Rare neurological manifestations in a Saudi Arabian patient with Ehlers-Danlos syndrome and a novel homozygous variant in the TNXB gene.

We report a 38-year-old Saudi male with Ehlers-Danlos Syndrome (EDS). The patient presented with rare and unusual neurological manifestations, including but not limited to ophthalmoplegia and myopathic pattern on his electromyography. In addition to hand weakness, there was skin hyperextensibility, joint hyperflexibility, and frontal baldness. Next-generation sequencing was performed on target exon sequences, using whole exome sequencing and Burrows-Wheeler Aligner for alignment/base calling. Genome Analysis Toolkit and reference genome Homo sapiens (UCSC hg19) were used for sequence processing and analysis. Variant classification was done according to standard international recommendations. A novel homozygous variant, NM_019105.6: c.8488C>T p.(Gln2830*), was detected in the TNXB gene. This variant is not reported in the literature nor dbSNP or gnomAD databases. Additionally, this variant is predicted to create a premature stop codon and produce a truncated protein or nonsense-mediated mRNA decay. Hence, it is classified as a likely pathogenic variant. The same point variant was found in a heterozygous state in the patient's father and sister. Both presented with milder symptoms associated with Ehlers-Danlos syndromes and heritable connective tissue disorders. Therefore, the patient was diagnosed as a tenascin-X (TNX) deficient type of EDS known as classical-like Ehlers-Danlos syndrome. TNX deficient patients may present with clinical and electrophysiological manifestations that are unusual in EDS like frontal baldness, ophthalmoplegia, and myotonia, which mimic myotonic dystrophy type I. Clinicians should be aware of the potential overlap of symptoms among these two diseases to ensure correct diagnosis is made.

Pain due to Ehlers-Danlos Syndrome Is Associated with Deficit of the Endogenous Pain Inhibitory Control.

OBJECTIVES: Although pain is a common complication of the hypermobile type of Ehlers-Danlos syndrome, its underlying mechanisms are still an issue of controversy. In this psychophysical study, we aimed at testing small-fiber function and the endogenous pain inhibitory control in patients with pain due to Ehlers-Danlos syndrome. METHODS: In 22 patients with pain due to Ehlers-Danlos syndrome and 22 healthy participants, matched for age and sex, we tested small-fiber function using quantitative sensory testing and the endogenous pain inhibitory control using the conditioned pain modulation (CPM) protocol. As quantitative sensory testing methods, we included thermal pain and mechanical pain thresholds and the wind-up ratio. The CPM protocol consisted of two heat painful stimuli, that is, a test stimulus and a conditioning stimulus. RESULTS: All patients complained of widespread pain. Quantitative sensory testing revealed no small-fiber deficit; in the area of maximum pain, we found an increased wind-up ratio. Whereas in the healthy participants the CPM protocol showed that the test stimulus rating was significantly reduced during conditioning, in patients with pain due to hEDS, the test stimulus rating increased during conditioning. CONCLUSIONS: Our psychophysical study showing that patients with pain due to hEDS have an increased wind-up ratio in the area of maximum pain and abnormal CPM protocol suggests that in this condition, pain is associated with central sensitization, possibly due to deficit of the endogenous pain inhibitory control. These data might be relevant to pharmacological treatment.

The spectrum of gastrointestinal functional bowel disorders in joint hypermobility syndrome and in an academic referral center.

Joint hypermobility syndrome (JHS) is a non-inflammatory hereditary disorder of connective tissue with varied clinical presentations, including frequent joint dislocations, hyperextensible skin, easy bruising, and abnormal paper-thin scar formation. Many of these patients have unexplained gastrointestinal (GI) symptoms. Our aim was to evaluate the prevalence of JHS in a tertiary gastroenterology motility clinic and the spectrum of functional bowel disorders in JHS patients. In this retrospective case series, we screened the medical records of 277 patients seen over 4 years at an academic GI Motility Center. The patients who met the criteria for JHS by Beighton hypermobility score were evaluated for the presence of functional GI disorders by Rome IV criteria. They also underwent gastric emptying study and glucose breath testing for small intestinal bacterial overgrowth. The prevalence of JHS in the study population was 9.7%. The mean age was 27 years, and 92.5% were female. The symptoms experienced by these patients include nausea/vomiting (89%), abdominal pain (70%), constipation (48%), and bloating (18.5%). The disorders associated with JHS include gastroparesis (52%), irritable bowel syndrome (55.5%), and gastroesophageal reflux disease (30%). Also, 10 patients (37%) were diagnosed with postural hypotension tachycardia syndrome secondary to autonomic dysfunction. Approximately 10% of patients with suspected functional bowel disorders have hypermobility syndrome. Hence, it is crucial to familiarize gastrointestinal practitioners with the criteria utilized to diagnose JHS and the methods to identify physical examination findings related to this condition.

