Case report: Management of pediatric gigantism caused by the TADopathy, X-linked acrogigantism.

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.

Diencephalic Syndrome: Misleading Clinical Onset of Low-Grade Glioma.

BACKGROUND: Diencephalic Syndrome is an atypical early manifestation of low-grade gliomas; so, it is important to detect it in patients that experience a failure to thrive despite adequate length growth and food intake. The purpose of this article is to focus attention on this rare but potentially dangerous cause of poor weight gain or stunting in childhood. MATERIALS AND METHODS: We describe four patients with Diencephalic Syndrome and low-grade gliomas who were evaluated in our institution from January 2017 to December 2021. CASE DESCRIPTION AND RESULTS: two patients presented with suspected malabsorption, and two presented with a suspected eating disorder. In all cases, neurological symptoms appeared late, explaining the reason for the diagnostic delay, which impacts negatively on prognosis and on quality of life. Currently, patients 1 and 2 have stable disease in second-line therapy, patient 3 has stable disease post end of second-line therapy, and patient 4 has stable disease in first-line therapy. Everyone is in psychophysical rehabilitation. CONCLUSIONS: A multidisciplinary evaluation is essential in order to make an early diagnosis and improve prognosis and quality of life.

Qualitative study on the perception of combustible cigarettes, e-cigarettes and heated tobacco cigarettes among pregnant women.

The research proposes to investigate the psychological reasons that may explain women's addiction to smoking during pregnancy and the perception of combustible cigarettes, electronic cigarettes and heated tobacco cigarettes. The sample included 30 participants who smoke or people who previously smoked who chose to quit or continue smoking during pregnancy. The data was gathered via a semi-structured interview and developed from three research questions: feelings, opinions and perceptions of pregnant women toward e-cigarettes, heated tobacco cigarettes, and combustible cigarettes. The study used thematic qualitative analysis for the methodological formulation of the results. The Standards for Reporting Qualitative Research Standards (QRRS) checklist was used. In this qualitative research, three psychological reasons for the onset of smoking were found and analyzed: feelings of stress, nervousness, and loneliness. According to the results: 40.91% of the women who smoked combustible cigarettes decided to keep on smoking and 59.09% decided to quit, 16.67% of participants who use heated tobacco cigarette decided to continue during pregnancy and the remaining 83.33% decide to stop; lastly, there is a condition of fairness for adults who use e-cigarette, 50% decided to continue smoking during pregnancy and the other 50% decided to stop smoking. The data indicate that those who continue to smoke during pregnancy are participants who smoke combustible cigarettes, stating that they reduce the amount of smoke inhaled. Meanwhile, participants who use heated tobacco cigarettes or e-cigarettes are certain that they pose less risk than combustible cigarettes; nevertheless, most of them decide to quit smoking during pregnancy. Another important aspect that has been noted is that of formal abandonment treatments, as quite unexpectedly, there has been a unanimous recognition of strong distrust toward the possible risks to the unborn child. There is a lot of distrust and little knowledge of official smoking cessation therapies, and because of this, participants stated that they can quit smoking whenever they want and only with their own willpower. Five categories and related themes emerged from the thematic analysis, such as reasons for starting with themes such as stress, irritation, loneliness, adolescence and integration; reasons for attachment to topics such as habit and carelessness about one's health; perceptions of traditional cigarettes compared to e-cigarettes and heated cigarettes with related topics such as sensory experiences and side effects; feelings and use of official smoking cessation therapies with issues as willpower and knowledge; information on the effects of smoke during pregnancy and breastfeeding, including risk information.

Resistance to Thyroid Hormones: A Case-Series Study.

