Distribution of plasma copeptin levels and influence of obesity in children and adolescents.

In recent years, a more stable AVP surrogate, called copeptin, has been used as an adjuvant diagnostic tool for dysnatremia in adults and appears to be promising even in the pediatric age. The aim of this study is to present the distribution of plasma copeptin in a large pediatric cohort and to observe the influence of fluid consumption and obesity on its values. A cohort of 128 children and adolescents was divided into two groups on the basis of nocturnal deprivation (group A) or free access to oral fluids in the 6-8 h before blood collection (group B). At all distribution percentiles, copeptin levels were higher (p < 0.0001) in group A, as were plasma sodium levels and osmolality (p = 0.02 and p = 0.008, respectively). The influence of BMI on copeptin levels was investigated by dividing the cohort into nonobese (group C) and obese children and adolescents (group D). Copeptin levels were higher in group D (p = 0.04).Conclusion: The measurement of copeptin could represent a useful tool for the diagnostic pathway of dysnatremic conditions, but its interpretation should take into consideration the state of hydration. Furthermore, it could also be a promising marker for obesity and metabolic syndrome, although this hypothesis needs further studies to be confirmed. What is Known: • Copeptin use as a diagnostic tool in AVP-related disorders, such as diabetes insipidus or syndrome of inappropriate secretion of antidiuretic hormone, is well established in adults • In pediatric age, few studies are available, but the preliminary data, including our previous study, seems to be promising. What is New: • In this study, we represent the distribution of copeptin levels in a pediatric cohort and show the significant influence of fluid ingestion on its plasma levels. • Also BMI seems to be a significant variable on copeptin levels and may be used as an obesity marker in pediatric age.

Copeptin role in polyuria-polydipsia syndrome differential diagnosis and reference range in paediatric age.

OBJECTIVE: Plasma arginine-vasopressin (AVP) analysis can help in the differential diagnosis of the polyuria-polydipsia syndrome (PPS), even if such investigation is hampered by technical difficulties, conversely to its surrogate copeptin. This study aims to enlarge the existing data on normal copeptin levels in childhood, to evaluate the correlation between copeptin, serum sodium and plasma and urine osmolality, and to assess the utility of the copeptin analysis in the diagnostic work-up of PPS in the paediatric age. PATIENTS AND METHODS: Plasma copeptin levels were evaluated in 53 children without AVP disorders (control population), in 12 hypopituitaric children and in 15 patients with PPS after water deprivation test (WDT). RESULTS: Mean basal copeptin levels were 5.2 ± 1.56 (range 2.4-8.6 pmol/L) in the control population, 2.61 ± 0.49 pmol/L in the hypopituitaric children with complete diabetes insipidus (CDI) (P = .04) and 6.21 ± 1.17 pmol/L in the hypopituitaric patients without DI (P = .02). After WDT, among 15 naïve polyuric/polydipsic children, copeptin values greater than 20 pmol/L allowed to identify nephrogenic diabetes insipidus (NDI), concentrations below 2.2 pmol/L complete central DI (CCDI) and between 5 and 20 pmol/L primary polydipsia (PP). Copeptin cut-off level of 3.5 pmol/L distinguished CDI from PP, with a sensitivity and specificity of 75% and 83.3%, respectively. CONCLUSION: Copeptin evaluation holds promises as a diagnostic tool in paediatric PPS; its interpretation might be useful to promptly distinguish NDI, even avoiding the WDT need.

Polyuric-polydipsic syndrome in a pediatric case of non-glucocorticoid remediable familial hyperaldosteronism.