An Absent Lingual Frenulum in a Non-syndromic Premature Infant.

The lingual frenulum (LF) is a fold of tissue that connects the tongue to the oral cavity's floor. Abnormal frenula are associated with speech alterations. The absence of the LF is associated with Ehler's Danlos syndrome (EDS). In this case report, we present a premature infant incidentally found to have an absent lingual frenulum, with recurrent desaturations during feeding. The desaturations were believed to be due to the absent lingual frenulum, but they resolved after one month without treatment and were then attributed to apnea of prematurity. Whole exome sequence showed no genetic disorders. The infant is now doing well with no interventions. An absent lingual frenulum warrants molecular genetic testing for EDS. However, it does not warrant any treatment; special considerations are only required during intubation.

Prevalence and outcomes of select rare vascular conditions in females: A descriptive review.

Rare vascular conditions frequently pose a diagnostic and therapeutic dilemma for health care providers. Several of these conditions have distinct relevance to females populations but, due to their infrequency, there has been little reported on the outcomes of rare vascular conditions specifically in females populations. We performed a literature review of a selection of three rare vascular conditions known to either disproportionately affect females (median arcuate ligament syndrome and fibromuscular dysplasia) or have unique manifestations in females populations (vascular Ehlers-Danlos syndrome). We performed a descriptive review of the literature focused on these three vascular conditions and identified aspects of the current available research describing sex-based differences in prevalence, any pathophysiology explaining the observed sex-based differences, and the contribution of sex to outcomes for each disease process. In addition, considerations for pregnant females with respect to each rare vascular disease process are discussed.

Mouse Models of Musculocontractural Ehlers-Danlos Syndrome.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by mutations in the gene for carbohydrate sulfotransferase 14 (CHST14) (mcEDS-CHST14) or dermatan sulfate epimerase (DSE) (mcEDS-DSE). These mutations induce loss of enzymatic activity in D4ST1 or DSE and disrupt dermatan sulfate (DS) biosynthesis. The depletion of DS causes the symptoms of mcEDS, such as multiple congenital malformations (e.g., adducted thumbs, clubfeet, and craniofacial characteristics) and progressive connective tissue fragility-related manifestations (e.g., recurrent dislocations, progressive talipes or spinal deformities, pneumothorax or pneumohemothorax, large subcutaneous hematomas, and/or diverticular perforation). Careful observations of patients and model animals are important to investigate pathophysiological mechanisms and therapies for the disorder. Some independent groups have investigated Chst14 gene-deleted (Chst14-/-) and Dse-/- mice as models of mcEDS-CHST14 and mcEDS-DSE, respectively. These mouse models exhibit similar phenotypes to patients with mcEDS, such as suppressed growth and skin fragility with deformation of the collagen fibrils. Mouse models of mcEDS-CHST14 also show thoracic kyphosis, hypotonia, and myopathy, which are typical complications of mcEDS. These findings suggest that the mouse models can be useful for research uncovering the pathophysiology of mcEDS and developing etiology-based therapy. In this review, we organize and compare the data of patients and model mice.

Uncovering Ankylosing Spondylitis from a Diagnosis of Parsonage-Turner Syndrome: A Case Report of Bilateral Shoulder Pain and Weakness.

Introduction: Parsonage-Turner syndrome is a rare condition that is often misdiagnosed by physicians due to the overlapping symptoms with other conditions such as rotator cuff injury and cervical radiculopathy. The etiology of the Parsonage-Turner syndrome is unknown, but has been associated with an immune-mediated response to rheumatic disease, infection, surgery, and immunizations. Case Presentation: A 18-year-old female former tennis player with a history of complex regional pain syndrome (CRPS), Ehler-Danlos syndrome (EDS), and two prior right shoulder surgeries presented to the orthopaedic clinic with bilateral shoulder pain. After a third surgery on the right shoulder, the patient later developed constant burning and sharp pain around the right shoulder that radiated toward the chest. She also experienced numbness, tingling, and weakness in the right shoulder along with pain and weakness in the left shoulder. The patient was tender over the right musculocutaneous nerve and both shoulders were inflamed on ultrasound. Electromyography (EMG) and nerve conduction studies were performed, which were consistent with a bilateral subacute on chronic brachial plexopathy, suggestive of Parsonage-Turner syndrome. Rheumatology was consulted due to an extensive family history of autoimmune diseases, leading to an additional diagnosis of ankylosing spondylitis. The patient's bilateral shoulder pain slowly improved over the following year with physical therapy and prolotherapy treatments. Conclusion: The case described, herein, represents a unique patient who presents with the rare conditions of ankylosing spondylitis, CRPS, EDS, and Parsonage-Turner syndrome. EMG was critical to differentiate Parsonage-Turner syndrome from the overlapping CRPS symptoms and without this, the diagnosis of ankylosing spondylitis may have been delayed. It is imperative physicians take a thorough history, include uncommon or rare conditions as a potential diagnosis, and undergo thorough testing while evaluating a patient to avoid unnecessary treatment therapies and patient dissatisfaction.

Obstructive sleep apnea in a case of ehlers-danlos syndrome.

Ehlers-Danlos Syndrome (EDS) is a group of rare connective tissue disorders characterized by genetic defects in collagen and connective tissue synthesis and structure, with manifestations ranging from asymptomatic or mild skin and joint hyperlaxity to severe physical disability. Mild asymptomatic forms of Ehlers-Danlos syndrome seems to be under diagnosed and may have severe systemic complications mainly cardio vascular. Cartilaginous defects in the head and neck region increase the risk of Sleep-Disordered Breathing (SDB) especially Obstructive Sleep Apnea (OSA). It is well admitted now that OSA has many, frequently cardiovascular, adverse effects which are added to the risk of Ehlers-Danlos Syndrome's itself cardiovascular complications. We report a case of EDS diagnosed since childhood with a long history of fatigue, daytime somnolence, snoring and unrefreshing sleep. Although the diagnosis of sleep apnea was suspected because of worsening of his symptoms ten years prior to his referral to our sleep laboratory, he was never investigated for Sleep-disordered breathing and was lost to follow up. This case report relays what is stated in the literature regarding the association of SDB, mainly OSA, with EDS and its toll on the health of such individuals.

Novel regulatory roles of small leucine-rich proteoglycans in remodeling of the uterine cervix in pregnancy.

The cervix undergoes rapid and dramatic shifts in collagen and elastic fiber structure to achieve its disparate physiological roles of competence during pregnancy and compliance during birth. An understanding of the structure-function relationships of collagen and elastic fibers to maintain extracellular matrix (ECM) homeostasis requires an understanding of the mechanisms executed by non-structural ECM molecules. Small-leucine rich proteoglycans (SLRPs) play key functions in biology by affecting collagen fibrillogenesis and regulating enzyme and growth factor bioactivities. In the current study, we evaluated collagen and elastic fiber structure-function relationships in mouse cervices using mice with genetic ablation of decorin and/or biglycan genes as representative of Class I SLRPs, and lumican gene representative of Class II SLRP. We identified structural defects in collagen fibril and elastic fiber organization in nonpregnant mice lacking decorin, or biglycan or lumican with variable resolution of defects noted during pregnancy. The severity of collagen and elastic fiber defects was greater in nonpregnant mice lacking both decorin and biglycan and defects were maintained throughout pregnancy. Loss of biglycan alone reduced tissue extensibility in nonpregnant mice while loss of both decorin and biglycan manifested in decreased rupture stretch in late pregnancy. Collagen cross-link density was similar in the Class I SLRP null mice as compared to wild-type nonpregnant and pregnant controls. A broader range in collagen fibril diameter along with an increase in mean fibril spacing was observed in the mutant mice compared to wild-type controls. Collectively, these findings uncover functional redundancy and hierarchical roles of Class I and Class II SLRPs as key regulators of cervical ECM remodeling in pregnancy. These results expand our understating of the critical role SLRPs play to maintain ECM homeostasis in the cervix.

Scleroderma and the Esophagus.

The gastrointestinal tract is the second largest organ system in the body and is often affected by connective tissue disorders. Scleroderma is the classic rheumatologic disease affecting the esophagus; more than 90% of patients with scleroderma have esophageal involvement. This article highlights esophageal manifestations of scleroderma, focusing on pathogenesis, clinical presentation, diagnostic considerations, and treatment options. In addition, this article briefly reviews the esophageal manifestations of other key connective tissue disorders, including mixed connective tissue disease, myositis, Sjogren syndrome, systemic lupus erythematosus, fibromyalgia, and Ehlers-Danlos syndrome.

