Role of the Lumbosacral Transition Vertebra and Vertebral Lamina in the Pathogenesis of Lumbar Disc Herniation.

OBJECTIVE: To investigate the prevalence of lumbosacral transition vertebrae (LSTVs) in both the normal population and the lumbar disc herniation (LDH) population and to determine the risk factors for LDH. METHODS: Between January 2019 and September 2020, all patients aged 18-39 years and underwent an anteroposterior (AP) X-ray of the lumbar vertebrae were retrospective reviewed in our institution. Those patients who were diagnosed with LDH were eligible for inclusion in the LDH group. During the same period, those patients admitted to our hospital who underwent an anteroposterior X-ray of the lumbar spine and had not been diagnosed with LDH were included in the control group. Those patients with disease that might affect the lumbar anatomy were excluded from both groups. The type of LSTV was classified according to the Castellvi classification. The height of the lumbar vertebral lamina was evaluated through the h/H index. The inter- and intra-observer reliability was evaluated by one senior radiologist and one senior orthopedist using intraclass correlation coefficient (ICC). The association between the LSTV and the herniation level was also investigated. Binary logistic regression was used to explore the association of different factors between the LDH group and the control group. RESULTS: Two hundred LDH patients (115 male and 85 female) and 200 individuals (108 male and 92 female) were investigated retrospectively. The prevalence of LSTVs was 71.5% (n = 143) in the LDH group and 34.0% (n = 68) in the control group. The most frequent LSTV types were type Ib and type IIa. The inter- and intra-observer ICCs of the measurement of "h/H" index and the classification of LSTV were all "excellent" (ICC > 0.90). The median h/H index in the control group was significantly higher than that in the LDH group (0.28 (0.26, 0.31) vs 0.34 (0.31, 0.37), P = 0.000). The distribution of the Castellvi classification in the L4/5 and L5/S1 herniation patients was significantly different (P = 0.048). LSTVs, BMI and the h/H index were closely associated with LDH, with odds ratios of 3.06 (95% CI: 2.12-4.43), 1.23 (95% CI: 1.13-1.33) and 0.09 (95% CI: 0.05-0.15), respectively. The incidence of L4/5 disc herniation in patients with an LSTV was significantly more common than that in patients with L5/S1 disc herniation (P = 0.048). CONCLUSION: The prevalence of LSTVs was 34.0% in the control group and 71.5% in the LDH group; LSTVs and BMI were positively correlated with LDH, and h/H was negatively correlated with LDH.

Determination of congenital absence of palmaris longus tendon with clinical examination and ultrasonography.

OBJECTIVES: The tendon of the palmaris longus is commonly used as a tendon graft in many reconstructive surgeries. Palmaris longus absence (PLA) was found in 15% among individuals worldwide. In this prospective study, we aimed to conduct an incidence study in which physical examination methods were confirmed by ultrasonography in PLA, and to evaluate the relationship of absence with age, gender, laterality and dominant hand. METHODS: The study included 490 cases. They were initially tested to evaluated by physical examination using the Schaeffer's and Hiz-Ediz test for the assessment of the palmaris longus tendon. Additional ultrasonography was performed to confirm its absence in 129 wrists of 78 cases whose tendons could not be visualized or palpated. RESULTS: The incidence of tendon absence was 13% by physical examination methods. According to the final results when we added ultrasonography to physical examination methods, the incidence of unilateral, bilateral and overall absence of the palmaris longus were 5%, 9% and 11% respectively. There was no statistically significant difference between individuals with and without PLA in terms of gender, side, age and dominant hand (p = 0.796, p = 0.622, p = 0.397 and p = 0.187, respectively). However, bilateral PLA was statistically significantly higher than unilateral in both genders (p = 0.011). CONCLUSIONS: We think that agenesis should be proven accurately by ultrasonographic examination for the final result before any surgical procedure with palmaris longus tendon. Furthermore measuring the diameter of the palmaris longus tendon by preoperative ultrasonography can be useful for surgeons who plan a procedure that requires specific measurements.

Musculoskeletal abnormalities in a large international cohort of boys with 49,XXXXY.

49,XXXXY is the rarest X and Y chromosomal variation, with an incidence of 1 in 80,000-100,000 live male births and has been associated with numerous musculoskeletal abnormalities. Data was collected from an international cohort of boys with 49,XXXXY over 10 years. Children were evaluated by a multidisciplinary team consisting of a pediatric orthopedist, a neurogeneticist, a neurodevelopmentalist, and two physical therapists. Increased rates of torticollis (32.4%), hamstring tightness (42%), radioulnar synostosis (67.6%), pes planus (65.2%), and other foot abnormalities (86.9%) were observed. Several anomalies increased with age, specifically hamstring tightness, kyphosis, and scoliosis. The elucidation of the orthopedic profile of this population is necessary in order to provide healthcare providers with current medical information. This research further supports the necessity for the comprehensive multidisciplinary treatment of boys with 49,XXXXY.

Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition.

BNAR syndrome (MIM608980) is a very rare condition: nine cases belonging to three unrelated families were reported since its first description in 2002. The distinctive clinical feature is the bifidity of the tip of the nose and its association with anorectal and/or renal anomalies. Its molecular basis consisting of biallelic FREM1 missense or nonsense mutations was elucidated after studying the original Egyptian family and was confirmed in two families originating from Afghanistan and Pakistan. We describe a fourth family originating from Turkey with signs challenging the diagnostic criteria suggested by the description of the three reported families.

Novel progressive acrodysostosis-like skeletal dysplasia, cerebellar atrophy, and ichthyosis.

Acrodysostosis refers to a rare heterogeneous group of bone dysplasias that share skeletal features, hormone resistance, and intellectual disability. Two genes have been associated with acrodysostosis with or without hormone resistance (PRKAR1A and PDE4D). Severe intellectual disability has been reported with acrodysostosis but brain malformations and ichthyosis have not been reported in these syndromes. Here we describe a female patient with acrodysostosis, intellectual disability, cerebellar hypoplasia, and lamellar ichthyosis. The patient has an evolving distinctive facial phenotype and childhood onset ataxia. X-rays showed generalized osteopenia, shortening of middle and distal phalanges, and abnormal distal epiphysis of the ulna and radius. Brain magnetic resonance imaging showed cerebellar atrophy without other brainstem abnormalities. Genetic workup included nondiagnostic chromosomal microarray and skeletal dysplasia molecular panels. These clinical findings are different from any recognized form of acrodysostosis syndrome. Whole exome sequencing did not identify rare or predicted pathogenic variants in genes associated with known acrodysostosis, lamellar ichthyosis, and other overlapping disorders. A broader search for rare alleles absent in healthy population databases and controls identified two heterozygous truncating alleles in FBNL7 and PPM1M genes, and one missense allele in the NPEPPS gene. Identification of additional patients is required to delineate the mechanism of this unique disorder.

Hip displacement in Wolf-Hirschhorn syndrome: Report on three cases and review of associated musculoskeletal pathologies.

Wolf-Hirschhorn syndrome is a rare genetic disease caused by a chromosomal deletion of the distal short arm of Chromosome 4. It is associated with multisystem abnormalities, including delayed growth, characteristic facial features, epilepsy, and skeletal abnormalities. We report three patients who developed hip displacement, and describe the occurrence of delayed and nonunion in patients who underwent corrective proximal femoral osteotomy for hip displacement. We also performed a literature review identifying common musculoskeletal presentations associated with the condition. Patients with Wolf-Hirschhorn Syndrome are at risk of hip displacement (subluxation), and we would advocate annual hip surveillance in this patient group.

Expanding the phenotypic and genotypic spectrum of Wiedemann-Steiner syndrome: First patient from India.

Wiedemann-Steiner syndrome (WWS) is a rare disorder characterized by hypotonia, postnatal growth restriction, striking facial dysmorphism, and hirsutism. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of WWS with syndromes caused by genes involved in chromatin remodeling. We describe an infant with a novel single base pair deletion in KMT2A with features consistent with WWS, as well as additional features of stenosis of aqueduct of Sylvius and broad toes. The usefulness of Face2Gene as a tool for identification of dysmorphology syndromes is discussed, as in this patient, it suggested WWS as the top candidate disorder. To the best of our knowledge, this is the first patient of WWS reported from India, with a novel genotype and expanded phenotype.

An Anatomical Basis for the Myofascial Trigger Points of the Abductor Hallucis Muscle.

Myofascial pain syndrome is characterized by pain and a limited range of joint motion caused by muscle contracture related to motor-end-plate dysfunction and the presence of myofascial trigger points (MTrPs). It is the most frequent cause of musculoskeletal pain, with a worldwide prevalence varying between 13.7% and 47%. Of the patients with myofascial pain syndrome, approximately 17% have pain in the medial hindfoot area. The abductor hallucis muscle is located in the medial, posterior region of the foot and is related to painful plantar syndromes. The objective of this study was to describe the distribution of the medial plantar nerve and their anatomical relationship with MTrPs found in the literature. Thirty abductor hallucis muscles were dissected from 15 human cadavers (8 males and 7 females). The muscles were measured, and the distribution data of the medial plantar nerve branches in each quadrant were recorded. For statistical analysis, we used generalized estimation equations with a Poisson distribution and a log logarithm function followed by Bonferroni multiple comparisons of the means. The data are expressed as the mean ± standard deviation. The level of significance was adjusted to 5% (p < 0.05). A high concentration of nerve branches was observed in the first quadrant (Q1) of the abductor hallucis muscle, which is the same area in which the MTrPs are described. The topography of the entry points of the branches of the medial plantar nerve to the abductor hallucis muscle correlates with the topography of the muscular trigger points. The anatomical structure of the MTrPs may be useful for a better understanding of the pathophysiology of myofascial disorders and provide a basis for surgical and clinical treatments.