Familial hyperaldosteronism (FH) encompasses 3 types of autosomal dominant hyperaldosteronisms leading to inheritable hypertension. FH type II (FH-II), undistinguishable from sporadic hyperaldosteronism, represents the most frequent cause of inheritable hypertension and is believed to only manifest in adults. FH-III is a severe variety of PA resistant to pharmacotherapy and recently demonstrated to be caused by mutations in the gene encoding the potassium channel KCNJ5. In this report, we describe a FH pediatric patient, remarkable both for age at onset and unusual presentation: a two-years old girl with polyuric-polydipsic syndrome and severe hypertension, successfully treated with canrenone and amiloride. The girl had severe hypertension, hypokalemia, hypercalciuria, suppressed renin activity, high aldosterone, and unremarkable adrenal imaging. FH type I was ruled out by glucocorticoid suppression test, PCR test for CYP11B1/CYP11B2 gene, and urinary 18-oxo-cortisol and 18-hydroxy-cortisol excretion, which was in FH-II range. In spite of a clear-cut FH-II phenotype, the girl and her mother were found to harbor a FH-III genotype with KCNJ5 mutation (c.452G>A). Treatment with canrenone was started, resulting in prompt normalization of electrolytes and remission of polyuric-polydypsic syndrome. The addition of amiloride led to a complete normalization of blood pressure. This report expands the phenotypic spectrum of FH-III to a milder end, mimiking FH-II phenotype demonstrating that pharmacotherapy may be effective. This also implies that FH-II/III should be considered in the differential diagnosis of hypertensive children and, perhaps, that the offspring of patients with hyperaldosteronism should be screened for hypertension.

Central precocious puberty: treatment with triptorelin 11.25 mg.

BACKGROUND: Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). AIM: To assess the efficacy of triptorelin 11.25 mg in children with CPP. PATIENTS: 17 patients (16 females) with CPP (7.9 ± 0.9 years) were treated with triptorelin 11.25 mg/90 days. METHODS: Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7 ± 16.5 IU/L at baseline to 0.9 ± 0.5 IU/L at M3 (P < 0.0001); they did not significantly changed at M6 and M12. CONCLUSIONS: Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Genetic Testing for a Patient with Suspected 3 Beta-Hydroxysteroid Dehydrogenase Deficiency: A Case of Unreported Genetic Variants.

3beta-hydroxysteroid dehydrogenase type II deficiency (HSD3B2 deficiency), a rare form of congenital adrenal hyperplasia (CAH), is characterized by varying degrees of salt loss and incomplete masculinization in males and mild virilization or normal external genitalia in females. We report the case of a patient (46XY) showing salt loss and incomplete masculinization, markedly elevated levels of 17OHP (17 hydroxyprogesterone), ACTH (Adreno Cortico Tropic Hormone), testosterone and delta4androstenedione (delta4A), low levels of cortisol and absence of bone skeletal alterations that frequently characterize POR (Cytochrome P450 oxidoreductase) deficiency. Mutation analysis by Sanger sequencing of the HSD3B2 gene showed that the patient presented with a compound heterozygote for two novel variants c.370A>G p.Ser124Gly and c.308-6 G>A. The two HSD3B2 gene variants were also present in the patient's older brother showing only incomplete masculinization. The in silico analysis revealed a probable damaging effect of c.370A>G p.Ser124Gly: residue p.Ser124 is highly conserved among species and seems to be located in the catalytic site of the enzyme, playing a pivotal role in NAD(H) binding to its substrate. Intronic c.308-6G>A variant is predicted to be likely pathogenic; the substitution seems to cause a change in the splice acceptor site located 6bp downstream of the variant. The two siblings seem to be affected by 3ß-HSD2 deficiency; nevertheless, the two novel variants are likely to cause variable expressivity of the disease.

Continuous subcutaneous hydrocortisone infusion (CSHI) in a young adolescent with congenital adrenal hyperplasia (CAH).

Congenital adrenal hyperplasia (CAH) is an autosomal recessive enzymatic defect caused by mutations or deletions of the cytochrome P450 21-hydroxylase CYP21 gene. Oral therapy with glucocorticoids and mineralcorticoids is administered to prevent adrenal crisis and to control hyperandrogenism. During puberty this type of therapy is difficult to manage owing to physiological and hormonal changes and poor compliance. We describe a case of a pubertal boy affected by CAH, in whom continuous subcutaneous infusion of hydrocortisone led to improved metabolic control and compliance.

Incidence of primary congenital hypothyroidism and relationship between diagnostic categories and associated malformations.

