Hypermobility Type Research Articles

Characteristics of the anterior eye segment in patients affected by ehlers‐danlos‐syndrome

AbstractPurpose Ehlers‐Danlos Syndrome (EDS) characterizes an inherited connective tissue disorder caused by a molecular defect in the synthesis of collagen. The refractive, biometrical and densitometrical characteristics of the anterior eye segment in patients affected by various forms of EDS were analysed.Methods 46 EDS patients in an age‐range of 6 to 62 years (mean age 33 years) affected by various types of EDS, as diagnosed by genetic screening or skin biopsies, were recruited on a voluntary basis for this study. They were subjected to a complete orthoptical and clinical examination including documentation of the anterior eye segment with the EAS 1000 (Eye Analysis System, Nidek, Gamagory, Japan). Apart from clinical parameters like visual acuity, ocular motility and intraocular pressure, biometric measurements have been performed for corneal thickness and curvature, anterior chamber geometry, lens biometry and densitometric analysis of corneal and lens light scattering.Results The EDS patient population comprised 37% classical type, 28% hypermobile type and 13 % vascular type. Among the clinical parameters, prevalence of myopia combined with astigmatism was 33% that of hyperopia combined with astigmatism 28%. Strabismus was found in 11% and about 59% of the EDS patients complained about dry eyes problems. Densitometric aanalyses of the lens revealed a normal age‐related scattering profile in all patients. Similarly the biometric data for lens thickness and anterior chamber depth were within the normal range. Patients with the classical type EDS showed thinner corneas compared to the vascular or hypermobility type of EDS.Conclusion Most of the clinical features described in association with EDS like thin and translucent sclera, keratoconus, lens luxation, retinal detachment or angoid streaks have not been observed in this study. Thinner cornea and perhaps more frequent anterior vitreal detachment were the only consistent pathological findings associated with the classical type of EDS which could be demonstrated in this study.

Screening for celiac disease in the joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type

Screening for Celiac Disease in the Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome Hypermobility Type Chiara Danese, Marco Castori,* Claudia Celletti, Silvia Amato, Caterina Lo Russo, Paola Grammatico, and Filippo Camerota Department of Clinical Science, Sapienza University, Umberto I Hospital, Rome, Italy Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy Department of Physical Medicine and Rehabilitation, Sapienza University, Umberto I Hospital, Rome, Italy

Coexistent tumor necrosis factor receptor–associated periodic fever syndrome and Ehlers–Danlos syndrome

A 32-year-old Caucasian woman had periodic fevers, skin disease, polyarthralgia and hypermobile joints that were consistent with tumor necrosis factor receptor-associated periodic fever syndrome confirmed with a finding of R92Q missense mutation of the TNFRSFA1 gene with Ehlers-Danlos hypermobility type syndrome. They are both autosomal dominant disorders, and their coexistence suggests that they could share some phenotypic features that may require special consideration in management. Conceivably, they could share common gene mutations although no such data are available.

Impairment and impact of pain in female patients with Ehlers-Danlos syndrome: A comparative study with fibromyalgia and rheumatoid arthritis

The purpose of this study was to investigate functional impairment and the impact of pain in patients with Ehlers-Danlos syndrome, hypermobility type (EDS-HT), and to compare the burden of disease with that in women with fibromyalgia (FM) and rheumatoid arthritis (RA). A total of 206 female patients were compared (72 with EDS-HT, 69 with FM, and 65 with RA). Functional impairment was assessed with the Sickness Impact Profile (SIP), and the psychosocial impact of chronic pain was quantified with the Multidimensional Pain Inventory (MPI). Data on symptoms were collected. SIP results showed clinically relevant health-related dysfunction in all groups. Significantly poorer physical, psychosocial, and overall function was found in the EDS-HT group compared with the RA group. In comparison with the FM group, the EDS-HT group reported similar physical and overall function, but better psychosocial function. T scores from the MPI revealed significantly higher levels of pain severity and life interference due to pain, and a lower level of perceived life control, in the EDS-HT group compared to the RA group. In contrast, the EDS-HT group showed significantly lower levels of pain severity, life interference, and affective distress in comparison with the FM group. Social support for help in coping with pain was similar between the 3 groups. EDS-HT is associated with a consistent burden of disease, similar to that of FM and worse than that of RA, as well as a broad impact of chronic pain on daily life, which needs to be addressed in the health care system.

