain female sex. Gonadal removal was performed and histological evaluation demonstrated deep fibrosis of testicular tissue. Follow-up till 8.5 years of age showed somatic and neuro-psychological development fitting with the female sex. CONCLUSIONS: Management of a child with the rare 17ß-HSD3 deficiency remains challenging. Any decision must be carefully evaluated with parents. Long-term follow-up must be warranted by a multidisciplinary DSD team to evaluate the adequacy of the choices made on quality of life in later life.

Providing high-quality care remotely to patients with rare bone diseases during COVID-19 pandemic.

During the COVID-19 outbreak, the European Reference Network on Rare Bone Diseases (ERN BOND) coordination team and Italian rare bone diseases healthcare professionals created the "COVID-19 Helpline for Rare Bone Diseases" in an attempt to provide high-quality information and expertise on rare bone diseases remotely to patients and healthcare professionals. The present position statement describes the key characteristics of the Helpline initiative, along with the main aspects and topics that recurrently emerged as central for rare bone diseases patients and professionals. The main topics highlighted are general recommendations, pulmonary complications, drug treatment, trauma, pregnancy, children and elderly people, and patient associations role. The successful experience of the "COVID-19 Helpline for Rare Bone Diseases" launched in Italy could serve as a primer of gold-standard remote care for rare bone diseases for the other European countries and globally. Furthermore, similar COVID-19 helplines could be considered and applied for other rare diseases in order to implement remote patients' care.

17beta-Hydroxysteroid dehydrogenase-3 deficiency: from pregnancy to adolescence.

OBJECTIVE: Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17beta-hydroxysteroid-dehydrogenase type 3 (17beta-HSD3) deficiency in Italy. SETTING: Pediatric Endocrine Departments, University Hospitals. PATIENTS: The cases of 5 Italian subjects affected by 17beta-HSD3 deficiency are presented in this study. INTERVENTIONS: Laboratory and genetic assessment. Gonadectomy and female sex assignment (4 patients) or GnRH analog therapy to regress puberty and gender identity disorder (1 patient). RESULTS: Presentation lasted from pregnancy (pre-natal diagnosis of a 46,XY fetus with female external genitalia) to infancy (inguinal hernia containing testes/clitoromegaly) and adolescence (virilisation). All subjects but one (subject 1, Central-Northern Italy) were from small areas of Southern Italy. Endocrine data (baseline and/or stimulated testosterone/ Delta4-androstenedione ratio) were informative. Two girls were homozygous for 17beta-HSD3 gene mutations (G289S/G289S; R80W/R80W), while the others were compound heterozygous (IVS325+4 A>T/A203V; L212Q/M235V; R80W/A235E). Four patients were confirmed as females and were well-adjusted with assigned sex; gender identity disorder improved during treatment with GnRH analog in the last subject. CONCLUSIONS: 17betaHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/Delta4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCGstimulation is mandatory in pre-puberty. Molecular analysis of 17beta-HSD3 gene should be performed to confirm the diagnosis. Temporary GnRH analog treatment may regress gender identity disorder and provide time to confirm or change the birth sex assignment. Female individuals seems to be compliant with their sex, providing that virilisation does not occur. In Italy, the disorder seems to be more prevalent in the Southern regions and shows genetic heterogeneity.

X-linked hypophosphatemic rickets: an Italian experts' opinion survey.

BACKGROUND: X-linked hypophosphatemic rickets (XLH) is the first cause of inherited hypophosphatemia and is caused by mutation in the PHEX gene, resulting in excessive expression of the phosphaturic factor FGF23. Symptoms are mainly related to rickets in children and osteomalacia in adults and cause several complications that can be highly invalidating. Due to its rarity, XLH is poorly known and diagnosis is frequently delayed. Conventional treatment is based on oral phosphate salts supplementation and activated vitamin D analogs, which however, cannot cure the disease in most cases. OBJECTIVE: Due to the low prevalence of XLH, an experts' opinion survey was conducted across Italian centers to collect data on XLH and on its management. METHODS: A questionnaire was developed by a group of experts to collect data on XLH epidemiology, diagnosis and treatment in Italy. RESULTS: Data from 10 Italian centers (nine of which pediatric) on 175 patients, followed between 1998 and 2017, were included in the survey. Most patients were followed since childhood and 63 children became adults during the investigated period. The diagnosis was made before the age of 1 and between 1 and 5 years in 11 and 50% of cases, respectively. Clinically apparent bone deformities were present in 95% of patients. These were ranked moderate/severe in 75% of subjects and caused growth stunting in 67% of patients. Other frequent complications included bone pain (40%), dental abscesses (33%), and dental malpositions (53%). Treatment protocols varied substantially among centers. Nephrocalcinosis was observed in 34% of patients. Tertiary hyperparathyroidism developed in 6% of patients. CONCLUSIONS: XLH remains a severe condition with significant morbidities.