PURPOSE: The incidence of primary congenital hypothyroidism (CH) has grown progressively and literature data indicate an association between CH and congenital malformations. The purpose of this study is to establish the current incidence of CH in the Italian Region of Piedmont and verify the relationship between CH diagnostic categories and associated malformations. METHODS: The biochemical and clinical data of 105 newborns with CH diagnosed in the period January 2014 to December 2019 were analyzed. RESULTS: The incidence of CH in the Italian Piedmont region in the 2014-2019 period increased to 1:1090. Thyroid dysgenesis was responsible for 47.6% (50/105) of all cases, with agenesis in 14.3% (15/105), while ectopia and hypoplasia in 23.8% (25/105) and 9.5% (10/105) of the cases, respectively; dyshormonogenesis defects were found in 52.4% (55/105) of cases. Congenital extra-thyroid anomalies were identified in 33/105 (31.4%) of newborns with CH and mainly involve the cardiac system (17/85, 16.1%), urogenital tract (7/85, 6.7%), gastrointestinal tract (5/105, 4.8%), and the musculoskeletal system (5/105, 4.8%). The highest rate of malformations was observed in patients with thyroid agenesis and dyshormonogenesis, respectively, in 53.5% and 36.4% of cases, while in the presence of thyroid ectopia and hypoplasia, the rate was 12% and 20%, respectively, (p = 0.03). CONCLUSION: In the Italian region of Piedmont, the incidence of primary CH has been increased over time, with a variation in the percentage of the different forms of CH. Congenital malformations, especially affecting the cardiovascular, urogenital, gastrointestinal, and musculoskeletal systems, seem to be mainly associated with thyroid agenesis or defects in hormonogenesis.

Growth in Children With Noonan Syndrome and Effects of Growth Hormone Treatment on Adult Height.

Objectives: Growth impairment is a common manifestation in Noonan syndrome (NS). Recombinant human GH (rhGH) treatment has been shown to increase growth and adult height (AH) in a few studies. We aimed to evaluate the growth trajectory towards the AH, and the effects of rhGH treatment in a large cohort of NS children. Methods: Retrospective, multicenter, cohort study including subjects with genetic diagnosis of NS. A total of 228 NS patients, 154 with PTPN11 mutations, 94 who reached AH, were recruited. Auxological data were collected at 2, 5, and 10 years, at pubertal onset, at AH. Sixty-eight NS subjects affected with GH deficiency (GHD) were treated with rhGH at a mean dose of 0.24 mg/kg per week until AH achievement. Results: ANOVA analysis showed a significant difference between birth length and height standard deviation scores (HSDS) at the different key ages (p<0.001), while no significant differences were found between HSDS measurements at 2, 5, and 10 years, at pubertal onset, and at AH. HSDS increased from -3.10 ± 0.84 to -2.31 ± 0.99 during rhGH treatment, with a total height gain of 0.79 ± 0.74, and no significant difference between untreated and treated NS at AH. Conclusions: rhGH treatment at the standard dose used for children with GH idiopathic deficiency is effective in improving growth and AH in NS with GHD. Further studies are needed to assess genotype-specific response to rhGH treatment in the different pathogenic variants of PTPN11 gene and in the less common genotypes.

International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry.

OBJECTIVE: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. DESIGN: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. METHODS: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. RESULTS: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m2/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m2/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. CONCLUSIONS: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.

BACKGROUND: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. METHODS: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. RESULTS: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively. CONCLUSIONS: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.

Teriparatide (rhPTH 1-34) treatment in the pediatric age: long-term efficacy and safety data in a cohort with genetic hypoparathyroidism.

