Benign Intracranial Hypertension Due to Hypoparathyroidism: A Case Report.

Objective: The objective of this study is to present the rare case of a young girl with idiopathic intracranial hypertension secondary to hypoparathyroidism. Background: Idiopathic intracranial hypertension is a neurological syndrome characterized by elevated intracranial pressure (> 25 cmH2O) in the absence of intracerebral abnormalities or hydrocephalus. The pathophysiology of idiopathic intracranial hypertension is unknown, and rare cases of idiopathic intracranial hypertension secondary to hypoparathyroidism have been described. It is supposed that hypocalcemia causes decrease in the absorption of cerebrospinal fluid in arachnoidal granulations. Methods: The workup of the girl with idiopathic intracranial hypertension and hypoparathyroidism included physical examination, blood tests, diagnostic imaging, and lumbar puncture. Results: We present a 9-year-old female patient who was hospitalized for headache associated with nausea and vomiting for 3 weeks. She underwent an ophthalmologic examination that revealed papilledema. Lumbar puncture revealed an opening pressure of 65 cm H2O; cerebrospinal fluid analysis and brain computed tomography scan were normal. The patient started taking acetazolamide. Blood tests revealed hypocalcemia associated with high phosphorus level and undetectable PTH hormone, which led us to suspect hypoparathyroidism. She had never had cramps, paraesthesias, or tetany. Chvostek's and Trousseau's signs were positive. In the neck ultrasonography, parathyroids were not visible. Oral supplementation with calcitriol and calcium was started. Headache, nausea, and vomiting immediately disappeared after the lumbar puncture, and the papilledema improved gradually. Conclusions: Several anecdotal cases of idiopathic intracranial hypertension secondary to hypoparathyroidism have been described. However, our case report is of particular interest, since the child did not present with typical neurological hypoparathyroidism symptoms. Therefore, we recommend that hypoparathyroidism should be included in diagnostic investigations on children with clinical findings of idiopathic intracranial hypertension, because clinical manifestations of hypoparathyroidism are variable and may involve almost all organ systems.

Routine screening by brain magnetic resonance imaging is not indicated in every girl with onset of puberty between the ages of 6 and 8 years.

CONTEXT: It is still controversial whether all girls with central precocious puberty (CPP) should undergo brain magnetic resonance imaging (MRI) for unveiling intracranial pathology. OBJECTIVES: The objectives of the study were to determine the prevalence and type of intracranial lesions in otherwise normal girls with central precocious puberty (idiopathic CPP) and to identify the clinical and biochemical predictors of brain abnormalities. DESIGN AND SETTING: This was a retrospective study conducted at the Endocrine Unit of "Bambino Gesù" Children's Hospital (Rome, Italy) from 1990 to 2012. PATIENTS: One hundred eighty-two girls were consecutively diagnosed with CPP. All girls underwent a thorough endocrine assessment and brain MRI with a detailed examination of the hypothalamic-pituitary area. None of them had a history of neurological diseases, endocrine disorders, neurofibromatosis or other genetic syndromes, or previous hormonal therapies. MAIN OUTCOME MEASURE: Prevalence of brain abnormalities at MRI scan was measured. RESULTS: Brain MRI showed no alteration in 157 (86%), incidentalomas of the hypothalamic-pituitary area unrelated to CPP in 19 (11%), and hamartomas in six girls (3%). Girls with hamartomas were younger than 6 years and had significantly higher mean baseline and stimulated LH values (P < .001), LH to FSH ratio (P < .001), serum 17ß-estradiol levels (P < .001), and uterine length (P < .05). However, all the parameters overlapped extensively in girls with or without cerebral alterations. CONCLUSIONS: Our data cast doubt on the need of routine screening by brain MRI in girls with idiopathic CPP older than 6 years. Evidence-based criteria to drive clinical decision making about the use of MRI are lacking.

Epigenetic mechanisms elicited by nutrition in early life.

A growing number of studies focusing on the developmental origin of health and disease hypothesis have identified links among early nutrition, epigenetic processes and diseases also in later life. Different epigenetic mechanisms are elicited by dietary factors in early critical developmental ages that are able to affect the susceptibility to several diseases in adulthood. The studies here reviewed suggest that maternal and neonatal diet may have long-lasting effects in the development of non-communicable chronic adulthood diseases, in particular the components of the so-called metabolic syndrome, such as insulin resistance, type 2 diabetes, obesity, dyslipidaemia, hypertension, and CVD. Both maternal under- and over-nutrition may regulate the expression of genes involved in lipid and carbohydrate metabolism. Early postnatal nutrition may also represent a vital determinant of adult health by making an impact on the development and function of gut microbiota. An inadequate gut microbiota composition and function in early life seems to account for the deviant programming of later immunity and overall health status. In this regard probiotics, which have the potential to restore the intestinal microbiota balance, may be effective in preventing the development of chronic immune-mediated diseases. More recently, the epigenetic mechanisms elicited by probiotics through the production of SCFA are hypothesised to be the key to understand how they mediate their numerous health-promoting effects from the gut to the peripheral tissues.

Exposure to uteroplacental insufficiency reduces the expression of signal transducer and activator of transcription 3 and proopiomelanocortin in the hypothalamus of newborn rats.

IUGR has been linked to the development of type 2 diabetes. Recent data suggest that some of the molecular defects underlying type 2 diabetes reside in the CNS. Disruption of the signal transducer and activator of transcription 3 (STAT3) in the hypothalamic neurons expressing leptin receptor, results in severe obesity, hyperglycaemia, and hyperinsulinemia. Our aim was to investigate the expression of STAT3 and its downstream effector proopiomelanocortin (POMC) in IUGR rats obtained by uterine artery ligation. On day 19 of gestation, time-dated Sprague-Dawley pregnant rats were anesthetized, and both the uterine arteries were ligated. At birth, hypothalamus was dissected and processed to evaluate the expression of STAT3, its phosphorylated form, and POMC. STAT3 mRNA, STAT3 protein, phosphorylated STAT3, POMC mRNA, and POMC protein were significantly reduced in IUGR versus sham animals (p < 0.0001, p < 0.05 and p < 0.001, p < 0.01, p < 0.01, respectively). No significant differences either in serum leptin concentrations or in hypothalamic leptin receptor expression were observed. Our results suggest that an abnormal intrauterine milieu can affect the hypothalamic expression of STAT3 and POMC at birth, altering the hypothalamic signaling pathways that regulate the energy homeostasis.

Changes in the expression of hypothalamic lipid sensing genes in rat model of intrauterine growth retardation (IUGR).

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. Recent data suggest that some of the molecular defects underlying type 2 diabetes reside in the CNS. The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where LCFA undergo beta-oxidation. Hypothalamic inhibition of CPT1 decreases food intake and suppresses endogenous glucose production. Our aim was to investigate the effects of uterine artery ligation, a procedure that mimics uteroplacental insufficiency, on the CNS expression of CPT1 and other key enzymes of LCFA metabolism. Bilateral uterine artery ligation was performed on d 19 of gestation in the pregnant rat; sham-operated pregnant rats served as controls. Hypothalamus, cerebellum, hippocampus, and cortex were dissected and analyzed at birth by real-time PCR. Nonesterified fatty acid (NEFA) serum levels were significantly higher in IUGR pups (p<0.0001). In IUGR rats, the hypothalamic expression of CPT1 isoform C (p=0.005) and acetyl-CoA carboxylase (ACC) isoforms alpha (p<0.05) and beta (p=0.005) were significantly decreased. The data presented here support the hypothesis that an abnormal intrauterine milieu can induce changes in hypothalamic lipid sensing.

Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.

The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice.