Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases. METHODS: While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA. RESULTS: All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant (TMEM216 c.218G>T) was significantly enriched in American compared with European patients with JS, while MKS1 c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes.Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from a MKS1 c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from a KIAA0586 c.428delG healthy homozygote. CONCLUSION: This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants.

Imaging of Anatomical Variants of the Long Head Biceps Tendon.

Anatomical variants of the long head of biceps (LHB) tendon are widely discussed in the literature. As one of the few intra-articular tendons, magnetic resonance arthroscopy can quickly evaluate the proximal part of LHB morphology. It provides good assessment of both intra-articular and extra-articular portions of the tendons. In-depth knowledge about imaging of the anatomical LHB variants discussed in this article is useful preoperatively for orthopaedists and also helps avoid potential diagnostic misinterpretations.

High degree of consensus on diagnosis and management of rotator cuff tears: a Delphi approach.

PURPOSE: To develop a consensus on diagnosis and treatment of rotator cuff tears. The study focused on selected areas: imaging, prognostic factors, treatment options, surgical techniques. METHODS: Panel was composed of all members of the shoulder committee of the Italian Society of Arthroscopy, Knee, Upper arm, Sport, Cartilage and Orthopedic techniques (SIAGASCOT). Four rounds were performed. The first round consisted of gathering questions which were then divided into seven blocks referring to: imaging, patient-related prognostic factors, treatment options, surgical steps, reparative techniques, surgical predictive factors, advanced techniques. Subsequent rounds consisted of condensation by means of online questionnaire and debates. Consensus was defined as two-thirds agreement on one answer. Descriptive statistic was used to summarize the data. RESULTS: Forty-one shoulder experts were involved. Fifty-six statements were finally formulated. A consensus could be achieved on 51. Experts agreed that preoperative magnetic resonance imaging is strongly recommended because it allows a careful evaluation of tear characteristics, while the role of US remains debatable. Controversial patient-related factors such as age, comorbidities, smoking and stiffness do not contraindicate the repair. From a surgical standpoint, the experts highlighted that pseudo-paralysis is not a contraindication to rotator cuff repair. Consensus on specific surgical steps was also achieved: capsular release should be performed only in stiff shoulders; footprint preparation is mandatory, while debridement of tendon edges is not essential. If necessary, a rotator interval release could be performed without interrupting the continuity between subscapularis and supraspinatus tendon; posterior delamination should be always included in the repair. Advanced techniques such as tendon transfers should be selected based on the main clinical deficit, while the superior capsule reconstruction plays a role only in combination with a functional repair. CONCLUSION: A consensus was achieved almost on every topic of controversy explored. Particularly, MRI was deemed necessary to determine tear characteristics, while radiographs remain important for differential diagnosis; age should not be considered a contraindication to surgery; pseudo-paralysis does not represent a contraindication to arthroscopic rotator cuff repair, but superior capsule reconstruction plays a role only in combination with a functional repair. Latissimus dorsi transfer plays a role when the main functional deficit is in elevation, while the lower trapezius transfer plays a role when the main functional deficit is the external-rotation. LEVEL OF EVIDENCE: V.

Glenoid bone loss in anterior shoulder dislocation: a multicentric study to assess the most reliable imaging method.

