Central precocious puberty in a 3 year-old girl with Phenylketonuria: a rare association?

Background Central precocious puberty (CPP) and phenylketonuria (PKU) are two rare conditions, the latter being the rarer. To date, only one case featuring both these conditions has been reported, and hyperphenylalaninemia was assumed triggering CPP. Case presentation We present a 3.2 years old girl referred with a 12 months history of breast and pubic hair development, and vaginal discharge. Hyperphenylalaninemia had been identified by newborn screening and PKU subsequently confirmed by plasma amino acid and genetic analysis. Early dietary control of plasma phenylalanine had been excellent afterwards, resulting in phenylalanine concentrations consistently within the recommended range. Clinical scenario, hormonal assessment and imaging were in keeping with true idiopathic central precocious puberty. Treatment with long lasting gonadotropin-releasing hormone analogue led to regression of secondary sexual characteristics. Conclusion We describe for the first time CPP in a girl affected with PKU but with persistently well controlled blood phenylalanine concentrations. This finding is in contrast to a previous report which suggested persistently high phenylalaninemia levels as potential trigger for CPP in PKU patients. Our report, together with the lack of evidence in published cohort studies of children with PKU, strongly suggests this rare association is coincidental and independent of the presence of severe hyperphenylalaninemia.</p

The measurement of urinary gonadotropins for assessment and management of pubertal disorder

OBJECTIVE: Measurement of urinary LH (uLH) and FSH (uFSH) may facilitate non-invasive pubertal assessment but there is a need for further validation by studying children and adolescents with disorders of puberty. DESIGN: 65 cases (Male: 25) with a median age of 12 years (2.9-18.1) supplied at least one non-timed urine sample for uLH and uFSH measurement by immunoassay and corrected for creatinine excretion. 25 cases were receiving GnRH-agonist (GnRH-a) at the time of sample collection. In 41 cases, urine samples were collected prior to a LH RH test and in 12 cases matched serum samples for basal LH (sLH) and FSH (sFSH) were also available. RESULTS: There was a significant correlation between sLH and uLH: uCr (r=0.82; p-value &lt;0.001) and sFSH and uFSH: uCr (r=0.93; p-value &lt;0.001). Based on receiver operator characteristics analysis, a uLH : uCr value of 0.05 IU/mmol as a cut-off would detect a LH peak &gt;5U I/L with a sensitivity of 86% and a specificity of 72% with a positive predictive value of 93%. In pubertal boys (6) and girls (22) with a sLH peak &gt;5UI/L, median uLH: uCr was 0.27 IU/mmol (0.27-0.28) and 0.17 IU/mmol (0.09-0.43), respectively. The median uFSH: uCr was 0.51 IU/mmol (0.41-0.60) for boys and 1.1 IU/mmol (0.21-2.44) for girls. In the 25 cases on GnRH-a, the median uLH : uCr for boys and girls was 0.02 IU/mmol (0.01-0.02) and 0.02 IU/mmol (0.004-0.07), respectively, and the median uFSH: uCr was 0.07 IU/mmol (0.05-0.09) and 0.27 IU/mmol (0.09-0.54), respectively. CONCLUSION: Urinary gonadotrophins reflect serum gonadotrophin concentration and may represent a reliable non-invasive method of assessing pubertal progress

Cancer risks in patients treated with growth hormone in childhood: the SAGhE European cohort study.

Context: Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited. Objective: To examine cancer risks in relation to GH treatment. Design: Cohort study. Setting: Population-based. Patients: Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics. Main Outcome Measures: Cancer incidence and cancer mortality. Results: Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer). Conclusions: Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation

Diabetes mellitus related to Williams syndrome: first report of childhood onset

Introduction: Williams syndrome (WS) is a multi-systemic disorder caused by a deletion in the region 7q11.23. Childhood endocrine follow-up is mainly aimed to monitor hypercalcemia and thyroid function. A high prevalence (63\u201371%) of impaired glucose tolerance (IGT) and diabetes mellitus (DM) in young adults with WS is reported. WS guidelines recommend Oral Glucose Tolerance Test (OGTT) starting from 30 years of age. We demonstrate evidence of IGT and DM in WS at a much earlier age. Case report: A 15.6 years old WS female presented with history of polyuria and polydipsia. She was never overweight and initially presented with glycosuria, moderate ketonuria and hyperglycaemia without acidosis, during a gastroenteritis at the age of 4.2. Subsequently diabetic ketoacidosis appeared, insulin was started but shortly stopped for persistent hypoglycaemia. Subsequent glucose monitoring was normal and remained off insulin. At the age of 10 nocturnal polyuria became evident. Glycosuria, without ketosis or hyperglycaemia, was confirmed and classified as \u2018renal glycosuria\u2019 due to WS renal impairment. Recent investigations confirmed glycosuria without ketonuria, and raised HbA1c (51 mmol/mol). OGTT confirmed DM (T0=7.8 mmol/l; T120=15.3 mmol/l). Insulin assessment was not available, C-peptide secretion was impaired (T0=<0.1mmol/l; peak T60=0.32 nmol/l). Autoimmunity is still pending. Type 2 like DM with \u3b2-cells impairment was considered most probable and diet modifications and Metformin treatment were started, improving glucose metabolism. Conclusions: We describe the youngest patient with DM associated with WS. Main hypothesis for the underling etiopathogenesis suggest hyperinsulinism secondary to insulin sensitivity reduction linked to genes involved in deletion. Lack of studies in childhood raises the issue about the timing of onset of DM. It is possible that hyperinsulinism could be present for many years before IGT. Our finding demonstrates for the first time the need for studies aimed to assess the prevalence of glucose metabolism abnormalities in WS during childhood with appropriate intervention

