Successful treatment with MEK-inhibitor in a patient with NRAS-related cutaneous skeletal hypophosphatemia syndrome.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic NRAS variants and characterized by melanocytic/sebaceous naevi, eye, and brain malformations, and FGF23-mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS/MAPK pathway, is a candidate for CSHS therapy. A 4-year-old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A > G;p.(Gln61Arg) somatic NRAS variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15 months investigating the transcriptional effects at different time points by whole blood RNA-seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch-up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS/MAPK, PI3 kinase, WNT and YAP/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified "core" genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action.

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.

Growth hormone-Insulin-like growth factor 1 axis hyperactivity on bone fibrous dysplasia in McCune-Albright Syndrome.

CONTEXT: In fibrous dysplasia (BFD), normal bone and bone marrow are replaced by fibro-osseous tissue, leading to fracture, deformity and pain. BFD may be isolated, or in association with cutaneous hyperpigmentation and/or hyperfunctioning endocrinopathies, termed McCune-Albright syndrome (MAS). GH hypersecretion has been described in 10%-20% of MAS-BFD patients. Aim of the study was to determine the impact of GH-insulin like growth factor 1 (IGF1) axis hyperactivity on MAS-BFD morbidities and the efficacy of GH excess therapy. DESIGN AND PATIENTS: A multicentric cross-sectional analysis was conducted on three different MAS cohorts. From 195 MAS patients, 37 subjects (19%) with GH excess were identified and compared with 34 MAS controls without GH hypersecretion. RESULTS: Mean head circumference SDS was significantly higher in GH excess: 4.025 SDS vs 0.683 SDS (P < .0001). The risk of optic neuropathy (Odds ratio 4.231; P = .039), hearing deficit (Odds ratio 2.961; P = .0481), facial asymmetry (Odds ratio 6.563; P = .0192), malignancies (Odds ratio 15.24; P = .0173) were higher in GH excess group. Overall, pharmacotherapy (octreotide alone 10-30 mg/mo or with pegvisomant 10-20 mg/d) was effective in IGF1 normalization (IGF1 Z-score between -2 and +2 SDS) in 21/29 patients (72.4%) with good compliance to the regimen. Late diagnosis and GH excess treatment after 16 years old of age was associated with an increased risk of optic neuropathy (Odds ratio 4.500; P = .0491) and growth of pituitary adenomas (Odds ratio 7.846; P = .050). CONCLUSIONS: GH-IGF1 hyperactivity increases risk of morbidities in MAS. Medical therapy is effective in normalizing IGF1 in most patients, and early treatment during paediatric age is associated with a decreased risk of optic neuropathy and GH-secreting adenomas growth.

Oral Health-Related Quality of Life in Italian Children and Adolescents Living with Bone Dysplasia: A Cross-Sectional Study.

Bone dysplasia (BD) refers to a group of rare disorders characterized by skeletal and dental anomalies which may negatively influence oral health-related quality of life (OHRQoL). The aim of this cross-sectional study was to assess the impact of BD on OHRQoL in Italian children and adolescents and to assess whether gender and age influence their OHRQoL. A total of 40 patients with BD and 40 age- and gender-matched controls (aged 8-14 years) were asked to complete the Oral Health Impact Profile-14 (OHIP-14), Child Oral Health Impact Profile (COHIP), and the short form of the Child Perceptions Questionnaire (SF-CPQ). Children with BD showed statistically significant lower overall scores of all the questionnaires than the controls (all p < 0.001), with the largest differences being detected in overall symptoms, functional well-being, and social well-being domains. While no statistically significant gender-related differences were observed, adolescents aged 11-14 years experienced worse perception in the emotional and social well-being SSF-CPQ domains (p = 0.042 and p = 0.045, respectively) and in the peer interaction COHIP domain (p = 0.011) compared to the younger age group. Based on these findings, children suffering from BD experience poorer OHRQoL than their healthy peers, suggesting that oral and dental issues may be of special importance for the socio-psychological well-being of these growing individuals.

Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia.

OBJECTIVE: The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants. DESIGN AND METHODS: To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs. RESULTS: Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT. CONCLUSIONS: This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.

Perinatal asphyxia and hypothermic treatment from the endocrine perspective.

Introduction: Perinatal asphyxia is one of the three most important causes of neonatal mortality and morbidity. Therapeutic hypothermia represents the standard treatment for infants with moderate-severe perinatal asphyxia, resulting in reduction in the mortality and major neurodevelopmental disability. So far, data in the literature focusing on the endocrine aspects of both asphyxia and hypothermia treatment at birth are scanty, and many aspects are still debated. Aim of this narrative review is to summarize the current knowledge regarding the short- and long-term effects of perinatal asphyxia and of hypothermia treatment on the endocrine system, thus providing suggestions for improving the management of asphyxiated children. Results: Involvement of the endocrine system (especially glucose and electrolyte disturbances, adrenal hemorrhage, non-thyroidal illness syndrome) can occur in a variable percentage of subjects with perinatal asphyxia, potentially affecting mortality as well as neurological outcome. Hypothermia may also affect endocrine homeostasis, leading to a decreased incidence of hypocalcemia and an increased risk of dilutional hyponatremia and hypercalcemia. Conclusions: Metabolic abnormalities in the context of perinatal asphyxia are important modifiable factors that may be associated with a worse outcome. Therefore, clinicians should be aware of the possible occurrence of endocrine complication, in order to establish appropriate screening protocols and allow timely treatment.

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.

Combined treatment with bicalutamide and anastrozole in a young boy with peripheral precocious puberty due to McCune-Albright Syndrome.

McCune-Albright Syndrome (MAS) is a congenital endocrine disorder due to mosaic tissutal hyper-function. We describe a boy with a molecularly confirmed MAS, clinically evident with congenital café-au-lait spots, bone fibrous dysplasia, hyperthyroidism, and renal phosphate wasting syndrome. At 4.6 years of age he disclosed a rapid progression of peripheral puberty, so we decided to treat him with bicalutamide 25 mg/day and anastrozole 1 mg/day. Combined third generation aromatase inhibitors - competitive androgen receptor blockers were employed in familial male precocious puberty (FMPP). Combined treatment was performed for 49 months from the age of 4.6 to 6.7 years. The patient underwent clinical, laboratory, and instrumental evaluation twice a year from the first admission to the current age. This treatment caused a rapid normalization of growth velocity, subsequent reduction of penile androgenization, and stabilization of testicular volume. The therapy was well tolerated for all its duration and neither side effects, nor secondary hypothalamic activation were noted. This report provides further evidence of effectiveness and safety of combined third generation aromatase inhibitors - competitive androgen receptor blockers in male precocious peripheral puberty, firstly employed in male MAS, and contributes to expand the spectrum of disorders in which their employment may reveal promising.

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.

Papillary thyroid microcarcinoma in a boy with Graves' disease: a case report and review of the literature.

A 16-years old boy with diagnosis of Grave's disease was treated with methimazole for one year before radical total thyroidectomy treatment due to persistence of clinical hormonal hyperthyroidism. Histological analysis revealed the presence of a papillary microcarcinoma. The management of Grave's disease in pediatric age is still under discussion. Therefore, close monitoring of the disease is required, as well as case-by-case tailored decision on how to manage treatment and when to perform the radical one, taking into account the association of Grave's disease with differentiated thyroid cancer in adults and the higher malignancy of thyroid cancer in childhood.

Surgical enucleation of testicular leydigioma in a young child: case report and literature review.