Prevalence and pathogenesis of dental and periodontal lesions in children with X-linked hypophosphatemic rickets.

AIM: To assess the prevalence and to investigate the pathogenetic mechanisms of dental and periodontal lesions in children with X-linked hypophosphatemic rickets (XLH) examined at diagnosis or during treatment. METHODS: Nine children with XLH (age 7.2 +/- 3.3 years) were enrolled in the study (at diagnosis, n = 2; during treatment with oral inorganic phosphate salts combined with 1,25-dihydroxyvitamin D3, n = 7). Oral examination was performed according to the evidence of carious and gingival lesions. Decayed or filled teeth (dft) index for primary teeth, and the decayed, missing, or filled teeth (DMFT) index for permanent teeth was assessed. All patients with a history of spontaneous dental abscesses underwent orthopantomography examination. RESULTS: d/D ranged from 0 to 9 and f/F from 0 to 3. DMFT/dft index was 0 in the three youngest patients. One patient had enamel hypoplasia and two had enamel dyschromic alterations. Six out of nine patients (67%) had a history of spontaneous fistulae as a consequence of periapical abscesses occurring in the absence of dental decay or history of injury. In these patients, orthopantomographies showed enlarged pulp chambers associated with prominent pulp horns extending up to the dentino-enamel junction in both primary and permanent dentition. CONCLUSION: XLH patients show some peculiar dentinal abnormalities. Treatment prevents only in part dental and periodontal lesions. Genetic mechanisms have a main role in causing defective dentin mineralisation.

Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption.

BACKGROUND: Genetic and epigenetic alterations in the GNAS locus are responsible for the Gsα protein dysfunctions causing Pseudohypoparathyroidism (PHP) type Ia/c and Ib, respectively. For these heterogeneous diseases characterized by multiple hormone resistances and Albright's Hereditary Osteodystrophy (AHO) the current classification results inadequate because of the clinical overlap between molecular subtypes and a standard clinical approach is still missing. In the present paper several members of the Study Group Endocrine diseases due to altered function of Gsα protein of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) have reviewed and updated the clinical-molecular data of the largest case series of (epi)/genetically characterized AHO/PHP patients; they then produced a common healthcare pathway for patients with these disorders. METHODS: The molecular analysis of the GNAS gene and locus identified the causal alteration in 74 subjects (46 genetic and 28 epigenetic mutations). The clinical data at the diagnosis and their evolution during up to 15 years follow-up were collected using two different cards. RESULTS: In patients with genetic mutations the growth impairment worsen during the time, while obesity prevalence decreases; subcutaneous ossifications seem specific for this group. Brachydactyly has been detected in half of the subjects with epigenetic alterations, in which the disease overts later in life, often with symptomatic hypocalcaemia, and also early TSH and GHRH resistances have been recorded. CONCLUSIONS: A dedicated healthcare pathway addressing all these aspects in a systematic way would improve the clinical management, allowing an earlier recognition of some PHP features, the optimization of their medical treatment and a better clinical-oriented molecular analysis. Furthermore, standardized follow-up data would provide new insight into less known aspects.

Short-term effect of testosterone treatment on reduced bone density in boys with constitutional delay of puberty.

