The role of the dentist and orthodontist in recognizing oro-facial manifestations of acromegaly: a questionnaire-based study.

PURPOSE: Oro-facial manifestations of acromegaly are among the earliest signs of the disease and are reported by a significant number of patients at diagnosis. Despite this high prevalence of acromegaly oral manifestation, dentists do not play a pivotal role in acromegaly identification and diagnosis. The aim of our study was to evaluate the ability of dentists and orthodontists in the early recognition of the oro-facial manifestations of acromegaly. METHODS: A telematic questionnaire was administered to dentists and orthodontists. The questionnaire included photos with facial and oral-dental details and lateral teleradiography of acromegaly patients (ACRO). RESULTS: The study included 426 participants: 220 dentists and 206 orthodontists. Upon reviewing the photos, dentists most often observed mandibular prognathism and lips projection, while orthodontists also reported the impairment of relative soft tissue. Orthodontists, who usually use photos to document patients' oral-facial characteristics, paid more attention to oral-facial impairment than dentists. During dental assessment, 90% of the participants usually evaluated tongue size and appearance, diastemas presence, and signs of sleep impairment (mainly orthodontists). Orthodontists were also more able to identify sella turcica enlargement at teleradiography. A total of 10.8% of the participants had ACRO as patients and 11.3% referred at least one patient for acromegaly suspicion. CONCLUSION: The study highlighted dentists' strategic role in identifying ACRO. Increasing dentists' awareness about acromegaly clinical issues may improve early diagnosis, potentially resulting in an increased quality of life and decreased mortality among ACRO.

Patient-reported outcomes in patients with acromegaly treated with pegvisomant in the ACROSTUDY extension: A real-world experience.

PURPOSE: To report the effects of pegvisomant (PEGV) treatment on patient-reported outcomes in acromegaly patients. METHODS: We conducted an extension study of an open-label, multinational, non-interventional study (ACROSTUDY) evaluating the long-term safety and efficacy of PEGV for acromegaly in routine clinical practice. Enrolled patients were rollover patients from ACROSTUDY, or treatment naïve/semi-naïve (NSN; no PEGV within 6 months of enrollment). Exploratory efficacy endpoints were changes in symptoms with the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and quality of life with the Acromegaly Quality of Life questionnaire (AcroQoL) analyzed by controlled or uncontrolled IGF-I levels. Results were analyzed in all patients, in NSN patient subgroup, and by diabetes status. RESULTS: A total of 544 patients with acromegaly were enrolled, including 434 rollover subjects from ACROSTUDY and 110 NSN patients. Mean PEGV treatment duration was 7.8 years (range, 0-19.6 years). Overall, the majority of PASQ scores improved over time, but there was no significant difference between IGF-I controlled or uncontrolled groups. In the NSN subgroup, most PASQ and AcroQoL scores remained similar to baseline up to 1 year, regardless of IGF-I control. Patients with diabetes reported better PASQ scores over time with PEGV treatment, regardless of IGF-I control. IGF-I normalization increased from 10% of patients at baseline to more than 78% at year 10, with a mean daily PEGV dose of 18.7 mg. CONCLUSIONS: Overall, patients treated with PEGV had small improvements in PASQ. While IGF-I normalization increased with PEGV treatment, IGF-I control had no effects on PASQ and AcroQoL scores.

Neurocognitive assessment and DNA sequencing expand the phenotype and genotype spectrum of Alström syndrome.

Alström syndrome (OMIM#203800) is an ultra-rare autosomal recessive monogenic disease presenting pathogenic variants in ALMS1 (chromosome 2p13). It is characterized by early onset of blindness, hearing loss and systemic comorbidities, with delayed development without cognitive impairment. We aimed to investigate the cognitive functions and describe new pathogenic variants in Alström syndrome patients. Nineteen patients (13 adults, 6 children) underwent a thorough clinical, genetic, laboratory, instrumental, and neurocognitive assessment. Six new pathogenic variants in ALMS1 including the first described in exon 6 were identified. Four patients displayed a "mild phenotype" characterized by slow disease onset or absence of complications, including childhood obesity and association with at least one pathogenic variant in exon 5 or 6. At neurocognitive testing, a significant proportion of patients had deficits in three neurocognitive domains: similarities, phonological memory, and apraxia. In particular, 53% of patients showed difficulties in the auditory working memory test. We found ideomotor and buccofacial apraxia in 74% of patients. "Mild phenotype" patients performed better on auditory working memory and ideomotor apraxia test than "typical phenotype" ones (91.9 + 16.3% vs. 41.7 + 34.5% of correct answers, Z = 64.5, p < .01 and 92.5 + 9.6 vs. 61.7 + 26.3, Z = 61, p < .05, respectively). Deficits in auditory working memory, ideomotor, and buccofacial apraxia were found in these patients and fewer neuropsychological deficits were found in the "mild" phenotype group. Furthermore, in the "mild" phenotype group, it was found that all pathogenic variants are localized before exon 8.

Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with CNGA3-Associated Autosomal Recessive Achromatopsia.

Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families.

Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction.

Despite their critical role in susceptibility to metabolic diseases such as obesity and type 2 diabetes, mechanisms regulating energy balance are extremely complex and far from being fully understood. Both central and peripheral feedback circuits are involved and, despite it was traditionally thought that the energy balance of an organism depends on the equality between calorie intake within the system and energy expenditure, the regulation of energy content in biological systems oversteps the classical physical laws of thermodynamics. The fine-tuned mechanism for body weight and energy storage regulation is aimed to preserve survival chances in response to the variations of energy availability, as expressed by the metabolic flexibility of this system adapting subjects to both starvation and overfeeding. However, these mechanisms can lose their flexibility, with consequent maladaptation to both increased energy intake and calorie restriction leading to the development of several metabolic disturbances.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Defining renal phenotype in Alström syndrome.

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. METHOD: Prospective observational cohort study. SETTING AND PARTICIPANTS: Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. OUTCOMES: First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. ANALYTICAL APPROACH: Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. RESULTS: The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of -16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. CONCLUSIONS: This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.

Preclinical markers of atherosclerosis in acromegaly: a systematic review and meta-analysis.

OBJECTIVE: Multiple studies investigated preclinical markers of peripheral vascular damage in acromegaly (ACRO) reporting discordant results. The aim of this study was to run a meta-analysis to examine whether intima media thickness (IMT), flow mediated dilation (FMD) and arterial pulse wave velocity (PWV) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes. STUDY SELECTION: Twenty-seven studies comparing ACRO vs control (CON) populations and active (ACT) vs inactive (INACT) ACRO were included in the meta-analysis. DATA SYNTHESIS: ACRO compared to CON have higher IMT (ES = 0.83, 95% C.I. 0.35-1.30), p = 0.001, impaired FMD (ES = - 1.59, 95% C.I. - 2.33 to - 0.85, p < 0.0001) and higher PWV (ES = 0.76 95% C.I. 0.37-1.16, p = 0.0001). When patients with ACT vs INACT disease were considered IMT was higher (ES = 0.43, 95% C.I. 0.02-0.84, p = 0.041) and FMD was impaired (ES = - 0.66, 95% C.I. - 1.28 to 0.04, p = 0.038) in ACT patients. Meta-regression analysis of studies comparing IMT in ACT vs INACT acromegalic patients showed a significant and inverse association between the effect size and the percent of hypertensive (p = 0.025) and diabetic (p = 0.041) patients. CONCLUSIONS: IMT, FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis. In patients with active disease these preclinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess.

Radiotherapy in acromegaly: Long-term brain parenchymal and vascular magnetic resonance changes.

BACKGROUND: Radiation therapy (RT) effectiveness on hormonal reduction is proven in acromegaly; however, collateral long-term effects are still undetermined. This transversal neuroimaging study on a large cohort of acromegalic patients aimed to investigate the rate of parenchymal and vascular changes after RT. MATERIALS AND METHODS: Thirty-six acromegalic patients underwent RT (RT+) after unsuccessful surgery and were compared to RT- acromegalic patients matched for age, gender, adenoma features, clinical and surgical history. All patients underwent magnetic resonance angiography (MRA) to investigate intracranial artery abnormalities and FLAIR sequence to assess white matter changes according to the Wahlund scale. RESULTS: RT+ acromegalic patients had a higher rate of controlled disease (29/36 vs. 12/36, P<0.001). RT+ acromegalic patients had MRI/MRA evaluation 15.3±9.6 years after RT. RT+ acromegalic patients had a significantly higher Wahlund score than RT- acromegalic patients (6.03±6.41 vs. 2.53±3.66, P=0.006) due to increased white matter signal abnormalities at the level of the temporal lobes, the basal ganglia (insula) and the infratentorial regions, bilaterally. Among RT+ patients one died because of temporo-polar anaplastic astrocytoma, one suffered from a stroke due to right internal carotid artery occlusion, one presented with cystic degeneration of the temporal poles. Long-dated RT (>10 years before MR evaluation) was associated with a higher rate of RT-related white matter changes (P=0.0004). CONCLUSIONS: RT seems to have created a cohort of patients with brain parenchymal changes whose clinical and cognitive impact is still unknown. These patients might require a prolonged MRI and MRA follow-up to promptly detect delayed RT-related complications and minimize their clinical consequences.