BACKGROUND: The leydigioma is the most frequent interstitial neoplasm of the testis. Clinical symptoms of all leydigioma usually are isosexual precocious pseudo-puberty due to autonomous testosterone overproduction, suppressed gonadotropin levels and a testis mass. Nowadays its therapy is debated. DESIGN AND METHODS: We report a case of a young child treated in 2008 for a leydigioma of the testis with atypical clinical behavior. Testicular oncologic markers and hormonal profile were assessed. RESULTS: The patient was treated successfully with organ-confined surgery. CONCLUSION: We want to confirm the safety of conservative surgery against radical orchiectomy and review the literature of the last decade on this debated matter.

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.

Cushing syndrome due to ectopic adrenocorticotropic hormone secretion in a 3-year-old child.

Ectopic adrenocorticotrophic hormone (ACTH) secretion is a rare cause of Cushing syndrome in paediatric age, due to tumours arising from different tissues. To date, only 11 reports of ACTH-secreting pancreatic tumours in children and adolescents exist in the literature. We present a paediatric case of Cushing syndrome caused by ectopic ACTH secretion. This was caused by a large acinar cell carcinoma that developed in the pancreas of a 3-year-old girl.

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.

"Primary Hyperparathyroidism (PHPT) in Children: Two Case Reports and Review of the Literature".

Primary hyperparathyroidism (PHPT) is a rare disorder in children and adolescents. Typical biochemical features are hypercalcemia and hypophosphatemia, but the clinical features can be heterogeneous, and in some cases, symptoms are vague and nonspecific, leading to misdiagnosis or late diagnosis. Herein, we report two cases of PHPT in pediatric age with different presenting symptoms, pain in the foot, and progressive alteration of the gait in the first case and recurrent abdominal pain with emotional lability in the second. Biochemical and radiological assessment confirmed PHPT. Both cases were treated surgically as definitive treatment, but in the second case, previous medical treatment with cinacalcet, a calcimimetic agent, was required to reduce serum PTH and calcium levels. After surgery, despite conventional treatment with calcium and calcitriol, case 1 developed a hungry bone syndrome. The analysis of the MEN-1 (Multiple Endocrine Neoplasia) gene was negative in both cases. A diagnosis of PHPT should be considered when children or adolescents present bone pain with radiological imaging of osteolytic lesion and biochemical feature of hypercalcemia associated with hypophosphatemia. In PHPT, the gold standard treatment is represented by surgery followed by strict postoperative endocrine monitoring to maintain adequate homeostasis of calcium and bone metabolism.

Multidisciplinary Approach for Hypothalamic Obesity in Children and Adolescents: A Preliminary Study.

Hypothalamic obesity (HO) is delineated by an inexorable weight gain in subjects with hypothalamic disorder (congenital or acquired). The aim of the present study was to evaluate the effect of a multidisciplinary approach on weight trend and metabolic outcome in children and adolescents with hypothalamic disease who were overweight or obese. Thirteen patients (aged 8.1-16.1 years) received a personalized diet, accelerometer-based activity monitoring, and psychological assessment. Height, weight, body mass index (BMI), and serum metabolic parameters were assessed at baseline (T0) and after six months (T1). Metformin was introduced at T1 in four subjects who were then re-evaluated after six months (T2). At T1, weight gain was significantly reduced compared with T0 (0.29 ± 0.79 kg/month vs. 0.84 ± 0.55 kg/month, p = 0.03), and weight standard deviation score (SDS) and BMI SDS did not change significantly, as serum metabolic parameters. The four subjects treated with metformin showed a reduction of weight SDS and BMI SDS at T2. In conclusion, patients treated with our multidisciplinary approach showed, after 6 months, favorable results characterized by decreased weight gain and stabilization of weight SDS and BMI SDS in a condition usually characterized by inexorable weight gain. However, further analysis, larger cohorts, and longer follow-up are needed to confirm these preliminary data.

Pseudohypoparathyroidism: application of the Italian common healthcare-pathway for a homogeneous clinical approach and a shared follow up.

BACKGROUND: Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies. METHODS: Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice. RESULTS: In addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism. CONCLUSIONS: The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.

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.