Is the Pain Just Physical? The Role of Psychological Distress, Quality of Life, and Autistic Traits in Ehlers-Danlos Syndrome, an Internet-Based Survey in Italy.

BACKGROUND: Ehlers-Danlos syndromes (EDS) have been associated with psychological distress, comorbid psychiatric disorders, and worsening in quality of life (QoL). Among the neurodevelopmental disorders, autism spectrum disorders (ASD) have shown the highest rates of co-occurrence with EDS. The reasons for these associations are unknown and a possible role of pain in increasing the risk of psychiatric disorders in EDS has been suggested. However, a detailed picture of an Italian EDS sample is still lacking. METHODS: We conducted a web-based survey in a third level center for the diagnosis of EDS in northern Italy, to investigate psychological distress, QoL, and the presence of autistic traits. Furthermore, we correlated the psychometric data with some clinical variables. RESULTS: We observed a high rate of psychological distress with 91% of the responders at high risk of common mental disorders, low QoL, and high prevalence of autistic traits in EDS patients. Specifically, patients lacking a specific genetic test, diagnosed as suspects of EDS appeared to be at greater risk and reported worse psychological QoL. Pain was significantly associated with both psychological distress and worse QoL. CONCLUSIONS: Our findings support the need of further research and of a multi-disciplinary approach to EDS including psychological and psychiatric liaison.

Sudden death as a result of colon perforation; Ehlers-Danlos type IV case with postmortem diagnosis.

Ehlers-Danlos Syndrome (EDS) is a connective tissue disease with heterogeneous subgroups. In type IV EDS, also known as vascular EDS (VEDS), the underlying genetic anomaly consists of a mutation of the COL3A1 gene encoding the type III procollagen. As a result of the mutation, pathological findings due to excessive brittleness of the tubular organs or vessels occur. In our case, we present a patient with sudden death due to colon perforation which was diagnosed with EDS type IV after further examination in the autopsy. Forensic medicine experts should consider the possibility of EDS type IV after the detection of spontaneous ruptures in the internal organs during the autopsy. We think that it would be appropriate to report this autosomal dominant and potentially fatal condition to family members.

Evaluation of Temporomandibular Disorders and Comorbidities in Patients with Ehler--Danlos: Clinical and Digital Findings.

OBJECTIVE: The objective of this study is to recognize representative cranio-cervico-mandibular features of patients with Ehler-Danlos syndrome and associated temporomandibular disorders (TMDs), to assess a targeted and integrated treatment plan. MATERIALS AND METHODS: After a diagnosis of disease, 38 individiuals with Ehler-Danlos syndrome and temporomandibular symptomatology referred were evaluated. Gnathological evaluation, according to the Diagnostic Criteria for TMDs, and radiographic imaging was performed. In addition, digital evaluation of occlusal and muscular balance, using surface electromyography of jaw muscles, was conducted. Statistical software for data analysis - STATA (StataCorp, College station, Texas, USA) - was used. RESULTS: Most common temporomandibular dysfunctions were arthralgia, myalgia, disc displacement with reduction and subluxation. Headache and neck pain were the most frequent comorbidities. Somatization, depression, anxiety, and obsessive-compulsive behavior were the most recurrent psychological disorders. Electromyographic analysis showed out of normal range data. CONCLUSION: Early diagnosis and interception are requested to avoid injuries and repeated traumatism. Multidisciplinary treatments are available to approach all the aspects of the syndrome.

Brugada Syndrome in a Patient with Vascular Ehlers-Danlos Syndrome: Sudden Death Risk Amplified.

The vast majority of sudden cardiac arrests occur in patients with structural heart disease and in approximately 10% of the cases, it can occur in those with structurally normal hearts. Brugada syndrome is an autosomal dominant sodium channelopathy that has been implicated in sudden deaths. Given their low prevalence, our knowledge about Brugada syndrome is still evolving. Apart from schizophrenia, there have been no reports of associated medical conditions. We recently encountered a patient with vascular Ehlers-Danlos syndrome who was also found to have Brugada syndrome. Both these conditions share some common clinical presentations including a propensity for sudden death.

Congenital keratoglobus with multiple cardiac anomalies: a case presentation and literature review.