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.

Ambulatory Arterial Stiffness Indexes in Cushing's Syndrome.

Long-standing exposure to endogenous cortisol excess is associated with high cardiovascular risk. The aim of our study was to investigate arterial stiffness, which has been recognized as an independent predictor of adverse cardiovascular outcome, in a group of patients with Cushing's syndrome. Twenty-four patients with Cushing's syndrome (3 males, mean age 49±13 years; 20 pituitary-dependent Cushing's disease and 4 adrenal adenoma) underwent 24-h ambulatory blood pressure monitoring (ABPM) and evaluation of cardiovascular risk factors. The Ambulatory Arterial Stiffness Index (AASI) and symmetric AASI (sAASI) were derived from ABPM tracings. Cushing patients were divided into 8 normotensive (NOR-CUSH) and 16 hypertensive (HYP-CUSH) patients, and were compared with 8 normotensive (NOR-CTR) and 16 hypertensive (HYP-CTR) control subjects, matched for demographic characteristics, 24-h ABPM and cardiometabolic risk factors. The AASI and sAASI indexes were significantly higher in Cushing patients than in controls, either in the normotensive (p=0.048 for AASI and p=0.013 for sAASI) or in the hypertensive (p=0.004 for AASI and p=0.046 for sAASI) group. No difference in metabolic parameters was observed between NOR-CUSH and NOR-CTR or between HYP-CUSH and HYP-CTR groups. AASI and sAASI were both correlated with urinary cortisol in patients with endogenous hypercortisolism (Spearman's rho=0.40, p=0.05, and 0.61, p=0.003, respectively), while no correlation was found in controls. Both AASI and sAASI are increased in Cushing syndrome, independent of BP elevation, and may represent an additional cardiovascular risk factor in this disease. The role of excess cortisol in arterial stiffness has to be further clarified.

Pituitary morphovolumetric changes in Alström syndrome.

PURPOSE: Alström syndrome (AS) is a rare monogenic ciliopathy characterized by cone-code dystrophy, leading to early blindness, and obesity. Early endocrinological dysfunctions, especially growth hormone deficiency and hypogonadism, are detected in about half of AS patients. This MRI study investigates the presence of pituitary gland abnormalities in a large cohort of AS patients. METHODS: Pituitary morphological changes (gland flattening with partial or total empty sella) were evaluated on midsagittal high-resolution T1-weighted images of 32 AS patients (mean-age 23.2±9.4 years; range: 6-45, 15 females) and 21 unrelated healthy subjects (mean age 23.2±11.2 years; range: 6-43; 10 females). RESULTS: Among AS patients, 11/32 (34%) had total empty sella and 6/32 (19%) partial empty sella, while 3/21 (14%) of controls had partial empty sella and none presented with total empty sella (P<0.005). AS patients harboring a total or partial empty sella did not differ from those with normal pituitary gland for gender (P=0.98), BMI (P=0.10) or visual impairment (P=0.21), while the presence of empty sella was associated with an older age (P=0.007) being especially frequent above the age of 30. CONCLUSIONS: Total or partial empty sella appears commonly during the course of AS. Pituitary gland flattening might represent the morphological underpinning of subtle endocrinologic dysfunctions and raises the need to further investigate the pituitary function in this rare ciliopathy.

Alström Syndrome: Mutation Spectrum of ALMS1.

Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.

Intracranial internal carotid artery changes in acromegaly: a quantitative magnetic resonance angiography study.