Medication, Surgery, and Physiotherapy Among Patients With the Hypermobility Type of Ehlers-Danlos Syndrome

Rombaut L, Malfait F, De Wandele I, Cools A, Thijs Y, De Paepe A, Calders P. Medication, surgery, and physiotherapy among patients with the hypermobility type of Ehlers-Danlos syndrome. Objectives To describe medication use, surgery, and physiotherapy, and to examine the effect of these treatment modalities on functional impairment and amount of complaints among patients with the hypermobility type of Ehlers-Danlos syndrome (EDS-HT). Design Cross-sectional study. Setting Physical and rehabilitation medicine department and center for medical genetics. Participants Patients with EDS-HT (N=79; 8 men, 71 women) were recruited for this study. Interventions Not applicable. Main Outcome Measures Patients filled out questionnaires regarding type of complaints, medication use, surgery, physiotherapy, and outcome of treatment. Functional impairment in daily life was measured by the Sickness Impact Profile. Pain severity was assessed with visual analog scales. Results Patients reported a large number of complaints, a considerable presence of severe pain, and a clinically significant impact of disease on daily functioning. Most patients (92.4%) used medications, among which analgesics were the most prevalent. Fifty-six patients (70.9%) underwent surgery, including mainly interventions of the extremities and abdomen. Forty-one patients (51.9%) are currently enrolled in a physical therapy program, mainly comprising neuromuscular exercises, massage, and electrotherapy. Patients with a high consumption of analgesics, who visited the physiotherapist, or who underwent surgery had a higher dysfunction in daily life. Only 33.9% of the patients who underwent surgery and 63.4% of patients in physical therapy reported a positive outcome. Conclusions Patients with EDS-HT have numerous complaints and an impaired functional status that strongly determine their high rate of treatment consumption. The outcome of surgical and physiotherapy treatment is disappointing in a large percentage, which illustrates a strong need for evidence-based therapy.

Fertilité et grossesse au cours de l’acromégalie

The aim of this study was to quantify the gait patterns of adults with joint hypermobility syndrome/Ehlers–Danlos syndrome (JHS/EDS-HT) hypermobility type, using Gait Analysis. We quantified the gait strategy in 12 JHS/EDS-HT adults individuals (age: 43.08 + 6.78 years) compared to 20 healthy controls (age: 37.23 ± 8.91 years), in terms of kinematics and kinetics. JHS/EDS-HT individuals were characterized by a non-physiological gait pattern. In particular, spatio-temporal parameters evidenced lower anterior step length and higher stance phase duration in JHS/EDS-HT than controls. In term of kinematics, in JHS/EDS-HT patients the main gait limitations involved pelvis, distal joints and ankle joint. Conversely, hip and knee joint showed physiological values. Ankle moment and power revealed reduced peak values during terminal stance. Differences in stiffness at hip and ankle joints were found between JHS/EDS-HT and controls. JHS/EDS-HT patients showed significant decreased of Kh and Ka parameters very probably due to congenital hypotonia and ligament laxity. These findings help to elucidate the complex biomechanical changes in JHS/EDS-HT and may have a major role in the multidimensional evaluation and tailored management of these patients.

Evaluation of balance and improvement of proprioception by repetitive muscle vibration in a 15‐year‐old girl with joint hypermobility syndrome

Joint hypermobility syndrome (JHS), alternatively termed hypermobility syndrome or benign joint hypermobility syndrome, is a relatively common rheumatologic condition most frequently diagnosed in women showing chronic pain and other musculoskeletal complaints. There is a significant clinical overlap with Ehlers-Danlos syndrome (EDS), which comprises a clinically variable and genetically heterogeneous group of inherited connective tissue disorders, mainly featuring joint hypermobility, skin hyperextensibility and tissue fragility (1). The revised classification identifies 6 major and other rarer forms (2). Among them, the most common is the hypermobility type (EDS-HT), which is dominated by joint laxity and lacks most cutaneous features observed in other variants (3). Recently, an international group of experts proposed that JHS and EDS-HT are the same condition (4), consisting in a wide clinical spectrum ranging from severe phenotypes with early manifestations to milder forms which are diagnosed in adulthood or, at worst, remain undiagnosed. Proprioception refers to the sense of static position and movement of the limbs and body without using vision. It usually comprises the sense of stationary position of the limbs (limb-position sense) and the sense of limb movement (kinesthesia). These sensations are important for controlling limb movements, manipulating objects that differ in shape and mass, and maintaining an upright posture (5). Lack of proprioception seems a prominent feature in JHS (6,7). Although its relationship with the underlying joint hypermobility is still largely obscure, a handful of studies suggest that improvement of proprioception may be effective for ameliorating both the functional status, including balance, and chronic pain (8). However, as JHS is a systemic, progressive and chronic condition, physical therapy very probably suffers of major limitations, such as time consumption and short-lasting effects. Recently, repetitive muscle vibration (rMV) has been outlined as a non-invasive method that can significantly and persistently improve muscle performance by acting as an important proprioceptive input (9). Although accumulated data are preliminary, this technique is promising for treating postural dysfunction correlated with chronic rheumatologic conditions, such as JHS or EDS-HT.