The aim of the study is to describe the clinical features of two unrelated patients with resistance to thyroid hormones (RTH), the first, a total thyroidectomized patient, and the second, a pregnant woman. We report the features found in her newborn who also showed RTH. Patient 1 is a 38-year-old man with total thyroidectomy managed for excessive thyroid stimulating hormone (TSH) production, which poorly responded to the replacement therapy. He was found with a THRß c.1378G>A p.(Glu460Lys) heterozygous mutation, which was also present in other members of his family (son, brother, and father). Interestingly, Patient 1 had hypertension, dyslipidemia, and hepatic steatosis, which have been recently suggested as RTH-related comorbidities. Patient 2 is a 32-year-old pregnant woman with multinodular goiter, and the THRß heterozygous variant c.959G>C, that, to the best of our knowledge, has been reported in literature only once. Her newborn had tachycardia and increased thyroid hormone levels, and showed the same mutation. After delivery, high parathyroid hormone (PTH) and calcium serum levels were found in Patient 2 and the scintigraphy showed the presence of adenoma of a parathyroid gland. This case-series study provides a practical example of the management of RTH in a thyroidectomized patient, a pregnant woman, and a newborn. A novel RTH pathogenic mutation is described for the second time in literature. Furthermore, the importance of metabolic assessment in patients with RTHß has been highlighted and the possible correlation between RTH and primary hyperparathyroidism is discussed.

Testicular Growth and Pubertal Onset in GH-Deficient Children Treated With Growth Hormone: A Retrospective Study.

The prevalence of idiopathic oligozoospermia has been esteemed as high as 75%. An Italian survey has reported bilateral testicular hypotrophy in 14% of final-year high school students. The search for determinants of testicular growth in childhood is important for the primary prevention of spermatogenic failure. Therefore, this retrospective study aimed to evaluate the testicular growth and pubertal onset in deficient children treated recombinant human growth hormone (rhGH). To accomplish this, the clinical charts of 93 patients with GH deficiency (GHD) were carefully reviewed. Their mean age at the time of diagnosis was 11.2 ± 2.4 years. rhGH was administered for 44.0 ± 22.4 months, and the onset of puberty was recorded after a mean of 25.8 ± 22.4 months from the first rhGH administration. As expected, serum insulin-like growth factor 1 (IGF1) levels increased significantly after treatment. Before rhGH therapy, the Tanner stage was I in 59 out of 70 boys (84.3%), II in 8/70 (11.4%), III in 3/70 (4.3%). No one was on stage IV or V. The mean Tanner stage was 1.19 ± 0.51. At the last visit, the Tanner stage was I in 8/72 boys (11.1%), II in 6/72 (8.3%), III in 6/72 (8.3%), IV in 16/72 (22.2%), and V in 36/72 (50.0%). After a mean of 44.0 ± 22.4 months of rhGH treatment, the mean Tanner stage was 4.05 ± 1.30. Patients treated with rhGH showed a significant testicular volume (TV) growth over time, whereas no growth was observed in age-matched but not yet treated patients, even when the age was compatible with a spontaneous start of puberty. The multivariate regression analysis showed that the duration of treatment and the mean rhGH dose significantly predicted the percentage of TV increase. In contrast, age, serum FSH, and IGF1 levels, and final rhGH dose did not impact TV growth over time. In conclusion, these findings suggest that GH may play a role in testicular growth and pubertal onset, despite the descriptive nature of this study. Further properly designed studies are needed to confirm these findings. This knowledge may be useful to implement the diagnostic-therapeutic algorithm in case of a lack of testicular growth in childhood.

Multiplex Ligation-Dependent Probe Amplification Accurately Detects Turner Syndrome in Girls with Short Stature.

AIMS: We aimed at evaluating a standard multiplex ligation-dependent probe amplification (MLPA) probe set for the detection of aneuploidy to diagnose Turner syndrome (TS). We first fixed an MLPA ratio cutoff able to detect all cases of TS in a pilot TS group. We then tested this value on a second group of TS patients and a short-stature population to measure specificity and sensitivity. METHODS: 15 TS patients with X mosaicism or X structural abnormalities (Pilot TS Group), 45 TS karyotype-assessed patients (TS Group), and 74 prepubertal female patients with apparent idiopathic short stature (Short-Stature Group) were enrolled. All subjects underwent MLPA and karyotype analysis. In the TS and Short-Stature Groups, MLPA testing was performed in blind. RESULTS: The choice of an MLPA threshold ratio of 0.76 for at least 1 probe allowed us to detect all TS cases, including mosaicisms. Sensitivity and specificity were 100% (CI 95%, 0.92-1) and 88.89% (CI 95%, 0.79-0.94), respectively. The positive predictive value was 88.5%, and the negative predictive value was 100%. MLPA detected the presence of Y chromosome material in 2 patients. CONCLUSION: MLPA is an accurate and inexpensive tool to screen for TS in girls with short stature. A customized MLPA kit may be useful for the screening of an even larger population.