PURPOSE: Although cerebrovascular mortality is increased up to eightfold in acromegaly, intracranial internal carotid artery (ICA) changes have not been well investigated. This is a magnetic resonance angiography (MRA) quantitative cross-sectional study of ICA tortuosity, ectasia and intercarotid distance in acromegalic patients with subsequent analysis of concomitant clinical, laboratory and neuroimaging findings. METHODS: One hundred seventy six acromegalic patients (mean-age 55 ± 14 years, age range 21-88, 92 females) and 104 subjects with headache or transient neurological deficits underwent MRA with the same 1.5 T scanner. Clinical data, laboratory and pituitary adenoma imaging findings were recorded. Using a commercially available software, we measured the tortuosity index [(curved/linear ICA length from C3-midpoint to intracranial bifurcation) - 1], ICA ectasia index (intracavernous/petrous ICA diameter) and intercarotid distance at C3 and C4 levels. RESULTS: Mean ICA tortuosity and ectasia indices were increased in acromegalic patients compared with controls (1.06 ± 0.29 vs 0.93 ± 0.26, p < 0.001; 1.02 ± 0.10 vs 0.92 ± 0.09, p < 0.001). Mean intercarotid distance was reduced at C3 and increased at C4 in acromegalic patients (16.7 ± 3.4 vs 17.9 ± 2.5 mm, p < 0.001; 16.7 ± 4.6 vs 15.4 ± 4.1 mm, p < 0.05; t test). ICA tortuosity and ectasia correlated neither with laboratory findings nor with previous or current treatment. On multivariate analysis, C3 intercarotid distance was reduced in patients on dopamine agonist treatment (p < 0.01) and increased in patients with GH-deficit (p = 0.01), while C4 intercarotid distance was increased with macroadenoma (p = 0.01) and reduced in patients under dopamine agonist (p < 0.01) or somatostatin analogue (p < 0.05) treatment. CONCLUSIONS: Intracranial ICA changes are common findings in acromegaly, and further studies focused on their possible clinical impact are needed.

Factors associated with disease control failure in acromegaly patients treated with pegvisomant: an ACROSTUDY analysis.

Purpose: The aim of this study was to examine the probability of achieving acromegaly disease control according to several patient-, disease- and treatment-related factors longitudinally. Methods: We analyzed data from ACROSTUDY, an open-label, noninterventional, post-marketing safety surveillance study conducted in 15 countries. A total of 1546 patients with acromegaly and treated with pegvisomant, with available information on baseline IGF-1 level, were included. Factors influencing IGF-1 control were assessed up to 10 years of follow-up by mixed-effects logistic regression models, taking into account changing values of covariates at baseline and at yearly visits. Twenty-eight anthropometric, clinical and treatment-related covariates were examined through univariate and multivariate analyses. We tested whether the probability of non-control was different than 0.50 (50%) by computing effect sizes (ES) and the corresponding 95% CI. Results: Univariate analysis showed that age <40 years, normal or overweight, baseline IGF-1 <300 µg/L or ranged between 300 and 500 µg/L, and all pegvisomant dose <20 mg/day were associated with a lower probability of acromegaly uncontrol. Consistently, in multivariate analyses, the probability of uncontrolled acromegaly was influenced by baseline IGF-1 value: patients with IGF-1 <300 µg/L had the lowest risk of un-controlled acromegaly (ES = 0.29, 95% CI: 0.23-0.36). The probability of acromegaly uncontrol was also lower for values 300-500 µg/L (ES = 0.37, 95% CI: 0.32-0.43), while it was higher for baseline IGF-1 values ≥700 µg/L (ES = 0.58, 95% CI: 0.53-0.64). Conclusion: Baseline IGF-l levels were a good predictor factor for long-term acromegaly control. On the contrary, our data did not support a role of age, sex, BMI and pegvisomant dose as predictors of long-term control of acromegaly. Significance statement: Among factors that could influence and predict the efficacy of pegvisomant therapy in controlling acromegaly, a central role of baseline IGF-1 values on the probability of achieving a biochemical control of acromegaly during the treatment with pegvisomant was identified, in a real-life setting.

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

Herniation of cerebellar tonsils in acromegaly: prevalence, pathogenesis and clinical impact.