Need for a consensus on the methods by which to measure joint mobility and the definition of norms for hypermobility that reflect age, gender and ethnic-dependent variation: is revision of criteria for joint hypermobility syndrome and Ehlers-Danlos syndrome hypermobility type indicated?

Need for a consensus on the methods by which to measure joint mobility and the definition of norms for hypermobility that reflect age, gender and ethnic-dependent variation: is revision of criteria for joint hypermobility syndrome and Ehlers-Danlos syndrome hypermobility type indicated?

Gait strategy in patients with Ehlers–Danlos syndrome hypermobility type: A kinematic and kinetic evaluation using 3D gait analysis

The aim of this study was to quantify the gait patterns of adults with joint hypermobility syndrome/Ehlers–Danlos syndrome (JHS/EDS-HT) hypermobility type, using Gait Analysis. We quantified the gait strategy in 12 JHS/EDS-HT adults individuals (age: 43.08 + 6.78 years) compared to 20 healthy controls (age: 37.23 ± 8.91 years), in terms of kinematics and kinetics. JHS/EDS-HT individuals were characterized by a non-physiological gait pattern. In particular, spatio-temporal parameters evidenced lower anterior step length and higher stance phase duration in JHS/EDS-HT than controls. In term of kinematics, in JHS/EDS-HT patients the main gait limitations involved pelvis, distal joints and ankle joint. Conversely, hip and knee joint showed physiological values. Ankle moment and power revealed reduced peak values during terminal stance. Differences in stiffness at hip and ankle joints were found between JHS/EDS-HT and controls. JHS/EDS-HT patients showed significant decreased of Kh and Ka parameters very probably due to congenital hypotonia and ligament laxity. These findings help to elucidate the complex biomechanical changes in JHS/EDS-HT and may have a major role in the multidimensional evaluation and tailored management of these patients.

Neuropathic Pain Is a Common Feature in Ehlers-Danlos Syndrome

Neuropathic Pain Is a Common Feature in Ehlers-Danlos Syndrome

Phenotypic effects of Ehlers–Danlos syndrome‐associated mutation on the FnIII domain of tenascin‐X

Tenascin-X (TNX) is an extracellular matrix (ECM) protein and interacts with a wide variety of molecules in the ECM as well as on the membrane. Deficiency of TNX causes a recessive form of Ehlers-Danlos syndrome (EDS) characterized by hyperelastic and fragile skin, easy bruising, and hypermobile joints. Three point mutations in TNX gene were found to be associated with hypermobility type EDS and one of such mutations is the V1195M mutation at the 7th fibronectin Type III domain (TNXfn7). To help elucidate the underlying molecular mechanism connecting this mutation to EDS, here we combined homology modeling, chemical denaturation, single molecule atomic force microscopy, and molecular dynamics (MD) simulation techniques to investigate the phenotypic effects of V1195M on TNXfn7. We found that the V1195M mutation does not alter the three-dimensional structure of TNXfn7 and had only mild destabilization effects on the thermodynamic and mechanical stability of TNXfn7. However, MD simulations revealed that the mutation V1195M significantly alters the flexibility of the C'E loop of TNXfn7. As loops play important roles in protein-protein and protein-ligand interactions, we hypothesize that the decreased loop flexibility by V1195M mutation may affect the binding of TNX to ECM molecules and thus adversely affect collagen deposition and fibrillogenesis. Our results may provide new insights in understanding the molecular basis for the pathogenesis of V1195M-resulted EDS.