We studied bone mineral content (BMC), bone mineral density (BMD), cortical thickness/total width (CT/TW) ratio and cortical area/total area (CA/TA) ratio in boys with constitutional delay of puberty and the effect of short-term testosterone treatment on bone mass. Seventeen boys (age 13.1-15.8 years) who met the family history and the clinical criteria of constitutional delay of puberty were selected and enrolled in the study. All subjects were eating a diet assuring an adequate intake of calories and calcium. A subset of 8 boys (group A) was treated with testosterone depot (100 mg/month x 6 months) while 9 boys (group B) were not. At inclusion, BMC and BMD were reduced in the patients according to their chronological age (BMC -4.04 +/- 1.34 standard deviation scores [SDS]; BMD -2.95 +/- 0.56 SDS), statural age (BMC -1.75 +/- 0.79 SDS; BMD -1.69 +/- 0.78 SDS), and bone age (BMC -1.80 +/- 0.65 SDS; BMD -1.86 +/- 0.68 SDS). No significant differences between the groups were found (group A: BMC 0.480 +/- 0.57 g/cm, BMD 0.488 +/- 0.037 g/cm2, CT/TW ratio 0.43 +/- 0.4, CA/TA ratio 0.68 +/- 0.04; group B: BMC 0.476 +/- 0.060, p = NS vs. group A; BMD 0.491 +/- 0.036 g/cm2, p = NS vs. group A). At 12 months of follow-up, BMC, BMD, CT/TW ratio, and CA/TA ratio significantly increased in group A (BMC 0.70 +/- 0.13 g/cm, delta +41.1 +/- 28.8%, p < 0.003 vs. 0 month; BMD 0.617 +/- 0.082 g/cm2, delta +26.2 +/- 13.6%, p < 0.005 vs. 0 month; CT/TW ratio 0.52 +/- 0.05, delta +20.59 +/- 10.65%, p < 0.001 vs. 0 month; CA/TA ratio 0.77 +/- 0.05 vs. 0 month; CT/TW ratio 13.60 +/- 6.65%, p < 0.004 vs 0 month), but not in group B (BMC: 0.48 +/- 0.05 g/cm; delta +5.1 7.8%, p = NS vs. 00 month; BMD: 0.492 +/- 0.037 g/cm2; delta +0.54 +/- 8.7%, p = NS vs. 0 month; CT/TW ratio 0.44 +/- 0.04, delta +4.04 +/- 6.75%, p = NS vs. 0 month; CA/TA ratio 0.68 +/- 0.05, delta +2.39 +/- 5.90%, p = NS vs. 0 month). We conclude that boys with constitutional delay of puberty have reduced BMC and BMD. The delay in statural and bone ages did not totally account for the decreased bone mass. Testosterone treatment for 6 months significantly increased BMC, BMD, CT/TW ratio, and CA/TA ratio in these patients, but definitive conclusions on the efficacy of the treatment in improving adult bone mass can be drawn only when our patients reach early childhood.

Mineral metabolism in Turner's syndrome: evidence for impaired renal vitamin D metabolism and normal osteoblast function.

We examined intact PTH and 1,25-dihydroxyvitamin D [1,25-(OH)2D] in both baseline and dynamic conditions (low calcium diet) in 14 patients with Turner's syndrome (mean age, 12.6 +/- 5.9 yr; range, 4.2-21.0 yr) and bone demineralization as well as in a control group of 15 healthy girls (mean age, 12.8 +/- 5.6 yr; range, 3.8-22.7 yr). In both groups we also measured osteocalcin serum levels in response to oral 1,25-(OH)2D3 administration (1.8 micrograms/m2/daily for 6 days) to assess osteoblast function. The low calcium diet decreased ionized calcium (Ca2+) levels and elevated PTH values to the same extent in both patients (Ca2+, -8.40 +/- 3.78%; intact PTH, +47.88 +/- 13.24%) and controls (Ca2+, -9.09 +/- 3.25%; intact PTH, +52.77 +/- 10.52%; P = NS vs. patients). While controls showed an increment in their serum 1,25-(OH)2D levels (+52.15 +/- 8.95%), patients did not (+10.93 +/- 4.71%; P = NS vs. baseline; P < 0.001 vs. controls). 1,25-(OH)2D3 administration caused a rise in the serum osteocalcin levels in a similar fashion in both groups (peak values: patients, +35.38 +/- 7.20%; controls, +34.09 +/- 7.98%; P = NS). We conclude that in patients with Turner's syndrome there is an altered renal vitamin D metabolism in response to physiological stimulus, while osteoblast function in response to 1,25-(OH)2D3 administration is not affected.

Measurement of volumetric bone mineral density accurately determines degree of lumbar undermineralization in children with growth hormone deficiency.