Physical therapy and migraine: musculoskeletal and balance dysfunctions and their relevance for clinical practice.

BACKGROUND: Migraine is a primary headache with high levels of associated disability that can be related to a variety of symptoms and comorbidities. The role of physical therapy in the management of migraine is largely unknown. Therefore, the aim of this review is to highlight and critically discuss the current literature and evidence for physical therapy interventions in individuals with migraines. METHODS: A narrative review of the literature was performed. RESULTS: Physical therapists assessing and treating patients with migraine should focus on two primary aspects: (1) musculoskeletal dysfunctions, and (2) vestibular symptoms/postural control impairment. Signs and symptoms of musculoskeletal and/or vestibular dysfunctions are prevalent among individuals with migraines and different disability levels can be observed depending on the presence of aura or increment of the migraine attacks. CONCLUSION: A proper physical examination and interview of the patients will lead to a tailored treatment plan. The primary aim regarding musculoskeletal dysfunctions is to reduce pain and sensitization, and physical therapy interventions may include a combination of manual therapy, exercise therapy, and education. The aim regarding postural control impairment is to optimize function and reduce vestibular symptoms, and interventions should include balance exercises and vestibular rehabilitation. However, consistent evidence of benefits is still lacking due to the lack of and therefore need for tailored and pragmatic clinical trials with high methodological quality.

Association between thoracic musculoskeletal abnormalities and lung function in preterm infants.

INTRODUCTION: In view of the difficulties and risks of performing lung function tests in infants and the hypothesis that children with abnormal pulmonary test may exhibit thoracic musculoskeletal alterations. OBJECTIVES: This study aimed to determine the frequency of abnormal lung function and their relationship. MATERIALS AND METHODS: This was a cross-sectional study with children from 6 to 12 months of corrected age, born at a gestational age of <37 weeks and with a birthweight ≤1500 g, who were subjected to a lung function test and photogrammetry--an objective and non-invasive procedure. To verify the association between the thoracic musculoskeletal abnormalities and measure changes in lung function, univariate linear regression was used. The level of statistical significance was setted at P < 0.05. RESULTS: Of the 38 infants, 12 (31.6%) exhibited abnormal lung function, including 9 (23.7%) with obstructive function and 3 (7.9%) with restrictive function. A significant association was noted between forced expiratory volume at 0.5 second <-2 z score and the acromion/xiphoid process/acromion angle (ß = 4.935); forced vital capacity <-2 z score and the angle of the manubrium/left acromion/trapezium (ß = 0.033) and forced expiratory volume at 0.5 second and forced vital capacity ratio <-2 z score and the inframammillary point/xiphoid process/inframammillary point angle (ß = 0.043). CONCLUSION: Preterm infants with very low birthweight presented a high frequency of abnormal lung function, particularly obstructive type and thoracic musculoskeletal abnormalities were associated with changes in lung function.

VPS26C homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.

In this report, we describe two cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Genome sequencing failed to identify variants in known disease-associated genes explaining the phenotype. Extended comprehensive analysis of the two affected cousins' genomes, however, revealed that both share the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The potential vital biological role of VPS26C, the nature of the variant which is predicted to result in loss-of-function, expression studies revealing significant reduction in the mutant transcript, and the co-segregation of the homozygous variant with the phenotype in two affected individuals all support that VPS26C is a novel gene associated with a previously unrecognized syndrome characterized by neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.

Bart syndrome associated with skeletal deformities: An uncommon case report.

Bart syndrome is a rare genetic disorder characterized by aplasia cutis congenita, epidermolysis bullosa (EB), and nail abnormalities. We reported an unusual case of Bart syndrome associated with skeletal abnormalities and bilateral clubfoot.

PAPSS2-related brachyolmia: Clinical and radiological phenotype in 18 new cases.

Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short-spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi-parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under-recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.

Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant.