EHLERS-DANLOS SYNDROME– AN OVERVIEW

Ehlers-Danlos syndrome, hypermobility type is generally considered the least severe type of EDS, although significant complications, primarily musculoskeletal, can and do occur. The skin is often soft or velvety and may be mildly hyperextensible. Subluxations and dislocations are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint disease is common. Chronic pain, distinct from that associated with acute dislocations or advanced osteoarthritis, is a serious complication of the condition and can be both physically and psychologically disabling. Easy bruising is common.

Ehlers–Danlos syndrome hypermobility type and the excess of affected females: Possible mechanisms and perspectives

Ehlers–Danlos Syndrome Hypermobility Type and the Excess of Affected Females: Possible Mechanisms and Perspectives Marco Castori,* Filippo Camerota, Claudia Celletti, Paola Grammatico, and Luca Padua Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy Physical Medicine and Rehabilitation Division, Sapienza University, Umberto I Hospital, Rome, Italy Don Carlo Gnocchi Onlus Foundation, Milan, Italy Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy

In this issue

Swarr et al (p. 565) offer several new findings about Potocki-Shaffer syndrome (PSS), a contiguous gene syndrome associated with deletions in 11p11.2. PSS is marked by openings in the two bones that form the top and sides of the skull, multiple benign bone tumors called exostoses, intellectual disability, delayed development, a distinctive facial appearance, and problems with vision. In this study, researchers identified and evaluated six patients with PSS according to a protocol that included assessments by practitioners of several medical specialties and various diagnostic studies. The researchers also used array comparative genomic hybridization to further characterize the deletion in five patients. The researchers newly identified an association of PSS syndrome with sensorineural hearing loss and autistic behaviors. The study data also highlight the characteristic facial features, biparietal foramina, moderate-to-severe developmental delay and intellectual disability, myopia and strabismus, and multiple exostoses already seen with this disorder. Based on these findings and a review of the 31 previously reported cases of PSS, the researchers made recommendations for the care of children with the syndrome. These include referral to early childhood intervention and a developmental-behavioral specialist at the time of diagnosis, a full skeletal survey at diagnosis or by age three, and screening for strabismus and nystagmus by primary care providers at every well-child examination, with referral to a pediatric ophthalmologist at diagnosis or by age six months. The researchers also suggest that infants with PSS be evaluated for sensorineural hearing loss by three months of age and get a behavioral audiogram at age one year and annually thereafter. Parents of children with PSS should get fluorescence in situ hybridization (FISH) studies to find chromosomal rearrangements that would increase risk of PSS in future offspring, researchers write. Castori et al (p. 556) describe the natural history and various manifestations of hypermobility type Ehlers-Danlos syndrome (HT-EDS). A relatively frequent but commonly misdiagnosed variant of Ehlers-Danlos syndrome, HT-EDS is characterized mainly by marked joint instability and mild cutaneous involvement, while additional manifestations include chronic pain, asthenia, and gastrointestinal and pelvic dysfunction. The researchers report on 21 patients selected from a group of 40 subjects with suspected mild hereditary connective tissue disorder. They outline six distinct clinical presentations in a tabulation the authors describe as mnemonic for clinical geneticists attempting to accurately diagnose this condition. HT-EDS's natural history includes three phases—hypermobility, pain, and stiffness—which the researchers delineate based on distinguishing manifestations.1 Main manifestations of Ehlers-Danlos syndrome hypermobility type. Joint hypermobility (e-i): hyperextension of the thumb in passive apposition to the flexor aspect of the forearm (e), hyperextension of the elbow (f) and knee (g) beyond 10°, forward flexion of the trunk with the knees extended and the palms resting flat on the floor (h), and hyperextension of the mecarpophalangeal joint of the V finger in passive dorsiflexion beyond 90° (i). They also identify a group of additional, apparently uncommon abnormalities associated with HT-EDS. These include dolichocolon, dysphonia, and Arnold-Chiari type I malformation. Further investigation of these abnormalities may contribute to an understanding of the pathogenesis of the protean manifestations of HT-EDS and lead to more effective evaluation and management of affected individuals, according to researchers. FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral microphthalmia, write Reis et al (p. 582).1 Patient photographs. B: Patient 1 with prosthetics removed demonstrating bilateral severe microphthalmia. Because autosomal dominant and recessive mutations in FOXE3 among humans have been associated with variable phenotypes, including anterior segment anomalies, cataracts, and microphthalmia, the researchers sequenced FOXE3 in 116 probands. The spectrum of ocular defects in these probands ranged from anterior segment dysgenesis and cataract to anophthalmia/microphthalmia. The researchers found recessive FOXE3 mutations in four of 26 probands affected with bilateral microphthalmia, representing 15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype. FOXE3-positive microphthalmia was accompanied by aphakia and/or corneal defects. The researchers identified missense variants at varying frequencies in patient and control groups. Because some of these variants appear to be race-specific, the researchers emphasized the importance of using race/ethnicity-matched control populations in evaluating the relevance of genetic screening results.