PURPOSE: The aim of this multicentric study was to assess which imaging method has the best inter-reader agreement for glenoid bone loss quantification in anterior shoulder instability. A further aim was to calculate the inter-method agreement comparing bilateral CT with unilateral CT and MR arthrography (MRA) with CT measurements. Finally, calculations were carried out to find the least time-consuming method. METHOD: A retrospective evaluation was performed by 9 readers (or pairs of readers) on a consecutive series of 110 patients with MRA and bilateral shoulder CT. Each reader was asked to calculate the glenoid bone loss of all patients using the following methods: best fit circle area on both MRA and CT images, maximum transverse glenoid width on MRA and CT, CT PICO technique, ratio of the maximum glenoid width to height on MRA and CT, and length of flattening of the anterior glenoid curvature on MRA and CT. Using Pearson's correlation coefficient (PCC), the following agreement values were calculated: the inter-reader for each method, the inter-method for MRA with CT quantifications and the inter-method for CT best-fit circle area and CT PICO. Statistical analysis was carried out to compare the time employed by the readers for each method. RESULTS: Inter-reader agreement PCC mean values were the following: 0.70 for MRA and 0.77 for CT using best fit circle diameter, 0.68 for MRA and 0.72 for CT using best fit circle area, 0.75 for CT PICO, 0.64 for MRA and 0.62 for CT anterior straight line and 0.49 for MRA and 0.43 for CT using length-to-width ratio. CT-MRA inter-modality PCC mean values were 0.9 for best fit circle diameter, 0.9 for best fit circle area, 0.62 for anterior straight line and 0.94 for length-to-width methods. PCC mean value comparing unilateral CT with PICO CT methods was 0.8. MRA best fit circle area method was significantly faster than the same method performed on CT (p = 0.031), while no significant difference was seen between CT and MRA for remaining measurements. CONCLUSIONS: CT PICO is the most reliable imaging method, but both CT and MRA can be reliably used to assess glenoid bone loss. Best fit circle area CT and MRA methods are valuable alternative measurement techniques.

Long head biceps tendon instability: diagnostic performance of known and new MRI diagnostic signs.

OBJECTIVE: The aim of this work was to evaluate the inter-observer agreement and diagnostic performance values of 7 MRI signs (3 known and 4 new) of long head biceps tendon instability. MATERIALS AND METHODS: MRI of 86 patients were retrospectively evaluated. Inter-observer agreement and diagnostic performance of each diagnostic sign and of all combined signs (with the exception of detour sign) were tested for identification of biceps tendon instability, with arthroscopy as the reference standard. RESULTS: Agreement between expert operators was moderate to good. Sensitivity, specificity, and sign accuracy showed a variation respectively of the following: humeral chondral print 72-80%, 62-68%, and 70-76%; subchondral bone edema 24-31%, 84-97%, and 50%; biceps tendon angle 60-71%, 97-100%, and 74-81%, biceps tendon-groove distance 31-47%, 90-100%, and 56-64%; long head biceps subluxation/dislocation on axial plane 49-53%, 97-100%, and 66-70%; displacement sign 74-80%, 74-100%, and 74-87%; detour sign 51-64%, 58-81%, and 62-64%; and all signs 98-100%, 32-61%, and 75-86%. CONCLUSION: These diagnostic signs, both known and new, individually and/or in combination, provide a valid tool in the MRI diagnosis of long head biceps tendon instability.

Arthroscopic reduction and subscapularis remplissage (ARR) of chronic posterior locked shoulder dislocation leads to optimized outcomes and low rate of complications.

PURPOSE: Unrecognized posterior shoulder dislocation with a concomitant humeral head fracture affects joint function and no consensus exists regarding treatment. The present study analyses clinical and radiographic outcomes of a novel arthroscopic technique for reducing chronic locked posterior shoulder dislocation associated with subscapularis remplissage. METHODS: The study comprises a retrospective analysis of consecutive chronic posterior locked shoulders (CPLS) with minimum 2-years follow-up of patients who had undergone McLaughlin technique arthroscopic modification for the treatment of CPLS with a reverse Hill-Sachs lesion. Active range of motion (ROM), Western Ontario (WOSI) and Constant Score (CS), were evaluated pre- and postoperatively. Plain radiographs and magnetic resonance imaging (MRI) scans were collected pre- and post-operatively, recording bone defect, osteoarthritis, cuff integrity/fatty infiltration, and the grade of filling of the reverse Hill-Sachs. RESULTS: Twelve male patients with a mean follow-up of 37.3 months ± 10.5 (range, 24-58) were included. Mean WOSI and CS scores improved from 41 to 92 and 28 to 94 points, respectively. ROM measurements all had significantly increased at final follow-up, with no significant differences in arm rotation. No defects were left unfilled at final MRI examination. CONCLUSION: The results of this uncontrolled study with a limited number of patients confirm that arthroscopic reduction and subscapularis remplissage is a highly effective and satisfactory treatment method resulting in no shoulder rotation deficits. LEVEL OF EVIDENCE: Level IV.