BACKGROUND: Hypoparathyroidism is characterized by the absence or inadequately low circulating concentrations of the parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia, and elevated fractional excretion of calcium in the urine. The use of activated vitamin D analogs and calcium supplements represent conventional therapy. Subcutaneous recombinant human parathormone [rhPTH(1-34)] has been proposed as a substitutive treatment, even to avoid side effects of vitamin D and calcium. OBJECTIVE: To assess the long-term safety and efficacy of rhPTH(1-34) in a pediatric cohort of patients with genetic hypoparathyroidism. METHODS: The study is a 9.2-year self-controlled study of six pediatric patients (four males and two females, aged 9.4 ± 5.2) with DiGeorge, hypoparathyroidism-deafness-renal dysplasia (HDR) or autoimmune-candidiasis-polyendocrinopathy-ectodermal-dysplasia (APECED) syndrome, associated with autoimmune intestinal malabsorption in a patient. The presence of clinical signs of hypocalcemia and biochemical parameters, such as calcium, phosphate, alkaline phosphatase in the blood and calcium-creatinine ratio in urine, were compared during conventional treatment and rhPTH(1-34) (teriparatide, 12.5 µg twice daily). RESULTS: The rhPTH(1-34) treatment allowed a reduction, although not always a complete suspension, of calcium supplementation and a slight reduction of calcitriol therapy. The number of tetanic episodes was reduced in four patients during the rhPTH(1-34) treatment. Mean blood calcium, alkaline phosphatase, and phosphate did not significantly change, while a significant reduction of the urinary calcium-to-creatinine ratio (0.55 ± 0.32 vs 0.16 ± 0.09, p = 0.03) was obtained. Renal ultrasound examination showed a worsening in three patients, while it did not change in the remaining three subjects during the follow-up. CONCLUSIONS: In children with syndromic hypoparathyroidism presented here, replacement therapy with rhPTH(1-34) allowed to maintain adequate levels of the calcium and phosphate in the blood, normalize urinary calcium excretion, and reduce tetanic episodes. In patients with low compliance to conventional therapy or intestinal malabsorption, the use of rhPTH(1-34) could be considered, also to reduce the side effects of treatment with vitamin D and calcium.

Growth Trajectory and Adult Height in Children with Nonclassical Congenital Adrenal Hyperplasia.

BACKGROUND: Children with nonclassical congenital adrenal hyperplasia (NCCAH) often present increased growth velocity secondary to elevation of adrenal androgens that accelerates bone maturation and might compromise adult height (AH). OBJECTIVE: The aim of the study was to analyze prognostic factors affecting growth trajectory (GT) and AH in children with NCCAH. METHODS: The study was a retrospective, multicentric study. The study population consisted of 192 children with a confirmed molecular diagnosis of NCCAH, followed by pediatric endocrinology centers from diagnosis up to AH. Clinical records were collected and analyzed. AH (standard deviation score; SDS), pubertal growth (PG) (cm), GT from diagnosis to AH (SDS), and AH adjusted to target height (TH) (AH-TH SDS) were evaluated as outcome indicators using stepwise linear regression models. RESULTS: The stepwise linear regression analysis showed that AH and AH-TH were significantly related to chronological age (CA) (p = 0.008 and 0.016), bone age (BA)/CA ratio (p = 0.004 and 0.001), height (H) (p < 0.001 for both parameters) at NCCAH diagnosis, and TH (p = 0.013 and <0.001). PG was higher in males than in females (22.59 ± 5.74 vs. 20.72 ± 17.4 cm, p = 0.002), as physiologically observed, and was positively related to height (p = 0.027), negatively to BMI (p = 0.001) and BA/CA ratio (p = 0.001) at NCCAH diagnosis. Gender, genotype, biochemical data, and hydrocortisone treatment did not significantly impair height outcomes of these NCCAH children. CONCLUSIONS: The results of this study suggest that AH and GT of NCCAH patients are mainly affected by the severity of phenotype (CA, BA/CA ratio, and H) at the time of diagnosis.

Severe arterial hypertension and hyperandrogenism in a boy: a rare case of catecholamine- and ß-HCG-secreting pheochromocytoma.

Background Pheochromocytomas (PCCs) and paragangliomas (PGLs) are known to physicians as the "great mimickers" because of their variable presentation, especially in the pediatric population. Rarely, they co-secrete other hormones. Case presentation An 11-year-old boy presented with severe hypertension (HTN) with cardiac target organ damage. Signs of genital and cutaneous androgenization were observed, but the gonadal volume was prepubertal (2 mL). Urine normetanephrine and norepinephrine levels were elevated. Increased beta-human chorionic gonadotropin (ß-HCG) and pubertal testosterone values with suppressed values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) suggested an androgenization secondary to HCG hyperproduction. Imaging revealed a right adrenal mass, suggestive for PCC. Histopathology confirmed a PCC with positive staining for ß-HCG. Postoperative resolution of symptoms of ß-HCG and catecholamine excess and normalization of hormonal levels confirmed the diagnosis. Conclusions Ectopic hormone secretion from PCC is possible, even if rare. Signs and symptoms attributable to ectopic hormones should be investigated in PCC patients. To date, this is the first case of a ß-HCG-secreting PCC.

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: A 4-week course of high-dose glucocorticoids may cause prolonged adrenal suppression even after a 9-day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high-dose prednisone (PDN) or dexamethasone (DXM). PROCEDURES: Sixty-four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD-ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1-2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. RESULTS: All patients had normal basal cortisol values at diagnosis. Twenty-four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD-ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7-14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. CONCLUSIONS: High-dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated.

Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.

CONTEXT: Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure. OBJECTIVE: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY disorders of sex development) with normal adrenal function. METHODS AND PATIENTS: The study included mutational analysis of NR5A1 in 30 individuals with 46,XY disorders of sex development, followed by functional studies of SF1 activity. RESULTS: Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered subnuclear localization (V15M, M78I), or disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change. CONCLUSIONS: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals.

Tolvaptan Treatment in Children with Chronic Hyponatremia due to Inappropriate Antidiuretic Hormone Secretion: A Report of Three Cases

Hyponatremia is the most common electrolyte disorder among hospitalized patients and it is sometimes considered as a poor outcome predictor. Its correction is thus indicated, even in asymptomatic patients. The conventional treatment consists of fluid restriction in presence of euvolemia or hypervolemia; loop diuretics are used in some hypervolemic conditions such as cardiac heart failure, liver cirrhosis and nephrotic syndrome, while intravenous isotonic or hypertonic solutions are administered in hypovolemic conditions. The utilization of demeclocycline and urea is not indicated in pediatric ages due to lack of data on their toxicity and poor tolerance. Recently, a new therapeutic option has been developed, a class of non-peptide arginine vasopressin receptor antagonists called vaptans. Tolvaptan is the only such agent approved in Europe for the treatment of hyponatremia caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH) in adults. In USA, tolvaptan and conivaptan have been approved for treatment of euvolemic and hypervolemic hyponatremia. Few data are so far available in paediatric patients, since only one trial has been registered in Europe which includes children and adolescents, but this trial is still ongoing. Here, we report three children with chronic hyponatremia due to SIADH in which tolvaptan has been used successfully.

Compound heterozygosity for two GHR missense mutations in a patient affected by Laron Syndrome: a case report.

BACKGROUND: Mutations localized in the Growth Hormone Receptor (GHR) gene are often associated with the pathogenesis of Laron Syndrome, an autosomal recessive hereditary disorder characterized by severe growth retardation. Biochemically, patients present normal to high circulating GH levels, in presence of very low or undetectable IGF-I levels, which do not rise after rhGH treatment. CASE PRESENTATION: We describe the case of a 3.8 years old girl with symmetrical short stature (-3.76 SDS), low IGF-1 and IGFBP-3, in presence of normal GH levels. Parents were not relatives and there was no family history of short stature. During the second day of birth, she developed severe hypoglycaemia that required glucose infusion. She presented frontal bossing and depressed nasal bridge. IGF-1 generation test showed no response, suggesting a GH resistance evidence. In the hypothesis of Laron Syndrome, we decided to perform a molecular analysis of Growth Hormone Receptor (GHR) gene. This analysis demonstrated that the patient was compound heterozygote for two missense mutations. CONCLUSIONS: GHR gene mutations are a well demonstrated cause of GH insensitivity. In heterozygous patients, probably the normal stature may be achieved by a compensatory mechanism of GH secretion or signalling. On the contrary, in homozygous or compound heterozygous patients these compensatory mechanisms are inadequate, and short stature may be the consequence.

Elucidating the underlying molecular pathogenesis of NR3C2 mutants causing autosomal dominant pseudohypoaldosteronism type 1.

CONTEXT: Pseudohypoaldosteronism type 1 (PHA1) is a rare salt-wasting syndrome. Mutations in the NR3C2 gene coding for the mineralocorticoid receptor (MR) cause autosomal dominant PHA1. OBJECTIVE: Our objective was to reveal the cause of renal salt loss in six PHA1 patients and analyze the mutants' functional impact on MR function. DESIGN: Our study included the following: clinical and hormonal characterization of the patients' phenotype, analysis of the NR3C2 gene, determination of receptor affinities to aldosterone and the transcriptional activation abilities of the MR mutants, investigation of subcellular translocation using fluorescence-labeled MR, and studying changes in mutant receptor conformation with proteolysis experiments and three-dimensional modeling. RESULTS: Six heterozygous NR3C2 mutations were detected. One frameshift mutation (c.1131dupT) has been reported previously. The second frameshift mutation (c.2871dupC), which has only recently been reported by our group, showed no aldosterone binding and no transactivation because of a major change in receptor conformation. Two novel nonsense mutations generate a truncated receptor protein. Two missense mutations differently affect MR function. S818L was reported recently without complete in vitro data. S818L does not bind aldosterone or activate transcription or translocate into the nucleus. A major displacement of several residues involved in aldosterone binding was PHA1 causing. The novel E972G mutation showed a significantly lower ligand-binding affinity and only 9% of wild-type transcriptional activity caused by major changes in receptor conformation. CONCLUSIONS: Our data on six mutations extend the spectrum of PHA1-causing NR3C2 gene mutations. Studying naturally occurring mutants helps to clarify their pathogenicity and to identify crucial residues for MR structure and function.

Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure.

CONTEXT: Premature ovarian failure (POF) is a cause of female infertility characterized by primary (PA) or secondary amenorrhea (SA) and elevated gonadotropins. The pathogenesis is unknown in most cases. We recently reported two sisters with PA carrying a heterozygous mutation of BMP15 gene (locus Xp11.2), but the prevalence of BMP15 variations in the POF population is unknown. OBJECTIVE: The objective of the study was to verify the involvement of BMP15 variations in a large POF population. DESIGN AND SUBJECTS: Genetic screening of 166 unrelated patients with idiopathic POF (25 PA, 141 SA) and controls (group A: 95 women with menopause beyond 50 yr of age; group B: 86 women and 30 men from the general population) of Caucasian origin. RESULTS: Investigation revealed four heterozygous variations affecting the proregion of BMP15. The previously reported p.Y235C mutation occurred in one and three novel variants in eight patients: two missense alterations (p.R68W in one case, p.A180T in five) and one insertion (p.262insLeu) in two cases. The p.262insLeu was found in five controls of group A, thus diminishing its potential biological impact, whereas the other three variants were not present in any of the controls. All new mutations were found in SA cases. CONCLUSION: We describe the significant association of heterozygous BMP15 gene variants with the POF phenotype in humans (seven of 166 patients: 4.2%; P < 0.003 vs. controls). These findings are consistent with the critical role played by BMP15 in human folliculogenesis.

McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age.

Gonadal hyperfunction is the most frequent endocrine dysfunction in females with McCune-Albright syndrome (MAS). Peripheral precocious puberty is usually the first MAS manifestation in children, characterized by episodes of hypersecretion of estrogens with a consequent reduction in gonadotropin secretion. Little is known about the course of this endocrine disease in adolescence and during young adult life. The aim of this study was to evaluate ovarian function in 10 females with MAS (age 11.4-20.1 years) to detect the persistence of autonomous ovarian hyperfunction throughout and following adolescence, after at least 1 year wash out of any treatment for precocious puberty. LH, FSH, estradiol, prolactin, androgen secretion, ovarian and breast sonography in luteal and follicular phases of some menstrual cycles were evaluated. We demonstrated the persistence of some ovarian autonomy, documented by hyperestrogenism and/or low or absent gonadotropin secretion and/or ovarian cysts.