Keratoglobus is a rare condition of bilateral corneal ectasia, which results in high myopia, irregular astigmatism, scarring, and rarely spontaneous globe rupture. Globoid protrusion of a clear, diffusely thin cornea is the pathology. The congenital form has been associated with blue sclera in which there is a systemic connective tissue disorder with abnormal collagen synthesis like Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta. Some concomitant abnormalities reported with kertoglobus include joint hypermobility, dental and skeletal abnormalities, osteal fragility, and deafness. Acquired forms have been reported to be associated with vernal keratoconjunctivitis and thyroid ophthalmopathy. We report the case of a 16-year-old boy with keratoglobus who presented with a history of photophobia and a low vision in both eyes since birth. He has been followed up by our pediatric cardiology department due to multiple cardiac anomalies. He had hypermobility of large joints, easy bruising, thin and hyperextensible skin with visible veins, which were also described in his elder brother. We aimed to discuss the etiology and the association of keratoglobus with some systemic abnormalities caused by collogen tissue disturbance, and make a brief review about the recent literature concerning the management of keratoglobus patients.

Spontaneous Carotid-Cavernous Fistula in the Type IV Ehlers-Danlos Syndrome.

Ehlers-Danlos syndrome (EDS) is a rare inherited connective disease. Among several subgroups, type IV EDS is frequently associated with spontaneous catastrophic bleeding from a vascular fragility. We report on a case of carotid-cavernous fistula (CCF) in a patient with type IV EDS. A 46-year-old female presented with an ophthalmoplegia and chemosis in the right eye. Subsequently, seizure and cerebral infarction with micro-bleeds occurred. CCF was completely occluded with transvenous coil embolization without complications. Thereafter, the patient was completely recovered. Transvenous coil embolization can be a good treatment of choice for spontaneous CCF with type IV EDS. However, every caution should be kept during invasive procedure.

Utilidad del método clínico en el diagnóstico de algunos síndromes genéticos / Use fulness of the clinical method for diagnosing a group of clinical syndromes

Introducción: El método científico es un método general, constituido por varias etapas necesarias en el desarrollo de toda investigación científica. Es la forma de abordar la realidad y estudiar los fenómenos de la naturaleza, para descubrir su esencia y sus interrelaciones. El método clínico es la aplicación particular del método científico en el ejercicio de la práctica médica, y en las condiciones económicas actuales prevalecientes a nivel mundial resulta de inestimable valor su aplicación por las ventajas que reporta desde ese punto de vista, así como también por el bienestar del paciente que no es sometido a innecesarios y costosos procedimientos diagnósticos. Objetivo: Proporcionar al personal médico los criterios clínicos para lograr, mediante el uso del método clínico, el diagnóstico de algunos síndromes genéticos; los que han sido elaborados luego de una exhaustiva delineación clínica de estos. Métodos: Se realizó una revisión de los textos básicos de genética clínica y sindromología con independencia del año de su publicación y se realizó una búsqueda en las bases de datos Medline, Lilacs y Cochrane en el periodo comprendido entre 2012 y 2016. Conclusiones: Fueron reflejados los criterios establecidos para el diagnóstico clínico de catorce síndromes genéticos(AU)

Introduction: The scientific method is a general method which consists of several stages necessary for the development of all scientific research. It is the way to approach reality and to study the phenomena of nature, to discover their essence and interrelations. The clinical method is the particular application of the scientific method in the medical practice, and in the current economic conditions prevailing worldwide, its application is of inestimable value because of the advantages it brings from that point of view, as well as for the well-being of the patient, who would not be subjected to unnecessary and expensive diagnostic procedures. Objective: To provide the medical personnel with the clinical criteria to achieve, through the use of the clinical method, the diagnosis of some genetic syndromes. Such criteria have been elaborated after an exhaustive clinical description of those conditions. Methods: A review of basic texts of clinical genetics and syndromology was carried out regardless the year of publication. A search was carried out in the databases Medline, Lilacs and Cochrane, in the period between 2012 and 2016. Conclusions: The criteria established for the clinical diagnosis of fourteen genetic syndromes have been presented(AU)

Niccolo Paganini: aspectos médicos de su vida y obra / Niccolo Paganini: medical aspects of his Ufe and work

Niccolo Paganini is the most virtuos violinist of the history of music. He even received the nick name of "the violinist of the evil" for his outstanding skills on stage performance. It has been suggested that he had syphilis and tuberculosis, the commonest diseases of that time, but this hypothesis remains speculative. There are suggestions that he was the victim of iatrogenic mercurial poisoning. Furthermore, his body build suggests the presence of Ehlers-Danlos syndrome which could give him special anatomical conditions allowing him to achieve an amazing level of vírtuousness in his art. We herein review the medical aspects ofthis brilliant musician's life.