The effect of anthropometric variables and bone size on bone mineral density (BMD) was examined in 22 children with GH deficiency (GHD) aged 6.1-8.0 yr at diagnosis and in 40 sex- and chronological age-matched controls. In all patients and controls, bone mineral content (BMC), BMDarea and BMD corrected for the apparent bone volume (BMDvolume) were measured by dual-energy x-ray absorptiometry in the lumbar spine at L2-L4 level. In patients, BMDarea was corrected for body height (BMDheight), body mass index (BMDBMI), and bone age (BMDBA). Patients showed significantly reduced (P < 0.0001) BMC (males 11.55 +/- 0.71 g, females 10.13 +/- 1.48 g) and BMDarea (males 0.502 +/- 0.033 g/cm2, females 0.515 +/- 0.034 g/cm2) compared with controls (BMC: males 18.09 +/- 1.23 g, females 15.58 +/- 1.87 g; BMDarea: males 0.689 +/- 0.065 g/cm2, females 0.685 +/- 0.059 g/cm2). In patients, BMDheight (males 0.537 +/- 0.031 g/cm2, females 0.548 +/- 0.032 g/cm2) and BMDBMI (males 0.641 +/- 0.028 g/cm2, females 0.624 +/- 0.035 g/cm2) remained significantly lower (P < 0.02 to P < 0.0001) than BMDarea of controls. BMDBA of patients was significantly reduced (-1.49 +/- 0.51 Z score, P < 0.0001) in comparison with bone age-matched controls (n = 35). BMDvolume was significantly lower (P < 0.01 to P < 0.0005) in patients (males 0.268 +/- 0.006 g/cm3, females 0.276 +/- 0.010 g/cm3) compared with chronological age-matched controls (males 0.283 +/- 0.013 g/cm3, females 0.293 +/- 0.017 g/cm3). Mean bone volume of patients was affected to a greater extent than bone area (-2.36 +/- 0.49 Z score and -1.56 +/- 0.70 Z score, respectively). Bone area/bone volume ratio was significantly higher in patients than in chronological age-matched controls (0.53 +/- 0.02 and 0.42 +/- 0.08, P < 0.0001, respectively). Chronological age, body height, BMI, and bone age correlated significantly with BMDarea (r2 = 0.389-0.450, P < 0.002 to P < 0.001) but not with BMDvolume (P = not significant). The results show that anthropometric variables and bone size affect lumbar BMC and BMDarea in children with GHD. Reduced lumbar BMDvolume indicates that apparent true bone density is decreased in children with GHD, suggesting a role of GH in bone mineralization.

Normal volumetric bone mineral density and bone turnover in young men with histories of constitutional delay of puberty.

It has been suggested that an appropriate timing of puberty is necessary for normal bone mineral density (BMD) acquisition, which may not be achievable in children with constitutional delay of puberty (CDP). To assess the effect of pubertal delay on BMD, we measured areal BMD (aBMD) at lumbar spine, by dual-energy x-ray absorptiometry (DEXA), in a group of patients with CDP (n=21; mean age, 21.8+/-1.7 yr) at final height and in healthy controls (n=12; mean age, 19.3+/-1.3 yr). A subset of seven patients (group a) were untreated, whereas six subjects (group b) had received im testosterone depot (100 mg/month, for 6-12 months) and 8 boys (group c) oral oxandrolone (1.25-2.5 mg/daily, for 6-28 months) for their pubertal delay. Volumetric BMD (vBMD) was calculated from DEXA measurements. aBMD was reduced in patients with CDP (1.101+/-0.134 g/cm2), in comparison with controls (1.222+/-0.091 g/cm2; P < 0.009); no significant differences were found among the groups (group a, 1.089+/-0.133 g/cm2; group b, 1.111+/-0.118 g/cm2; group c, 1.103+/-0.160 g/cm2). vBMD was not significantly different in patients with CDP (0.327+/-0.021 g/cm3) and in controls (0.337+/-0.017 g/cm3; P= not significant); no significant differences were found among the groups (group a, 0.326+/-0.016 g/cm3; group b, 0.332+/-0.022 g/cm3; group c, 0.330+/-0.021 g/cm3). No differences were found in mineral metabolism and in bone markers between patients and controls; patients did not report an increased fracture rate, compared with controls. Our data indicate that: 1) men with CDP have normal vBMD; 2) the reduced aBMD may be the result of uncritical use of DEXA measurements in subjects with altered growth pattern; and 3) androgen administration during pubertal years did not improve BMD in young men with a history of CDP.

The effect of long-term growth hormone (GH) treatment on bone mineral density in children with GH deficiency. Role of GH in the attainment of peak bone mass.

The effect of long-term GH treatment on bone mass was examined in 32 children with GH deficiency (GHD) aged 7.2-16.3 yr by measuring radial (distal third, single-photon absorptiometry) and lumbar (L2-L4, dual energy x-ray absorptiometry) bone mineral density (BMD) (group A). All patients were longitudinally followed and received recombinant hGH therapy for a mean period of 48.2 +/- 13.2 months. BMD values were corrected for bone age and expressed as Z-score in comparison with normative data. In addition, lumbar BMD and lumbar BMD corrected for the estimated vertebral volumes were assessed in 11 patients with GHD aged 16.0 - 18.7 yr at the time they reached their final height (group B) and, in 17 subjects with familial short stature aged 16.4 - 19.8 yr, as controls (group C) for patients of group B. Patients of group B had received discontinuous treatment with pituitary-derived hGH and subsequently recombinant hGH (total duration of treatment 151.5 +/- 9.7 months). The off-treatment period was 4.7 +/- 2.6 months. Before treatment, patients of group A showed significantly reduced (P < 0.001) radial and lumbar BMD (-1.7 +/- 0.4 Z-score and -1.5 +/- 0.5 Z-score, respectively) compared with normative data. During treatment, radial and lumbar BMD Z-scores improved significantly (P < 0.001); in the patients treated for the longest time, the BMD was within 0.5 SD of age-matched mean levels. In patients of group B, lumbar BMD and lumbar BMD corrected for the estimated vertebral volumes were significantly reduced in comparison with subjects of group C (-1.2 +/- 0.4 Z-score and -1.0 +/- 0.4 Z-score, P < 0.01 and P < 0.03, respectively). The results show that children with GHD have reduced BMD. Optimal GH treatment improves BMD, whereas inappropriate treatment is a main cause of reduced BMD at time of final height. These findings suggest an important role of GH therapy in the attainment of peak bone mass in children with GHD. GH treatment should be continued until the attainment of peak bone mass irrespective of the height achieved.

Central precocious puberty in Klinefelter syndrome: a case report with longitudinal follow-up of growth pattern.

We report idiopathic central precocious puberty in a boy with Klinefelter syndrome and describe the pattern of linear growth and body proportion from the onset of precocious puberty to final height. The patient was not treated for precocious puberty. He reached adequate adult height, for both general population and normative values of Klinefelter syndrome and normal body proportions. We conclude that precocious puberty in Klinefelter syndrome may result in normal body proportion by inducing a major growth spurt of the trunk rather than in the limbs, and that adult height prognosis is not altered by precocious puberty. Given the possible occurrence of precocious puberty in Klinefelter syndrome, we advise a karyotype analysis in boys with sexual precocity, mainly in those who show small rather than enlarged testes.

Dynamics of bone turnover in children with GH deficiency treated with GH until final height.

OBJECTIVE: To examine the dynamics of bone turnover in children with growth hormone deficiency (GHD) during long-term treatment. DESIGN: We longitudinally measured growth velocity and serum concentrations of osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP), and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) in 24 patients with GHD during long-term GH treatment until final height (age: 7.7+/-0.7 and 16.9+/-0.5 years at baseline and at final height respectively). RESULTS: At baseline, OC, PICP, and ICTP levels were significantly (P<0.0001) reduced in comparison with prepubertal bone age-matched controls (10.2+/-2.3 microgram/l and 22.5+/-7.6 microgram/l; 187.8+/-26.2 microgram/l and 328. 4+/-74.3 microgram/l; 7.7+/-2.0 microgram/l and 14.2+/-1.3 microgram/l respectively). During the first year of treatment mean levels of the bone markers increased significantly (P<0.0001) with a peak at 12 months. After the first year of treatment, OC and PICP levels progressively declined, whereas ICTP levels remained stable until the final height; in any case, bone marker levels remained significantly higher (P<0.03-P<0.0001) than baseline. The change in bone marker levels at 6 and 12 months of treatment with respect to the baseline values was not related to growth rate during long-term treatment or final height. CONCLUSIONS: The results show that children with GHD have reduced bone turnover at baseline, and that long-term GH treatment is associated with a stimulation of bone turnover. OC, PICP, and ICTP do not predict growth rate during long-term treatment or final height in children with GHD.

Mucus of the human olfactory epithelium contains the insulin-like growth factor-I system which is altered in some neurodegenerative diseases.