Natural history and manifestations of the hypermobility type Ehlers–Danlos syndrome: A pilot study on 21 patients

Hypermobility type Ehlers-Danlos syndrome (HT-EDS) is a relatively frequent, although commonly misdiagnosed variant of Ehlers-Danlos syndrome, mainly characterized by marked joint instability and mild cutaneous involvement. Chronic pain, asthenia, and gastrointestinal and pelvic dysfunction are characteristic additional manifestations. We report on 21 HT-EDS patients selected from a group of 40 subjects with suspected mild hereditary connective tissue disorder. General, mucocutaneous, musculoskeletal, cardiovascular, neurologic, gastrointestinal, urogynecological, and ear-nose-throat abnormalities are investigated systematically and tabulated. Six distinct clinical presentations of HT-EDS are outlined, whose tabulation is a mnemonic for the practicing clinical geneticist in an attempt to diagnose this condition accurately. With detailed clinical records and phenotype comparison among patients of different ages, the natural history of the disorder is defined. Three phases (namely, hypermobility, pain, and stiffness) are delineated based on distinguishing manifestations. A constellation of additional, apparently uncommon abnormalities is also identified, including dolichocolon, dysphonia, and Arnold-Chiari type I malformation. Their further investigation may contribute to an understanding of the pathogenesis of the protean manifestations of HT-EDS, and a more effective approach to the evaluation and management of affected individuals.

Absence of Inferior Labial and Lingual Frenula in Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (EDS) is a heterogenous group of diseases that can be potentially life threatening in the vascular form. The diagnosis is mainly based on a clinical score including many items that demonstrate skin, mucosa, joint, and vessel involvement. The score is particularly helpful in hypermobile and classical forms but can be normal in the vascular type. The absence of the lingual and inferior labial frenula was reported to be a useful diagnostic tool in a series of 12 patients with classical and hypermobile EDS. However, two further reports have contested the value of this sign. To determine the diagnostic value of the absence of inferior labial or lingual frenula in EDS. Patients with EDS were prospectively recruited from November 2006 to April 2007 in a French tertiary center. Each patient was examined to check for the presence or absence of the oral frenula and matched with two controls seen from February to May 2007. Forty-three patients (ratio female/male of 2.07 : 1, mean age 31 years, range 4-63 years), 4 with classical EDS, 19 with hypermobile EDS, and 20 with vascular-type EDS, were included and matched with 86 controls. The sensitivity of the absence of the inferior labial frenulum was 42% (95% CI 27, 58) and for the lingual frenulum was 53.5% (95% CI 38, 69). The specificity was 99% (95% CI 94, 100) and 98% (95% CI 92, 100), respectively. In the vascular group, 13 of 20 patients were affected (sensitivity = 65% [95% CI 41, 85]; specificity = 97% [95% CI 87, 100]; odds ratio = 72 [95% CI 8, 645]). Inter-observer agreement was excellent (kappa value 0.91). The absence of the inferior labial frenulum or lingual frenulum is a specific sign of EDS that can be easily checked by a physician. It can be helpful in the early diagnosis of the disease, including the vascular type, in affected families. It can also be helpful to distinguish between joint hypermobility syndrome and the hypermobile type of EDS in patients with joint hypermobility.

Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers–Danlos syndrome hypermobility type

Purpose. To investigate the musculoskeletal complaints, physical activity (PA) and health-related quality of life (HRQoL) in patients with the Ehlers–Danlos syndrome hypermobility type (EDS-HT).Methods. Thirty-two female EDS-HT patients as defined by the Villefranche criteria and 32 gender- and age-matched healthy control subjects participated in the study. Data about musculoskeletal complaints were collected from a specific form developed for the study. Daily PA and HRQoL were evaluated by the Baecke questionnaire and the RAND 36-Item Health Survey (distributed by RAND), respectively.Results. A significant presence of joint pain, joint dislocations, muscle cramps, tendinitis, fatigue and headache were revealed in the EDS-HT patient group. Joint pain was reported as the most frequent and most severe symptom. The habitual PA level was diminished in the patient group. Specifically, EDS-HT subjects had significantly lower sport participation, but a comparable leisure time excluding sports compared to the healthy control subjects. All eight HRQoL dimensions of the RAND-36 and both physical and emotional summary scores were significantly impaired in EDS-HT.Conclusions. EDS-HT is characterised by various severe musculoskeletal complaints and has a detrimental effect on the habitual level of PA and HRQoL, in both physical and psychosocial dimension. An appropriate treatment and management in healthcare is needed.

Joint position sense and vibratory perception sense in patients with Ehlers–Danlos syndrome type III (hypermobility type)

Neurophysiological deficits could make patients with Ehlers-Danlos syndrome (EDS) type III (hypermobility type) more vulnerable to musculoskeletal problems, particularly to joint instability. The purpose of this study was to investigate whether joint position sense (JPS) and vibratory perception sense (VPS) in EDS type III patients in the knee and shoulder joints are impaired. Thirty-two female EDS type III patients as defined by the Villefranche criteria and 32 individually gender- and age-matched healthy control subjects were included in the study. Range of motion was determined using a goniometer, passive and active JPS were assessed with an isokinetic dynamometer system, and the VPS was measured by a biothesiometer. Daily physical activity was evaluated by the Baecke questionnaire. The EDS type III group showed significantly larger ranges of movement (P < 0.05) and lower levels of sport physical activity (SPA) compared to the control group (P = 0.023). Considering SPA as covariate, the EDS type III group demonstrated a significant impairment in knee joint reposition compared to the control group (P = 0.018). No significant differences were found for shoulder JPS. The VPS was not significantly different in the EDS type III group compared to the control group. In addition, no significant correlation was found between JPS and VPS, neither at the knee nor at the shoulder joint. This is the first study examining proprioception deficits in EDS type III patients as defined by the Villefranche criteria. Further research on the neurophysiological dysfunctions and mechanisms in this pathologic entity is needed.

The phenotypic spectrum of contiguous deletion of CYP21A2 and tenascin XB: Quadricuspid aortic valve and other midline defects

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder and is the most common cause of ambiguous genitalia in the newborn. The genes encoding 21-hydroxylase, CYP21A2, and tenascin-X (TNX), TNXB, are located within the HLA complex, in a region of high gene density termed the RCCX module. The module has multiple pseudogenes as well as tandem repeat sequences that promote misalignment during meiosis leading to complex gene rearrangements, deletions and gene conversion events. CYP21A2 mutations cause CAH, and TNX deficiency has been identified as a cause of hypermobility type Ehlers-Danlos syndrome (EDS). Here we report on a three-generation family with a heterozygous deletion encompassing CYP21A2 and TNXB that initially came to medical attention due to the diagnosis of CAH in the proposita. Southern blotting and PCR-based analysis of the RCCX module revealed a CYP21A2 deletion extending into TNXB in one allele and a CYP21A2 point mutation in the other allele. Family history is notable for joint hypermobility. Additional radiological and clinical investigations showed a quadricuspid aortic valve, single kidney, bicornuate uterus and a bifid uvula in the proposita, and mitral valve prolapse in her mother. These findings further delineate the phenotype of the CAH-TNX contiguous gene deletion syndrome and point to an intersection of connective tissue dysplasias with a common gene-mediated endocrine disorder.

The lack of clinical distinction between the hypermobility type of Ehlers–Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome)

The Lack of Clinical Distinction Between the Hypermobility Type of Ehlers–Danlos Syndrome and the Joint Hypermobility Syndrome (a.k.a. Hypermobility Syndrome) Brad T. Tinkle,* Howard A. Bird, Rodney Grahame, Mark Lavallee, Howard P. Levy, and David Sillence Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio University of Leeds, West Yorkshire, United Kingdom University College Hospital, London, United Kingdom Memorial Sports Medicine Institute, South Bend, Indiana Johns Hopkins University, Baltimore, Maryland Connective Tissue Dysplasia Management Service, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia