Abnormal linear growth in paediatric adrenal diseases: Pathogenesis,prevalence and management

Abnormal adrenal function can interfere with linear growth, potentially causing either acceleration or impairment of growth in paediatric patients. These abnormalities can be caused by direct effects of adrenal hormones, particularly glucocorticoids and sex steroids, or be mediated by indirect mechanisms such as the disturbance of the growth hormone-insulin-like growth factor-1 axis and aromatization of androgens to oestrogens. The early diagnosis and optimal treatment of adrenal disorders can prevent or minimize growth disturbance and facilitate improved height gain. Mechanisms of growth disturbance in the following abnormal states will be discussed; hypercortisolaemia, hyperandrogenaemia and obesity. Prevalence and features of growth disturbance will be discussed in ACTH-dependent and ACTH-independent Cushing's syndrome, adrenocortical tumours, premature adrenarche, congenital adrenal hyperplasia and adrenal insufficiency disorders. Recommendations for management have been included.     

Enzyme replacement therapy in juvenile glycogenosis type II: a longitudinal study

Glycogenosis type II, a genetic muscle-wasting disorder, results in a spectrum of clinical phenotypes. Enzyme replacement therapy is effective in the infantile form of the disease, while little is known about its effectiveness in late-onset disease, especially in juvenile patients. The purpose of this retrospective cohort study was to assess the long-term effects of enzyme replacement therapy (ERT) in juvenile glycogenosis type II (GSDII). Eight Italian juvenile GSDII patients, receiving biweekly infusions of 20 mg/kg recombinant human α-glucosidase for at least 72 months, were enrolled (median age at therapy start was 11.8 years). Six-minute walk test (6MWT) and forced vital capacity (FVC), measured in upright position, were chosen as the principal outcome measures. Global motor disability (modified Walton scale (WS)), muscle enzymes levels [creatine phosphokinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT)] and body mass index (BMI) were also analysed both at baseline (therapy start) and annually afterwards. At baseline, most patients (six out of eight) did not show muscle function impairment (WS?≤?2). The performance at 6MWT showed a slight improvement during follow-up as well as FVC. Muscle enzymes levels showed a clear decrease after the 1st year of treatment while remained stable afterwards. An overall decrease in BMI was also observed during follow-up, although at the individual level, trends were variable. Conclusion: ERT is effective in stabilising both motor and lung functions in juvenile patients with GSDII, possibly slowing down the rate of disease progression. Randomised controlled trials are needed to understand whether early treatment allows juvenile patients to reach adulthood with a more beneficial residual muscular function than untreated patients.     

Spinal ultrasound in patients with anorectal malformations: is this the end of an era?

Purpose

Even if lumbar magnetic resonance imaging (MRI) is considered the gold standard in the diagnosis of occult spinal dysraphism (SD) in patients with anorectal malformations (ARMs), spinal ultrasound (US) performed up to 5 months of life have been largely used as a screening test. The aim of the present study was to evaluate the accuracy in terms of sensibility and specificity of neonatal US to detect occult SD in patients with ARMs.

Methods

Retrospective analysis of all patients treated for ARMs between 1999 and 2013 at our institution who underwent both spinal US (up to 5 months of life) and MRI. Sensibility and specificity have been calculated for US based on MRI results.

Results

Of 244 patients treated for ARMs at our institution, 82 (34 females, 48 males) underwent both the imaging studies and have been included in this study. ARMs types were: anal stenosis (7), recto-vestibular fistula (19), recto-perineal fistula (3) and cloaca (5) in female and imperforate anus (7) recto-perineal fistula (14), recto-urethral fistula (22), recto-vesical fistula (5) in males. Forty-seven patients (57, 3 % of total, 18 females, 29 males) had some occult SD (tethered spinal cord, spinal lipoma, syringomyelia) at MRI. Only 7 (14, 8 %) patients of those with spinal anomalies at MRI had pathological US studies. In our population, sensibility and specificity of US for diagnosis of occult SD were, respectively, 14, 8 and 100 %.

Conclusion

Since it is well known that a screening test must have a high sensibility, our data suggest that spinal ultrasound is not suitable as a screening test for occult spinal dysraphism in patients with ARMs. Furthermore, we strongly advise against the use of US as a screening test for spinal dysraphism to prevent a false sense of security in physician and patients’ families.     

Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease

Management of osteonecrosis of the jaw associated with antiresorptive agents is challenging, and outcomes are unpredictable. The severity of disease is the main guide to management, and can help to predict prognosis. Most available staging systems for osteonecrosis, including the widely-used American Association of Oral and Maxillofacial Surgeons (AAOMS) system, classify severity on the basis of clinical and radiographic findings. However, clinical inspection and radiography are limited in their ability to identify the extent of necrotic bone disease compared with computed tomography (CT). We have organised a large multicentre retrospective study (known as MISSION) to investigate the agreement between the AAOMS staging system and the extent of osteonecrosis of the jaw (focal compared with diffuse involvement of bone) as detected on CT. We studied 799 patients with detailed clinical phenotyping who had CT images taken. Features of diffuse bone disease were identified on CT within all AAOMS stages (20%, 8%, 48%, and 24% of patients in stages 0, 1, 2, and 3, respectively). Of the patients classified as stage 0, 110/192 (57%) had diffuse disease on CT, and about 1 in 3 with CT evidence of diffuse bone disease was misclassified by the AAOMS system as having stages 0 and 1 osteonecrosis. In addition, more than a third of patients with AAOMS stage 2 (142/405, 35%) had focal bone disease on CT. We conclude that the AAOMS staging system does not correctly identify the extent of bony disease in patients with osteonecrosis of the jaw.     