Biallelic loss of function variants in the TMCO1 gene have been previously demonstrated to result in cerebrofaciothoracic dysplasia (CFTD; MIM #213980). The phenotype of this condition includes severe intellectual disability, as well as distinctive craniofacial features, including brachycephaly, synophrys, arched eyebrows, "cupid's bow" upper lip, and microdontia. In addition, nonspecific skeletal anomalies are common, including bifid ribs, scoliosis, and spinal fusion. Only 19 molecularly confirmed patients have been previously described. Here, we present four patients with CFTD, including three brothers from a Pakistani background and an additional unrelated white Scottish patient. All share the characteristic craniofacial appearance, with severe intellectual disability and skeletal abnormalities. We further define the phenotype with comparison to the published literature, and present images to define the dysmorphic features in a previously unreported ethnic group. All of our patient series are homozygous for the same c.292_293del (p.Ser98*) TMCO1 pathogenic variant, which has been previously reported only in an isolated Amish population. Thus we provide evidence that CFTD may be more common than previously thought. The patients presented here further delineate the phenotypic spectrum of CFTD and provide evidence for a recurrent pathogenic variant in TMCO1.

The progression of Wiedemann-Steiner syndrome in adulthood and two novel variants in the KMT2A gene.

Wiedemann-Steiner syndrome is a genetic condition associated with dysmorphic facies, hypertrichosis, short stature, developmental delay, and intellectual disability. Congenital malformations of the cerebral, cardiac, renal, and optic structures have also been reported. Because the majority of reported individuals with this condition have been under age 20, the long-term prognosis is not well defined. Here we report on two further unrelated individuals diagnosed with Wiedemann-Steiner syndrome, one of whom is in her third decade of life. In addition, both individuals have novel KMT2A mutations. The information provided below about the outcome in Wiedemann-Steiner syndrome is important for families of affected individuals.

A new ovine model of spine and chest wall deformity at birth with alteration of respiratory system mechanics and lung development: a feasibility study.

PURPOSE: To develop an animal model of spine and chest wall deformity (CWD) at birth and to evaluate its effects on respiratory system mechanics and lung development. METHODS: A spine and CWD was created in utero between 70 and 75 days of gestation in six ovine fetuses by resection of the seventh and eighth left ribs. Two days after birth, respiratory system mechanics was assessed in anesthetized lambs using the flexiVent apparatus, followed by postmortem measurement of lung mechanics as well as histological lung analysis. RESULTS: A range of severity of CWD was found (Cobb angle from 0° to 48°) with a mean decrease in compliance of 47% and in inspiratory capacity of 39% compared to control lambs. Proof-of-concept histological analysis in one lamb showed marked lung hypoplasia. CONCLUSION: Our ovine model represents a pilot proof-of-concept study evaluating the impact of a spine and CWD present at birth on lung respiratory mechanics and development. This study lays down the groundwork for future studies evaluating the impact of these deformities on lung development and potential treatments. These slides can be retrieved under Electronic Supplementary Material.

Induction of a thoracolumbar supernumerary rib in rat developmental toxicity studies: A short discussion on the critical window.

Thoracolumbar supernumerary ribs (TSRs) are classified as less severe skeletal anomalies in rat developmental toxicity studies, although their incidence is relatively high in rodent studies. To investigate the characteristics of the critical window for chemically-induced TSR, in this study, rats were administered 5-fluorocytocine (5-FC) or sodium salicylate (SAL) at one of three time periods on gestational day (GD) 9, early morning (7:00 am), midday (12:00 pm to 1:00 pm), or late afternoon (4:00 pm or 7:00 pm). The incidence of TSR and other anomalies were assessed in GD20 fetuses. A single treatment with both chemicals on GD9-induced TSR, with the incidence highest when administered at 7:00 Am, decreasing gradually when administered later. This trajectory was clearer in rats treated with 5-FC than with SAL. The critical period of TSR induction is shorter in rats administered 5-FC than SAL. The characteristics of the critical window may cause variability in the incidence of TSR observed in developmental toxicity studies.

Next-generation phenotyping using computer vision algorithms in rare genomic neurodevelopmental disorders.

PURPOSE: The interpretation of genetic variants after genome-wide analysis is complex in heterogeneous disorders such as intellectual disability (ID). We investigate whether algorithms can be used to detect if a facial gestalt is present for three novel ID syndromes and if these techniques can help interpret variants of uncertain significance. METHODS: Facial features were extracted from photos of ID patients harboring a pathogenic variant in three novel ID genes (PACS1, PPM1D, and PHIP) using algorithms that model human facial dysmorphism, and facial recognition. The resulting features were combined into a hybrid model to compare the three cohorts against a background ID population. RESULTS: We validated our model using images from 71 individuals with Koolen-de Vries syndrome, and then show that facial gestalts are present for individuals with a pathogenic variant in PACS1 (p = 8 × 10-4), PPM1D (p = 4.65 × 10-2), and PHIP (p = 6.3 × 10-3). Moreover, two individuals with a de novo missense variant of uncertain significance in PHIP have significant similarity to the expected facial phenotype of PHIP patients (p < 1.52 × 10-2). CONCLUSION: Our results show that analysis of facial photos can be used to detect previously unknown facial gestalts for novel ID syndromes, which will facilitate both clinical and molecular diagnosis of rare and novel syndromes.