Prehypertension in adolescents with cardiovascular risk: a comparison between type 1 diabetic patients and overweight subjects.

BACKGROUND: Adolescents with type 1 diabetes and obesity present higher cardiovascular risk and ambulatory blood pressure measurements (ABPM) has been shown to predict vascular events, especially by identifying the nondipper status. The aim of our observational cross-sectional study conducted in adolescents with type 1 diabetes, overweight subjects and healthy controls was to assess mean blood pressure parameters to identify subclinical cardiovascular risk. METHODS: The study included adolescents patients with type 1 diabetes followed in our Pediatric Department in University of Catania between January 2011 and 2013. A total of 60 patients were enrolled, and 48 (32 male and 16 female) completed the study. For each subject we performed systolic and diastolic Ambulatory Blood Pressure Measurements (ABPM) during wakefulness and sleep recording blood pressure every 30 min for 24 h with the Tonoport V/2 GE CardioSoft V6.51 device. We compared the data of patients with those of overweight subjects and healthy controls. RESULTS: ABPM revealed no significant difference between type 1 diabetic patients and overweight subjects in 24 h Systolic, 24 h Diastolic, Day-time Systolic, Night-time systolic and Day-time Diastolic blood pressure values but significantly different values in Night-time Diastolic blood pressure values (p < 0.001). We found significant differences between type 1 diabetic patients and healthy controls in all 24 h Systolic (p < 0.001), 24 h Diastolic (p < 0.01), Day-time Systolic (p < 0.01), Night-time Systolic (p < 0.001), Day-time Diastolic (p < 0.05) and Night-time Diastolic (p < 0.001) blood pressure values. We detected hypertension in 12/48 (25%) type 1 diabetic patients and in 10/48 overweight subjects (p = 0.62; OR 1.2; CI 0.48-3.29), whereas no-one of healthy controls presented hypertension (p < 0.001). We observed nondipper pattern in 40/48 (83.3%) type 1 diabetic patients, in 33/48 (68.8%) overweight subjects (p = 0.094; OR 2.27; CI 0.85-6.01), and in 16/48 (33.3%) of healthy controls (p < 0.001; OR 10; CI 3.79-26.3). CONCLUSIONS: ABPM studies might help to define a subset of patients at increased risk for the development of hypertension. In evaluating blood pressure in type 1 diabetes and overweight subjects, ABPM should be used since a reduced dipping can indicate incipient hypertension.

Hepatoblastoma presenting as precocious puberty: a case report.

Hepatoblastoma (HB), a primary liver tumor in childhood, is often accompanied by alpha-fetoprotein (AFP) secretion, and sometimes by ß-human chorionic gonadotropin hormone (ß-hCG) secretion, and this can cause peripheral precocious puberty (PPP). We describe a case of PPP associated with HB. Laboratory tests showed an increase in AFP, ß-hCG and testosterone values, and suppression of follicle-stimulating hormone and luteinizing hormone levels. After chemotherapy and surgery, AFP, ß-hCG and testosterone levels normalized and signs of virilization did not progress further. The child did not show evidence for tumor recurrence after 16 months of follow-up. New therapeutic approaches and early diagnosis may ensure a better prognosis of virilizing HB, than reported in the past. Assessment of PPP should always take into account the possibility of a tumoral source.

Unusual heme binding properties of the dissimilative nitrate respiration regulator, a bacterial nitric oxide sensor.

