The different applications of Vertebral Body Tethering - Narrative review and clinical experience.

Background: Vertebral body tethering (VBT) has been originally developed as a growth modulation technique for the surgical management of skeletally immature patients with adolescent idiopathic scoliosis (AIS). Given the positive results obtained in this setting, the use of VBT is gradually expanding to other patient categories, such as those with no or limited remaining growth or with non-idiopathic scoliosis. Aim of this manuscript is to offer an overview over the current applications of VBT, along with imaging and comments derived from the clinical experience. The work was based on a literature search conducted in January 2023 on Pubmed, Scopus and Web of Science databases. Following keywords were used for the search: vertebral body tethering, adolescent idiopathic scoliosis, early onset scoliosis, neuromuscular scoliosis, syndromic scoliosis. Results: Three patient categories in which VBT has been applied have been highlighted: VBT for growth modulation in AIS, VBT as anterior scoliosis correction in AIS and VBT for non-idiopathic curves or early-onset scoliosis. Conclusion: While growth modulation in AIS still represents the most widespread use of VBT, the use of this technique has yielded positive results in different settings as well, such as scoliosis correction in AIS or temporary or definitive curve management in non-AIS curves. While long-term results are lacking, patient selection seems to play a central role to reduce the complication rate and ensure predictable and stable results.

The timing of tether breakage influences clinical results after VBT.

INTRODUCTION: Tether breakage is a frequent mechanical complications after vertebral body tethering (VBT), but not all patients with a breakage show loss of correction. The reason of this clinical finding has not yet been clarified. We hypothesized that the integrity of the tether is relevant only in the early stages after VBT, when it drives growth modulation and tissue remodelling. After these mechanisms have taken place, the tether loses its function and a breakage will not alter the new shape of the spine. Thus, tether breakage would have a greater clinical relevance when occurring shortly after surgery. METHODS: All consecutive patients who underwent VBT and had a min. 2-year follow-up were included. The difference in curve magnitude between the 1st standing x-ray and the last follow-up was calculated (ΔCobb). For each curve, the presence and timing of tether breakage were recorded. The curves were grouped according to if and when the breakage was observed (no breakage, breakage at 0-6 months, 6-12 months, > 12 months). The ΔCobb was compared among these groups with the analysis of variance (ANOVA). RESULTS: Data from 152 curves were available: 68 with no breakage, 12 with a breakage at 0-6 months, 37 at 6-12 months and 35 > 12 months. The ANOVA found significant difference in the ΔCobb among the groups (Sum of square 2553.59; degree of freedom 3; mean of square 851.1; Fisher test 13.8; P < 0.0001). Patients with no breakage or breakage at > 12 months had similar ΔCobb (mean 4.8° and 7.8°, respectively, P = 0.3), smaller than the 0-6 or 6-12 groups (15.8° and 13.8°, respectively). CONCLUSION: Tether breakage leads to a consistent loss of correction when occurring within the first 12 months, while it has limited clinical relevance when occurring later on.

Analysis of the risk factors for early tether breakage following vertebral body tethering in adolescent idiopathic scoliosis.

INTRODUCTION: Tether breakage is a common mechanical complication after VBT. When this occurs shortly after surgery, patients may be at higher risk for loss of correction. Aim of this study was to analyze demographic and radiographic parameters that may potentially be risk factors for early tether breakage, as no data are yet available on this topic. MATERIALS AND METHODS: All skeletally immature patients who underwent VBT and for whom a 1-year follow-up was available were included in the study. Demographic, intraoperative and coronal and sagittal parameters from the preoperative and 1st standing X-rays were collected. Patients were divided in two groups according to the presence or absence of a breakage and the outcomes of interest were compared. RESULTS: Data from 105 patients were available (age 14.2 ± 1.5, 153 curves). Lumbar curves showed a higher risk of breakage than thoracic ones (71% vs. 29%, P < 0.0001). Overall, preoperative risk factors were a high curve magnitude (MD, mean difference - 4.1°, P = 0.03) and a limited flexibility (MD 8.9%, P = 0.006); postoperative risk factors were a large residual curve (MD - 6.4°, P = 0.0005) and a limited correction (MD 8.4%, P = 0.0005). The same risk factors were identified in thoracic curves, while in lumbar instrumentation only a higher preoperative Cobb angle represented a risk factor for breakage. Age and skeletal maturity did not represent risk factors. CONCLUSION: The main preoperative risk factors for early tether breakage after VBT are a high curve magnitude and a limited flexibility. A limited curve correction also represents a risk factor for this complication.