Comma sign of subscapularis tear: diagnostic performance and magnetic resonance imaging appearance.

BACKGROUND: The main aim of this study was to evaluate the performance of magnetic resonance imaging (MRI) and interobserver agreement in the identification of the comma sign. The second objective was to look for a correlation between the comma sign and the detachment of the superficial fascia of the subscapularis. MATERIALS AND METHODS: Two radiologists, blinded to the arthroscopic findings, retrospectively assessed the magnetic resonance images of 110 shoulders and were asked to assess the presence of the comma sign and the intact subscapularis fascia. The inter-reader agreement and the MRI performance values for detection of the comma sign were calculated. In addition, the association between the intact superficial subscapularis fascia and the comma sign was evaluated. RESULTS: The agreement between the 2 radiologists was perfect. The following values were obtained: sensitivity, 90.9%; specificity, 98.8%; positive predictive value, 95.2%; negative predictive value, 97.7%; and accuracy, 97.2%. No association between the comma sign and subscapularis fascia lesions was found. CONCLUSION: MRI appears to be a reliable method for preoperative assessment of the comma sign. The comma sign appears not to be formed by the detached subscapularis fascia.

Problems, complications, and reinterventions in 4893 onlay humeral lateralized reverse shoulder arthroplasties: a systematic review (part I-complications).

BACKGROUND: Several modifications to the original Grammont reverse shoulder arthroplasty (RSA) design have been proposed to prevent distinctive issues, such as both glenoid and humeral lateralization. The aim of this systematic review was to determine rates of problems, complications, reoperations, and revisions after onlay lateralized humeral stem RSA, hypothesizing that these are design related. METHODS: This systematic review was performed in accordance with the PRISMA statement guidelines. A literature search was conducted (01.01.2000-14.04.2020) using PubMed, Cochrane Reviews, Scopus, and Google Scholar employing several combinations of keywords: "reverse shoulder arthroplasty," "reverse shoulder prosthesis," "inverse shoulder arthroplasty," "inverse shoulder prosthesis," "problems," "complications," "results," "outcomes," "reoperation," "revision." RESULTS: Thirty-one studies with 4893 RSA met inclusion criteria. The 892 postoperative problems and 296 postoperative complications represented overall problem and complication rates of 22.7% and 7.5%, respectively. Forty-one reoperations and 63 revisions resulted, with an overall reoperation rate of 1.7% and overall revision rate of 2.6%. CONCLUSIONS: Problem, complication, and reintervention rates proved acceptable when implanting a high humeral lateralization stem in RSA. The most frequent problem was scapular notching (12.6%), and the most common postoperative complication was scapular stress fracture (1.8%). An overall humeral complication rate of 1.9% was identified, whereas short stems reported no humeral fractures or stem loosening. Infections (1.3%) proved to be the most common reason for component revision, and instability had a complication rate of 0.8%. LEVEL OF EVIDENCE: Systematic review IV.

Problems, complications, and reinterventions in 4893 onlay humeral lateralized reverse shoulder arthroplasties, a systematic review: part II-problems and reinterventions.

BACKGROUND: Several modifications to the original Grammont reverse shoulder arthroplasty (RSA) design have been proposed to prevent distinctive issues, such as both glenoid and humeral lateralization. The aim of this systematic review was to determine rates of problems, complications, reoperations, and revisions after onlay lateralized humeral stem RSA, hypothesizing that these are design related. METHODS: This systematic review was performed in accordance with the PRISMA statement guidelines. A literature search was conducted (1 January 2000 to 14 April 2020) using PubMed, Cochrane Reviews, Scopus, and Google Scholar, employing several combinations of keywords: "reverse shoulder arthroplasty," "reverse shoulder prosthesis," "inverse shoulder arthroplasty," "inverse shoulder prosthesis," "problems," "complications," "results," "outcomes," "reoperation," and "revision." RESULTS: Thirty-one studies with 4893 RSA met inclusion criteria. The 892 postoperative problems and 296 postoperative complications represented overall problem and complication rates of 22.7% and 7.5%, respectively. Forty-one reoperations and 63 revisions resulted, with overall reoperation and revision rates of 1.7% and 2.6%, respectively. CONCLUSIONS: Problem, complication, and reintervention rates proved acceptable when implanting a high humeral lateralization stem RSA. The most frequent problem was scapular notching (12.6%), and the most common postoperative complication was scapular stress fracture (1.8%). An overall humeral complication rate of 1.9% was identified, whereas no humeral fractures or stem loosening were reported with short stems. Infections (1.3%) were the most common reason for component revision, followed by instability (0.8%). LEVEL OF EVIDENCE: Systematic review IV.