AIMS: In the opportunistic pathogen Pseudomonas aeruginosa, nitric oxide (NO) triggers the respiration of nitrate (denitrification), thus allowing survival in chronic infection sites as a microaerobic-anaerobic biofilm. The NO-dependent induction of denitrification is mediated by the dissimilative nitrate respiration regulator (DNR), a transcription factor forming a stable complex with heme, which is required to sense the physiological messenger (i.e., NO). The molecular details of NO sensing in DNR and, more in general, in this class of sensors are largely unknown, and a study aimed at integrating microbiology and biochemistry is needed. RESULTS: Here we present a comprehensive study, including in vivo results and spectroscopy, kinetics, and protein engineering, that demonstrates the direct involvement of a histidine residue in heme iron coordination. Moreover, a peculiar phenomenon of ligand switching around heme iron, which hampers the identification of the second heme axial ligand, is also suggested. These results indicate that DNR is characterized by a remarkable flexibility in solution, as observed for other cAMP receptor protein/fumarate and nitrate reductase regulators (CRP-FNR) to which DNR belongs. INNOVATION: The present work represents one of the few studies focused on the biochemistry of NO sensing by bacterial transcriptional regulators. The data presented demonstrate that structural plasticity of DNR is crucial for the sensing activity and confers to the protein unusual heme binding properties. CONCLUSIONS: Protein flexibility and dynamics is a key structural feature essential to explain the evolutionary success and adaptability of CRP-FNR, and may represent a common strategy employed by heme-based redox sensors, which presents features deeply different from those of canonical hemeproteins.

The Pseudomonas aeruginosa DNR transcription factor: light and shade of nitric oxide-sensing mechanisms.

In response to environmental conditions, NO (nitric oxide) induces global changes in the cellular metabolism of Pseudomonas aeruginosa, which are strictly related to pathogenesis. In particular, at low oxygen tensions and in the presence of NO the denitrification alternative respiration is activated by a key regulator: DNR (dissimilative nitrate respiration regulator). DNR belongs to the CRP (cAMP receptor protein)-FNR (fumarate and nitrate reductase regulatory protein) superfamily of bacterial transcription factors. These regulators are involved in many different pathways and distinct activation mechanism seems to be operative in several cases. Recent results indicate that DNR is a haem protein capable of discriminating between NO and CO (carbon monoxide). On the basis of the available structural data, a suggested activation mechanism is discussed.

Neonatal autoimmune hypothyroidism: a patient report.

BACKGROUND: Acquired primary hypothyroidism in neonates and infants under 3 years of age is very rare. Herein we report the case of an infant female affected by acquired autoimmune hypothyroidism. PATIENT REPORT: The infant was transferred to the Pediatric Clinic, University of Catania, Italy for evaluation of dysmorphic features, growth and motor retardation, and hypothyroidism on laboratory testing. Neonatal screening test for TSH and PKU was negative. An ultrasound scan showed a non-homogeneous thyroid gland which was increased in volume. Based on the laboratory results, the diagnosis of autoimmune hypothyroidism was made and L-thyroxine treatment was initiated at 50 microg/day. CONCLUSIONS: Autoimmune hypothyroidism in infancy is rare, but early recognition and therapy are essential to prevent neurologic damage and growth deficits. In this patient we would like to underline the early age of appearance of autoimmune thyroid disease and the possible onset of pathologic events before birth.

A dramatic conformational rearrangement is necessary for the activation of DNR from Pseudomonas aeruginosa. Crystal structure of wild-type DNR.

The opportunistic pathogen Pseudomonas aeruginosa can grow in low oxygen, because it is capable of anaerobic respiration using nitrate as a terminal electron acceptor (denitrification). An intermediate of the denitrification pathway is nitric oxide, a compound that may become cytotoxic at high concentration. The intracellular levels of nitric oxide are tightly controlled by regulating the expression of the enzymes responsible for its synthesis and degradation (nitrite and nitric oxide reductases). In this article, we present the crystallographic structure of the wild-type dissimilative nitrate respiration regulator (DNR), a master regulator controlling expression of the denitrification machinery and a putative target for new therapeutic strategies. Comparison with other structures among the CRP-FNR class of regulators reveals that DNR has crystallized in a conformation that has never been observed before. In particular, the sensing domain of DNR has undergone a rotation of more than 50 degrees with respect to the other structures. This suggests that DNR may undergo an unexpected and very large conformational rearrangement on activation.