Improvement of facial scar appearance and microcirculation by autologous lipofilling.

BACKGROUND: Autologous lipofilling has become a standard procedure for many indications in plastic surgery. Single-case studies have reported improvements in scars, especially in burn patients, after autologous lipofilling. Despite its widespread use, little is known about the mechanisms responsible for this improvement. It is hypothesized that the mesenchymal stem cells and numerous growth factors contained in the lipoaspirate contribute to the skin and scar remodeling. MATERIAL AND METHODS: Between 2008 and 2012, 35 facial scars (n=35) on 26 patients (n=26) were treated by autologous lipofilling. The preoperative examinations and postoperative follow-up included use of the patient and observer scar assessment scale (POSAS), photo documentation, and laser Doppler spectrometry (O2C) measurements of tissue oxygen saturation, hemoglobin levels, and microcirculation on the second, seventh, and ninetieth postoperative days. RESULTS: The scar quality improved in all cases, leading to a high patient satisfaction rate at the final follow-up examination. The POSAS scores were significantly increased for pain (p=0.0331), color (p=0.0007), stiffness (p=0.0030), irregularity (p=0.0039), pigmentation (p=0.0282), and pliability (p=0.0404). In addition, we observed increased hemoglobin levels in the early postoperative period (second day) and a reduction in the microcirculation, which normalized to the preoperative values after 7-90 days. CONCLUSIONS: We demonstrated that autologous lipofilling represents a valuable technique for the treatment of facial scars. Further prospective observational studies are needed to better understand the mechanisms leading to scar enhancement and to make this procedure more reliable and predictable for patients.

Prenatal genetic counseling referrals for advanced maternal age: still room for improvement.

OBJECTIVE: The objective of this study is to evaluate genetic risks already present before pregnancy in a cohort of pregnant women referred for prenatal genetic counseling exclusively for advanced maternal age (AMA). METHOD: We retrospectively reviewed the records of 1353 women referred over 1 year (2010) for pre-test genetic counseling with the only indication of AMA at three Italian Clinical Genetic Services. RESULTS: Of the 1353 women fulfilling the inclusion criteria of the study, 87 (6.4%) had cumulatively 94 genetic risk factors not previously identified (one risk factor in 80 patients and two risk factors in seven). Twenty-six risk factors (27.7%) concerned heterogeneous or multifactorial conditions and 68 (72.3%) Mendelian or chromosomal disorders and consanguinity.In nine out of these 87 women, the estimated risk for the offspring of a genetic disease or a significant structural anomaly was >5%. Additional testing according to the identified risks was performed in 36 of these 87 women/families. CONCLUSIONS: The proportion of cases with additional risk factors is smaller than reported in previous studies, but it remains substantial and confirms the need for strategies to increase awareness of the public and health professionals responsible for the care of women in childbearing age.

The Italian external quality assessment scheme in classical cytogenetics: four years of activity.

BACKGROUND: The Italian external quality assessment scheme in classical cytogenetics was started in 2001 as an activity funded by the National Health System and coordinated by the Italian Public Institute of Health. OBJECTIVES: The aim of our work is to present data from the first 4 years of activity, 2001-2004. METHODS: Italian cytogenetics public laboratories were enrolled on a voluntary basis, and this nationwide program covered prenatal, postnatal and oncological diagnosis. The scheme is annual and retrospective; a panel of experts reviewed the quality of images and reports in order to assess technical, analytical and interpretative performance. RESULTS: Over the 4-year period, the number of participating laboratories increased: from 36 in 2001, 46 in 2002, 49 in 2003 to 51 in 2004. The overall technical performance was satisfactory. Inadequacy or lack of information in reporting was the most frequent analytical inaccuracy identified in all parts of the scheme. However, the percentage of complete reports increased significantly during the period: by 36% in postnatal diagnosis between 2001 and 2004 (p < 0.001) and by 42% in oncological diagnosis between 2002 and 2004 (p = 0.003). CONCLUSIONS: Our experience reveals that participation in external quality assessment programs has significant advantages, helping to standardize and to assure quality in cytogenetic testing.

Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome.

INTRODUCTION: The 22q13.3 deletion syndrome (MIM 606232) is characterised by neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. We report the molecular characterisation of the deletion breakpoint in two unrelated chromosome 22q13.3 deletion cases. METHODS: The deletions were characterised by FISH, checked for other abnormalities by array-CGH, and confirmed by Real-Time PCR, and finally the breakpoints were cloned, sequenced, and compared. RESULTS: Both cases show the cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. The cases show a breakpoint within the same 15 bp repeat unit, overlapping the results obtained by Wong and colleagues in 1997 and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. The direct repeat involved in these 22q13 deletion cases is presumably able to form slipped (hairpin) structures, but it also has a strong potential for forming tetraplex structures. DISCUSSION: Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech. The two cases presented here, having a deletion partially overlapping the commercial subtelomeric probe, highlight the difficulties in interpreting FISH results and suggest that many similar cases may be overlooked.

International cooperation and networking in genetic health care provision: issues arising from the genetic services plan for the Emilia-Romagna region, Italy.

The aims of this report are to describe the genetic plan for Emilia-Romagna, a region in Italy, and to contribute to the international exchange of information on developing and applying policy frameworks to provide high-quality and comprehensive genetic health care in the publicly funded health systems. At the present time there is no national policy for genetic medicine in Italy, and only two regions, Emilia-Romagna and Liguria, have formally agreed to a strategic plan for health care in genetics. The current provision of genetic services in Emilia-Romagna is described focusing on the intra- and inter-organizational linkages to ensure a comprehensive system of coordinated activities. Strengths and implementation areas are highlighted. Points that must be solved within the regional or national context are the definition of the level of assistance required in genetic medicine, the formal professional recognition of the genetic counselor and the adjustment of the billing mechanisms to the complexities of clinical genetic services. Issues that need to be addressed at a wider level include full assessment of genetic tests before their introduction into clinical practice, networking to provide tests for the rarest genetic diseases, consensus on fundamental terminology and clinical and administrative data sets to promote a cohesive framework for the flow of information throughout the health care systems with respect to genetics.

Congenital heart defects: 15 years of experience of the Emilia-Romagna Registry (Italy).

OBJECTIVES: Collection and assessment of data from the Emilia-Romagna Region on the occurrence of congenital heart defects in order to identify an homogeneous group of patients for further aetiologic and genetic studies. MATERIALS AND METHODS: The present study is based on 1549 stillborn and live born babies affected by congenital heart defect out of 330,017 consecutive births (4.7 per 1000). RESULTS: The frequency and type of congenital heart defects have been identified together with the sex ratio, associated extracardiac anomalies, chromosomal anomalies and the risk of precurrence in relatives. The impact of prenatal diagnosis on prevalence was low during the study period. CONCLUSIONS: The study has provided epidemiological data for public health surveillance of congenital heart defects in the Emilia-Romagna region. The creation of a system for the nationwide recording of congenital heart defects designed with regard to the sources of ascertainment, the diagnostic criteria, and the system of classification is emphasised.

Inverted duplications are recurrent rearrangements always associated with a distal deletion: description of a new case involving 2q.

We studied the case of a subject with an inverted duplication of 40 cM of 2q33-q37 concurrent with a 10 cM deletion of the distal 2q, the latter not being detectable by cytogenetics. Microsatellite analysis demonstrated the absence of maternal alleles in the deleted region and a double dosage for one of the maternal alleles in the duplication region. We hypothesised that this type of rearrangement occurs at meiosis I, while the two homologues are synapsed for most of their length. The presence of inverted duplicons in the same chromosome arm would favour the partial refolding of one homologue into itself so leading to the intrachromatid synapsis and recombination of the inverted repeats. The arising recombinant chromosome is deleted for the region beyond the most distal repeat and with the chromatids joined together at the level of the region located between the two duplicons. At meiosis II, the two linked chromatids can join the opposite poles provided that a breakage between the two centromeres occurs leading to a duplicated/deleted chromosome and a simply deleted chromosome. This model can be extended to all the so-called inverted duplication cases and to part of the terminal deletions. In fact the finding that, in our invdup(2q), the entire 40 cM duplication region involves only one of the two maternal alleles, indeed indicates that the abnormal crossover occurs between sister chromatids. The phenotype associated with our 2q rearrangement led us to narrow the critical region for the Albright-like syndrome to 10 cM in the subterminal 2q region.