Sonography of chondral print on humeral head.

OBJECTIVE: The aim of this study is to determine the diagnostic accuracy of sonography in order to identify the chondral print on the humeral head. MATERIALS AND METHODS: In total, 44 patients who had already been candidates for arthroscopic surgery were prospectively studied with ultrasound to assess the presence of humeral subchondral erosion at the level of the biceps pulley; no patient had undergone previous surgery or radiographic calcification of rotator cuff tendons. Using arthroscopy as the reference standard the sensitivity, specificity, positive predictive, negative predictive and diagnostic accuracy values were calculated. RESULTS: Of the 44 patients, arthroscopy showed the humeral chondral print in 30 patients. Of the 30 arthroscopy proven humeral chondral prints, ultrasound identified 28 subchondral erosions at the same level, with two false negatives. One of the 14 patients without arthroscopic humeral chondral print was positive for subchondral erosion at ultrasound. The sensitivity, specificity, positive predictive, negative predictive, and diagnostic accuracy values of ultrasound were respectively of 93, 93, 96, 87 and 93%. CONCLUSION: Ultrasound has a good diagnostic accuracy in identifying the chondral print sign.

A chaperone enhances blood α-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy.

Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone.

Magnetic intragap states and mixed parity pairing at the edge of spin-triplet superconductors.

We show that a spontaneous magnetic moment may appear at the edge of a spin-triplet superconductor if the system allows for pairing in a subdominant channel. To unveil the microscopic mechanism behind such an effect, we combine numerical solution of the Bogoliubov-de Gennes equations for a tight-binding model with nearest-neighbor attraction, and the symmetry based Ginzburg-Landau approach. We find that a potential barrier modulating the electronic density near the edge of the system leads to a nonunitary superconducting state close to the boundary where spin-singlet pairing coexists with the dominant triplet superconducting order. We demonstrate that the spin polarization at the edge appears due to the inhomogeneity of the nonunitary state and originates in the lifting of the spin degeneracy of the Andreev bound states.

Spin-orbital coupling in a triplet superconductor-ferromagnet junction.

We study the interplay of spin and orbital degrees of freedom in a triplet superconductor-ferromagnet junction. Using a self-consistent spatially dependent mean-field theory, we show that increasing the angle between the ferromagnetic moment and the triplet vector order parameter enhances or suppresses the p-wave gap close to the interface, according to whether the gap antinodes are parallel or perpendicular to the boundary, respectively. The associated change in condensation energy establishes an orbitally dependent preferred orientation for the magnetization. When both gap components are present, as in a chiral superconductor, first-order transitions between different moment orientations are observed as a function of the exchange field strength.

The Pediatric Symptom Checklist as screening tool for neurological and psychosocial problems in a paediatric cohort of patients with coeliac disease.

AIM: To screen for neurological and behavioural disorders in a paediatric cohort of patients with coeliac disease (CD) in order to detect possible differences related to compliance with gluten-free diet (GFD). METHODS: We recruited a cohort of 139 patients divided into three groups: A (40 patients with newly diagnosed CD), B (54 patients with CD in remission after GFD) and C (45 patients with potential CD). Patients first underwent a screening neurological visit, detecting signs associated with CD, and then were evaluated with Pediatric Symptom Checklist (PSC), a psychosocial screen for cognitive, emotional and behavioural problems. RESULTS: In the group B as compared to group A, there was a statistically significant decrease (p < 0.05) in the incidence of chronic fatigue, headache and inattention. The same applied to patients compliant to GFD vs. non-compliant. Potential coeliacs turning into overt CD had a higher incidence of headache and inattention compared with potential coeliacs showing normal mucosa. The PSC mean score in group A was statistically higher than in group B. CONCLUSION: Gluten-free diet had a positive impact on neuropsychiatric symptoms. We suggest the use of PSC in the routine follow-up of coeliacs in order to allow an early detection of psychosocial problems.