Urinary gonadotrophins: role in assessment and management of disorders of puberty

Introduction: With improvements in assays and the increasing need for non-invasive, out-patient based investigations, there is a renewed interest in the use of urinary gonadotrophins (UG) for assessing pubertal progress. This study aims to establish the correlation between serum and urinary LH and FSH in patients undergoing investigation or management of pubertal disorders. Methods/design: Retrospective evaluation of eight patients undergoing investigation for pubertal delay (five males and three females) and 21 patients (six males and 15 females) for early puberty or suppression of puberty by GnRH agonist (GnRH-a) therapy. Median ages (range) for the boys and girls were 14.4 years (8.9–17.2) and 9.2 years (4.2–17.3), respectively. Non-timed spot urine samples were collected for all cases and 11 (five males and six females) of these were on GnRH-a. Of the 29 cases, matched serum gonadotrophins were available in 15 cases (seven males and eight females). UG were measured by chemiluminescent microparticle immunoassay and corrected for urinary creatinine. Results: In both pubertal males and females, UG were significantly higher than during-GnRH-a treatment: For the 15 cases with matched serum and urine samples, median serum LH and ULH:creat were 1.5 U/l (0.1–21.9) and 0.16 (0–1.37), respectively. There was a strong correlation between these values (r2, 0.92), independent of sex. Conclusion: These preliminary data suggest that UG reflect serum gonadotrophin concentrations and the finding of low UG in patients on GnRH-a therapy suggest that this test may represent a useful non-invasive method of assessing and monitoring effectiveness of GnRH-a therapy

Weight-bearing CT Technology in Musculoskeletal Pathologies of the Lower Limbs: Techniques, Initial Applications, and Preliminary Combinations with Gait-Analysis Measurements at the Istituto Ortopedico Rizzoli

Musculoskeletal radiology has been mostly limited by the option between imaging under load but in two dimensions (i.e., radiographs) and three-dimensional (3D) scans but in unloaded conditions (i.e., computed tomography [CT] and magnetic resonance imaging in a supine position). Cone-beam technology is now also a way to image the extremities with 3D and weight-bearing CT. This article discusses the initial experience over a few studies in progress at an orthopaedic center. The custom design of total ankle replacements, the patellofemoral alignment after medial ligament reconstruction, the overall architecture of the foot bones in the diabetic foot, and the radiographic assessment of the rearfoot after subtalar fusion for correction of severe flat foot have all taken advantage of the 3D and weight-bearing feature of relevant CT scans. To further support these novel assessments, techniques have been developed to obtain 3D models of the bones from the scans and to merge these with state-of-the-art gait analyses

Micropatterning of Substrates for the Culture of Cell Networks by Stencil-Assisted Additive Nanofabrication

The fabrication of in vitro neuronal cell networks where cells are chemically or electrically connected to form functional circuits with useful properties is of great interest. Standard cell culture substrates provide ensembles of cells that scarcely reproduce physiological structures since their spatial organization and connectivity cannot be controlled. Supersonic Cluster Beam Deposition (SCBD) has been used as an effective additive method for the large-scale fabrication of interfaces with extracellular matrix-mimicking surface nanotopography and reproducible morphological properties for cell culture. Due to the high collimation of SCBD, it is possible to exploit stencil masks for the fabrication of patterned films and reproduce features as small as tens of micrometers. Here, we present a protocol to fabricate micropatterned cell culture substrates based on the deposition of nanostructured cluster-assembled zirconia films by stencil-assisted SCBD. The effectiveness of this approach is demonstrated by the fabrication of micrometric patterns able to confine primary astrocytes. Calcium waves propagating in the astrocyte networks are shown

Isolated childhood growth hormone deficiency: a 30-year experience on final height and a new prediction model

Purpose We aimed to evaluate the near-final height (nFHt) in a large cohort of pediatricpatients with growth hormone deficiency (GHD) and to elaborate a new predictive method of nFHt. Methods We recruited GHD patients diagnosed between 1987 and 2014 and followed-up until nFHt. To predict the values of nFHt, each predictor was run in a univariable spline. Results We enrolled 1051 patients. Pre-treatment height was -2.43 SDS, lower than parental height (THt) (-1.09 SDS, p &lt; 0.001). The dose of recombinant human GH (rhGH) was 0.21mg/kg/week at start of treatment. nFHt was -1.08 SDS (height gain 1.27 SDS), higher than pre-treatment height (p &lt; 0.001) and comparable to THt. 1.6% of the patients were shorter than -2 SDS from THt. The rhGH dose at nFHt was 0.19 mg/kg/week, lower than at the start (p &lt; 0.001). The polynomial regression showed that nFHt was affected by gender, THt, age at puberty, height at puberty, age at the end of treatment (F = 325.37, p &lt; 0.0001, R-2 87.2%). Conclusion This large national study shows that GHD children can reach their THt. The rhGH/kg/day dose significantly decreased from the start to the end of the treatment. Our model suggests the importance of a timely diagnosis, possibly before puberty, the beneficial effect of long-term treatment with rhGH, and the key-role of THt. Our prediction model has a very acceptable error compared to the majority of other published studies

Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study.

BACKGROUND Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. METHODS This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). FINDINGS The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. INTERPRETATION In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. FUNDING European Union