To define numerically the clinical severity of facioscapulohumeral muscular dystrophy (FSHD), we developed a protocol that quantifies muscle weakness by combining the functional evaluation of six muscle groups affected in this disease. To validate reproducibility of the protocol, 69 patients were recruited. Each patient was evaluated by at least five neurologists, and an FSHD severity score was given by each examiner. The degree of agreement among clinicians' evaluations was measured by kappa-statistics. Nineteen subjects received a score between 0 and 1, 9 had a score between 2 and 4, 20 received a score between 5 and 10, and 8 had a score between 11 and 15. Of the 13 subjects with D4Z4 alleles within the normal range (ranging from 10 to 150 repeats), 12 obtained a score of 0 and only 1 had a score of 1. Kappa-statistics showed a very high concordance for all muscle groups. We developed a simple, reliable, easily used tool to define the clinical expression of FSHD. Longitudinal studies will assess its sensitivity and utility in measuring changes for widespread use.

Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (≤8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4-8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1-8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.

Background Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disease with a prevalence of 1 in 20 000. Almost all patients with FSHD carry deletions of integral copies of tandem 3.3 kb repeats (D4Z4) located on chromosome 4q35. However, FSHD families have been reported in which individuals carrying a D4Z4-reduced allele remain asymptomatic. Recently, it has been proposed that the D4Z4-reduced allele is pathogenic only in association with the permissive haplotype, 4APAS. Methods and results Through the Italian National Registry for FSHD (INRF), genotype-phenotype correlations were extensively studied in 11 non-consanguineous families in which two D4Z4-reduced alleles segregate. Overall, 68 subjects carrying D4Z4-reduced alleles were examined, including 15 compound heterozygotes. It was found that in four families the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of subjects carrying a single D4Z4-reduced 4A161PAS haplotype were non-penetrant carriers; moreover, the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was found to be as high as 1.2%. Conclusions This study reveals a high frequency of compound heterozygotes in the Italian population and the presence of D4Z4-reduced alleles with the 4A161PAS pathogenic haplotype in the majority of non-penetrant subjects in FSHD families with compound heterozygosity. These data suggest that carriers of FSHD-sized alleles with 4A161PAS haplotype are more common in the general population than expected on the basis of FSHD prevalence. These findings challenge the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with relevant repercussions for genetic counselling and prenatal diagnosis.

Eagle's syndrome is a condition associated with the elongation of the styloid process or calcification of the stylohyoid ligament, clinically characterised by throat and neck pain, radiating into the ear. In this report, we describe the case of a 60-year-old woman who presented with a severe unilateral trigeminal and glossopharyngeal neuralgia. The patient was subjected to conservative therapy for four months and did not report improvement of the symptoms. After several consultations with different physicians, a diagnosis was accomplished by radiological investigation (multidetector computer tomography with multi-planar reconstructions and 3D volumetric reconstructions). Surgical styloidectomy was performed, with subsequent sudden remission of symptoms. Eagle's syndrome represents a commonly unrecognised nosological entity, clinically characterised by non-specific cranio-facial pain. Differential diagnosis includes glossopharyngeal and trigeminal neuralgia, temporal arteritis, migraine, myofascial pain dysfunction and cervical arthritis. Eagle's syndrome should always be suspected, mostly in adult women when the pain is unilateral and not responsive to painkillers. KEY WORDS: Eagle's syndrome • Elongation of the stylohyoid process • Oropharyngeal pain • Glossopharyngeal neuralgia RIASSUNTO La sindrome di Eagle è caratterizzata dall'allungamento del processo stilo-ioideo e/o dalla progressiva calcificazione del legamento stiloioideo. Il reperto è molto diffuso nella popolazione generale ma tale sindrome appare sintomatica solo in una piccola percentuale di casi. I sintomi sono rappresentati da: dolore ricorrente di tipo "trafittivo" riferito alla gola, regione antero-laterale del collo e orecchio, disfagia e sensazione di corpo estraneo in faringe. Riportiamo il caso clinico di una donna di 60 anni giunta alla nostra attenzione per dolore monolaterale sinistro, comparso da circa un mese, di tipo nevralgico, irradiato inizialmente solo lungo la branca mandibolare del nervo trigemino (nevralgia trigeminale) e successivamente alla regione laterocervicale omolaterale (nevralgia glossofaringea). La paziente era stata precedentemente valutata da numerosi specialisti e sottoposta per 4 mesi a terapia conservativa senza beneficio. La diagnosi è stata raggiunta mediante esami radiologici (Tomografia Computerizzata Multidetettore con ricostruzioni multiplanari e volumetriche 3D). È stata eseguita una stiloidectomia per via trans-cervicale, con successiva remissione dei sintomi. La sindrome di Eagle rappresenta un'entità nosologica comunemente misconosciuta, caratterizzata clinicamente da dolore cranio-facciale aspecifico. La diagnosi differenziale include la nevralgia del trigemino e glossofaringeo, l'arterite temporale, l'emicrania, il dolore miofasciale e l'artrosi cervicale. La sindrome di Eagle dovrebbe essere sempre sospettata, soprattutto nelle pazienti donne adulte e quando il dolore è unilaterale e non risponde agli antidolorifici.

The objectives of the study are to develop a new way to assess stability and discrimination capacity of radiomic features without the need of test-retest or multiple delineations and to use information obtained to perform a preliminary feature selection. Apparent diffusion coefficient (ADC) maps were computed from diffusion-weighted magnetic resonance images (DW-MRI) of two groups of patients: 18 with soft tissue sarcomas (STS) and 18 with oropharyngeal cancers (OPC). Sixty-nine radiomic features were computed, using three different histogram discretizations (16, 32, and 64 bins). Geometrical transformations (translations) of increasing entity were applied to the regions of interest (ROIs), and the intra-class correlation coefficient (ICC) was used to compare the features computed on the original and modified ROIs. The distribution of ICC values for minimal and maximal entity translations (ICC10 and ICC100, respectively) was used to adjust thresholds of ICC (ICCmin and ICCmax) used to discriminate between good, unstable (ICC10 < ICCmin), and non-discriminative features (ICC100 > ICCmax). Fifty-four and 59 radiomic features passed the stability-based selection for all the three histogram discretizations for the OPC and STS datasets, respectively. The excluded features were similar across the different histogram discretizations (Jaccard’s index 0.77 ± 0.13 and 0.9 ± 0.1 for OPC and STS, respectively) but different between datasets (Jaccard’s index 0.19 ± 0.02). The results suggest that the observed radiomic features are mainly stable and discriminative, but the stability depends on the region of the body under observation. The method provides a way to assess stability without the need of test-retest or multiple delineations.Electronic supplementary materialThe online version of this article (10.1007/s10278-018-0092-9) contains supplementary material, which is available to authorized users.