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst.

The immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agamma-globulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café-au-lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations abnormalities have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases.

De novo 13q12.3-q14.11 deletion involving BRCA2 gene in a patient with developmental delay, elevated IgM levels, transient ataxia, and cerebellar hypoplasia, mimicking an A-T like phenotype.

We report on a child with a de novo deletion of approximately 12 Mb detected through array comparative genomic hybridization (CGH). The deletion involved chromosome bands 13q12.3-13q14.11 and determined the loss of ≥50 genes. A second deletion on chromosome 12p11.3p11.22 of 43-167 kb, including about 12 genes, was unlikely of clinical relevance because inherited from the asymptomatic father. The child had developmental delay, dysmorphisms, and many features reminiscent of ataxia-telangiectasia (A-T), as cerebellar ataxia, oculocutaneus telangiectasia, and recurrent upper airway infections. Atraumatic fractures of the metatarsus were noted. Moreover, this is a rare case of 13q deletion syndrome associated with peripheral blood white cells radiosensitivity to bleomycin, reminiscent of what previously reported on X-ray hypersensitivity of fibroblasts from patients with alterations of this chromosome. The immunological evaluation revealed increased IgM serum levels and a low proliferative response to mitogens, PHA, and CD3 cross-linking (CD3 XL). After 12 years of age only a mild dysmetria persisted, while the proliferative response to mitogens became normal by 9 years of age.

Diagnosis delay in West syndrome: misdiagnosis and consequences.

West syndrome or infantile spasms is one of the most frequent epileptic syndromes in the first year of life. The clinical symptoms of infantile spasms are very different than any other type of seizure because of both the absence of paroxysmal motor phenomena (i.e., as in a convulsion) and the lack of significant duration of loss of consciousness (i.e., as in absence epilepsy). Infantile spasms may lead to misdiagnosis by pediatricians and other primary care providers. We assessed the missed diagnoses prior to the diagnosis of infantile spasms. We hypothesized that a delay in treatment may have consequences on neurologic outcome. We conducted a multicenter, retrospective, observational study to evaluate occurrence of misdiagnosis and its possible consequences. We performed a multivariate analysis to evaluate the risk for the outcome 2 years after the diagnosis of infantile spasms. We included 83 infants over a 5-year period. The majority of consulted physicians (301 of 362) did not suggest any specific diagnosis while the others suggested gastroesophageal reflux (7 %), constipation (7 %), or colitis (3 %). Results indicated that a poor outcome was related to a delay in diagnosis, which was observed regardless of the existence of cognitive involvement prior to the start of infantile spasms (Relative Risk: RR 12.08 [1.52-96.3]). These results highlight the importance of making an early diagnosis of infantile spasms.

Magnetic Instabilities in the Quasi-One-Dimensional K2Cr3As3 Material with Twisted Triangular Tubes.

The magnetic response of a frustrated K2Cr3As3 sample having triangular arrays of twisted tubes has been studied by means of dc magnetization measurements as a function of the magnetic field (H) at different temperatures ranging from 5 K up to 300 K. Looking at the magnetic hysteresis loops m(H), a diamagnetic behavior of the sample was inferred at temperatures higher than 60 K, whereas at lower temperatures the sample showed a hysteresis loop compatible with the presence of ferrimagnetism. Moreover, spike-like magnetization jumps, both positive and negative, were observed in a narrow range of the magnetic field around 800 Oe, regardless of the temperature considered and they were compared with the theoretical predictions on frustrated systems. The field position of the magnetization jumps was studied at different temperatures, and their distribution can be described by a Lorentzian curve. The analogies between the expected features and the experimental observations suggest that the jumps could be attributed to the magnetic frustration arising from the twisted triangular tubes present in the crystal lattice of this compound.