Growth factors are believed to be involved in the mitotic regulation of the animal olfactory epithelium (OE). We investigated mucus covering the human OE area to see if it contained the insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) and to examine their behaviour in neurodegenerative diseases. Thirty patients with idiopathic late onset cerebellar ataxia (ILOCA), Parkinson's disease, and amyotrophic lateral sclerosis (ALS) and 30 age- and sex-matched healthy subjects were studied. In 10 controls, we also analyzed the mucus of the respiratory mucosa of the nose and tears. We detected IGF-I in the mucus covering the OE and Western ligand blot analysis (WLB) showed IGFBPs with an apparent Mr of 41, 500/38,500, 34,000 and 24,000, which were immunoprecipitated by specific antisera to IGFBP-3, -2 and -4, respectively. Their levels were higher than those observed in the respiratory mucosa of the nose or in tears. Mucus of the OE of the patients contained significantly reduced levels of IGF-I in comparison with those of controls. The intensity of all the IGFBPs-related bands were reduced in the ILOCA, while the remaining patients had a loss in the amounts of IGFBP-3. Plasma IGF-I and IGFBPs levels were similar in patients and controls. In conclusion, our data show that mucus covering the human OE contains IGF-I and IGFBPs, suggesting that these factors have a role in the activity of the OE. The amounts are reduced in the patients' mucus, possibly reflecting a dysfunction of the OE itself.

Osteoporosis in children and adolescents: diagnosis, risk factors, and prevention.

Bone mass acquired during childhood and adolescence is a key determinant of adult bone health. Peak bone mass, which is achieved in late adolescence, is a main determinant of osteoporosis in adulthood. Therefore, any factor adversely impacting on bone acquisition during childhood or adolescence can potentially have long-standing detrimental effects on bone health predisposing to osteoporosis and fracture risk. Thus, osteoporosis can well have its origin in childhood and adolescence. Pediatricians should be playing an active role in osteoporosis diagnosis and prevention. It is increasingly recognized that osteoporosis may occur in some disorders of children and adolescents. In this paper we review the diagnostic criteria of osteopenia/osteoporosis by densitometric assessment of bone mineral density, the contributing factors, and the mechanisms whereby several disorders may affect the acquisition of bone mass in children and adolescents. Finally, some recommendations to optimize peak bone mass in order to prevent osteopenia/osteoporosis are suggested.

Effects of 12 months rhGH treatment on bone and collagen turnover in children with constitutional growth delay.

Serum bone Gla protein (BGP), marker of osteoblast function, serum carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and urinary free deoxypyridinoline (DPD), markers of bone resorption, and the aminoterminal propeptide of type III procollagen (PIIINP), marker of type III collagen turnover, were determined in eight prepubertal children (8 males, age range 7-9.6 yr, Tanner stage I) with constitutional growth delay (CGD), before and after 6-12 months of treatment with rhGH (Saizen, Serono, 0.6 IU/kg/week, s.c.). Serum BGP (mean+/-SD: 15.4+/-1.7 ng/ml), ICTP (9.4+/-1.6 ng/ml) and urinary DPD/creatinine (11.3+/-1.7 nmol/mmol) levels were significantly lower (p<0.02, p<0.0001 and p<0.02, respectively) in children with CGD than in healthy age-matched controls (BGP: 18.9+/-3.6 ng/ml, ICTP: 14.3+/-2.6 ng/ml, DPD: 20.7+/-10.0 nmol/mmol), while PIIINP levels of patients were similar to those recorded in controls (6.3+/-0.7 vs 6.7+/-2.3 ng/ml, respectively). Serum BGP, urinary free DPD/creatinine and PIIINP levels significantly increased after 6 (BGP: 20.9+/-2.1 ng/ml, p<0.0001; DPD/creatinine: 16.3+/-3.6 nmol/mmol, p<0.001; PIIINP: 8.1+/-1.6 ng/ml, p<0.005) and 12 months (BGP: 19.2+/-2.0 ng/ml, p<0.0001; DPD/creatinine: 19.7+/-5.1 nmol/mmol, p<0.001; PIIINP: 8.8+/-1.9 ng/ml, p<0.002) of GH treatment. Serum ICTP levels did not significantly change after 6 months (10.6+/-2.1 ng/ml), while a significant increase (p<0.002) was evident after 12 months of therapy (13.6+/-1.3 ng/ml). Our study shows that BGP, ICTP and DPD/creatinine levels are significantly reduced in children with CGD, thus indicating the presence of low bone turnover in this form of short stature. Since GH treatment is able to reactivate bone remodeling and increase collagen synthesis, it is tempting to speculate that a partial GH-IGF-I defect (i.e. locally at bone level) might be one of the factors involved in determining the biochemical alterations of bone metabolism found in this clinical condition.