Combined use of cytogenetic analysis and FISH for the identification of two antenatal de novo markers as Robertsonian translocations involving the p arms.

In two prenatal cases, de novo nonmosaic bisatellited marker chromosomes were studied with the combined use of fluorescence in situ hybridization (FISH) with chromosome specific probes and cytogenetic heteromorphisms. The FISH studies showed that one of the small accessory chromosome could be a heterozygous 14/15 or 15/22 translocation involving the p arms of these chromosomes, the other showed only one hybridization spot with the classical satellite probe of chromosome 15. The analysis of heteromorphisms of the parental acrocentric chromosomes demonstrated that the two markers were Robertsonian translocations involving in the first case the p arms of the maternal 15 and 22 chromosomes and in the second case the p arms of the maternal 14 and 15 chromosomes.

[Blackfan-Diamond disease with ambiguous genitalia]. / Malattia di Blackfan-Diamond con genitali ambigui.

The Authors describe a case of Blackfan-Diamond anemia with ambiguous genitalia and other minor anomalies. They point out the elements of differential diagnosis with other precocious erythroblastopenic conditions and suppose a recessive inheritance of the disease because of family consanguinity in two generations.

A new family with chorioretinal dystrophy, spinocerebellar ataxia and hypogonadotropic hypogonadism (Boucher-Neuhäuser syndrome).

A family is described in which two brothers have spinocerebellar ataxia, hypogonadotropic hypogonadism and chorioretinal dystrophy. This report provides further evidence to support the previous suggestion that this triad of manifestations represents a specific single-gene disorder, designated Boucher-Neuhäuser syndrome. Analysis of affected individuals shows that neurological signs usually develop during adolescence or young adulthood (range: early childhood-fourth decade) and are slowly progressive or non-progressive, whereas ophthalmologic manifestations have an age of onset which varies from the first to the sixth decade of life and a pronounced variability in progression.

Distal 12p deletion in a stillborn infant.

A stillborn female with a "de novo" deletion of band 12p13 is described. Her main clinical manifestations are intrauterine growth retardation, unilateral cleft lip, protruding tongue, and small, low set, and posteriorly angulated ears. Comparison of this case with 4 previous reported patients with an isolated distal del(12p) fails to show significant common phenotypic characteristics.

Ring chromosome 7: report of the fifth case.

A 13-year-old boy with a 46,XY,r(7) karyotype presented with growth failure, microcephaly, achromic spots and multiple pigmented naevi. Psychomotor development was normal and no major malformations were present. Comparison with four previously reported patients with ring chromosome 7 shows that the most frequent findings in these subjects were short stature, microcephaly and dermatological abnormalities.

The phenotype of partial dup(7q) reconsidered: a report of five new cases.

Five unrelated patients with partial trisomy 7q are described. In two of them the duplicated region was 7q21----qter and in the others 7q22----qter, 7q34----qter and 7q35----qter, respectively. Clinical features were compared with those reported in published cases. Karyotype-phenotype correlations showed a relationship between the size of the unbalanced region and the survival, and prenatal and postnatal growth. In contrast, the same proportionality was not demonstrated between the severity of dysmorphic features and the size of the duplicated region. However, cleft palate seemed associated rather characteristically with dup 7q22/31----qter.

Mosaicism for an extra small ring chromosome.

A new case for mosaicism for an extra small ring chromosome is described in a 13-year-old girl with minimal phenotype anomalies and moderate mental retardation. The origin of the extra chromosome could not be determined either cytogenetically or clinically. The present case is compared with six similar cases in the literature.