Herniation of cerebellar tonsils (CTH) might occur in acromegaly patients and improve after acromegaly treatment. Our study investigated CTH prevalence in acromegaly, its relationship with clinical, laboratory and neuroimaging findings and its possible pathogenesis and clinical impact. 150 acromegaly patients (median-age 56 years, age-range 21-88, 83 females) underwent brain magnetic resonance imaging (MRI). Clinical data, laboratory and pituitary adenoma imaging findings were recorded. CTH, posterior cranial fossa area, tentorial angle, clivus, supraocciput and Twining's line length were measured in acromegaly patients and controls, who included MRI of 115 consecutive subjects with headache or transient neurological deficits (control group-1) and 24 symptomatic classic Chiari 1 malformation patients (control group-2). Acromegaly patients were interviewed for symptoms known to be related with CTH. 22/150 acromegaly patients (15 %) and 8/115 control group-1 subjects presented with CTH (p = 0.04). In acromegaly patients, CTH correlated positively with younger age and inversely with GH-receptor antagonist treatment. Control group-2 had a shorter clivus than CTH acromegaly patients (40.4 ± 3.2 mm vs 42.5 ± 3.3 mm, p < 0.05), while posterior fossa measures did not differ among acromegaly subgroups (with and without CTH) and control group-1. Headache and vision problems were more frequent in CTH acromegaly patients (p < 0.05); two acromegaly patients presented with imaging and neurological signs of syringomyelia. Despite no signs of posterior fossa underdevelopment or cranial constriction, CTH is more frequent in acromegaly patients and seems to contribute to some disabling neurological symptoms.

EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alström syndrome and Bardet-Biedl syndrome.

BACKGROUND: Wolfram, Alström and Bardet-Biedl (WABB) syndromes are rare diseases with overlapping features of multiple sensory and metabolic impairments, including diabetes mellitus, which have caused diagnostic confusion. There are as yet no specific treatments available, little or no access to well characterized cohorts of patients, and limited information on the natural history of the diseases. We aim to establish a Europe-wide registry for these diseases to inform patient care and research. METHODS: EURO-WABB is an international multicenter large-scale observational study capturing longitudinal clinical and outcome data for patients with WABB diagnoses. Three hundred participants will be recruited over 3 years from different sites throughout Europe. Comprehensive clinical, genetic and patient experience data will be collated into an anonymized disease registry. Data collection will be web-based, and forms part of the project's Virtual Research and Information Environment (VRIE). Participants who haven't undergone genetic diagnostic testing for their condition will be able to do so via the project. CONCLUSIONS: The registry data will be used to increase the understanding of the natural history of WABB diseases, to serve as an evidence base for clinical management, and to aid the identification of opportunities for intervention to stop or delay the progress of the disease. The detailed clinical characterisation will allow inclusion of patients into studies of novel treatment interventions, including targeted interventions in small scale open label studies; and enrolment into multi-national clinical trials. The registry will also support wider access to genetic testing, and encourage international collaborations for patient benefit.

Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome.

Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits. The gene involved in Alström syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alström syndrome and the common diseases that characterize it.

SGLT2 Inhibitors in the Management of Type 1 Diabetes (T1D): An Update on Current Evidence and Recommendations.

SGLT2i (sodium glucose transporter type 2 inhibitors) are pharmacological agents that act by inhibiting the SGLT2, by reducing the renal plasma glucose threshold and inducing glycosuria, resulting in a blood glucose lowering effect. In recent years, studies demonstrating some additional positive effects of SGLT2i also in the treatment of T1D have increased progressively. The SGLT2i dapagliflozin and sotagliflozin have been temporarily licensed for use by the European Medical Agency (EMA) as an adjunct to insulin therapy in adults with T1D with a body mass index of 27 kg/m2 or higher. However, in the meantime, the US Food and Drug Administration (FDA) Endocrinologic and Metabolic Drugs Advisory Committee was divided, citing concerns about the main side effects of SGLT2i, especially diabetic ketoacidosis (DKA). The aim of this manuscript was to conduct an update on current evidence and recommendations of the reported use of SGLT2i in the treatment of T1D in humans. Preclinical studies, clinical trial and real world data suggest benefits in glycaemia control and nefro-cardiovascular protection, even though several studies have documented an important increase in the risk of DKA, a serious and life-threatening adverse event of these agents. SGLT2i potentially addresses some of the unmet needs associated with T1D by improving glycaemic control with weight loss and without increasing hypoglycemia, by reducing glycaemic variability. However, due to side effects, EMA recommendation for SGLT2 use on T1D was withdrawn. Further studies will be needed to determine the safety of this therapy in T1D and to define the type of patient who can benefit most from these medications.