Disease Reactivation after Fingolimod Discontinuation in Pregnant Multiple Sclerosis Patients

Recent studies estimated an incidence of 4–25% of disease rebound after withdrawal of fingolimod (FTY) for any reason, but specific data on disease reactivation after FTY withdrawal due to pregnancy are limited. The aim of the study was to evaluate the frequency and predictors of disease reactivation in patients who stopped FTY for pregnancy. A multicentre retrospective cohort study was conducted in four Italian MS centres in 2013–2019. Both planned and unplanned pregnancies were included. The annualized relapse rate (ARR) was calculated before FTY treatment, during FTY treatment, during pregnancy and during the year after delivery. In total, 27 patients (mean age 29 years) were included. The ARR 1 year before FTY treatment was 1.3. Patients were exposed to FTY for a median of 2.9 years. The ARR was 0.04 during the last year before conception (p < 0.001 compared with the ARR before FTY treatment). Eleven patients became pregnant after a mean of 88 days following FTY discontinuation, whereas 16 patients stopped FTY after pregnancy confirmation. Relapses were observed in 22% of patients during pregnancy and in 44% in the postpartum period. ARR increased both during pregnancy (0.49; p = 0.027) and in the first year after delivery (0.67; p < 0.001) compared to the last year before pregnancy. Compared with radiological assessment before pregnancy, more patients showed new or enlarging T2 lesions (63% vs 30%; p = 0.02) and gadolinium-enhancing lesions (44% vs 0; p = 0.0001) on brain Magnetic Resonance Imaging. Relapses during pregnancy were the only significant predictor for postpartum relapses (OR 1.9, 95% CI 1.11–3.1). One case of spontaneous abortion and no cases of abnormal foetal development were observed. Despite adequate and prolonged control of disease activity, women who discontinue FTY because of pregnancy are at risk for disease reactivation. In patients who relapsed during pregnancy, the initiation of high-efficacy disease modifying drugs (DMDs) soon after delivery is advisable to prevent postpartum relapses.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01106-6.     

RPE65-Associated Retinopathies in the Italian Population: A Longitudinal Natural History Study

PurposeTo investigate the course of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene.MethodsThis longitudinal multicentric retrospective chart-review study was designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements. The data, including imaging, were collected using an electronic clinical research form and were reviewed at a single center to improve consistency.ResultsFrom an overall cohort of 60 Italian patients with RPE65-associated IRD, 43 patients (mean age, 27.8 ± 19.7 years) were included and showed a mean BCVA of 2.0 ± 1.0 logMAR. Time-to-event analysis revealed a median age of 33.8 years and 41.4 years to reach low vision and blindness based on BCVA, respectively. ERG (available for 34 patients) showed undetectable responses in most patients (26; 76.5%). OCT (available for 31 patients) revealed epiretinal membranes in five patients (16.1%). Central foveal thickness significantly decreased with age at a mean annual rate of −0.6%/y (P = 0.044). We identified 43 different variants in the RPE65 gene in the entire cohort. Nine variants were novel. Finally, to assess genotype-phenotype correlations, patients were stratified according to the number of RPE65 loss-of-function (LoF) alleles. Patients without LoF variants showed significantly (P < 0.05) better BCVA compared to patients with one or two LoF alleles.ConclusionsWe described the natural course of RPE65-associated IRD in an Italian cohort showing for the first time a specific genotype-phenotype association. Our findings can contribute to a better management of RPE65-associated IRD patients.     

Olfactory perception rehabilitation after total laryngectomy (OPRAT): proposal of a new protocol based on training of sensory perception skills

European Archives of Oto-Rhino-Laryngology - We aim to propose a new protocol for olfaction rehabilitation after total laryngectomy based on training of sensory perception levels using the Nasal...     

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

We have previously reported that prostaglandin D2 Synthase (L-PGDS) participates in peripheral nervous system (PNS) myelination during development. We now describe the role of L-PGDS in the resolution of PNS injury, similarly to other members of the prostaglandin synthase family, which are important for Wallerian degeneration (WD) and axonal regeneration. Our analyses show that L-PGDS expression is modulated after injury in both sciatic nerves and dorsal root ganglia neurons, indicating that it might play a role in the WD process. Accordingly, our data reveals that L-PGDS regulates macrophages phagocytic activity through a non-cell autonomous mechanism, allowing myelin debris clearance and favoring axonal regeneration and remyelination. In addition, L-PGDS also appear to control macrophages accumulation in injured nerves, possibly by regulating the blood–nerve barrier permeability and SOX2 expression levels in Schwann cells. Collectively, our results suggest that L-PGDS has multiple functions during nerve regeneration and remyelination. Based on the results of this study, we posit that L-PGDS acts as an anti-inflammatory agent in the late phases of WD, and cooperates in the resolution of the inflammatory response. Thus, pharmacological activation of the L-PGDS pathway might prove beneficial in resolving peripheral nerve injury.