Pediatric joint hypermobility: a diagnostic framework and narrative review.

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. OBSERVATIONS: The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age. CONCLUSIONS: This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population.

Health Supervision for Children and Adolescents With Marfan Syndrome.

Marfan syndrome is a heritable connective tissue disorder that affects many different organ systems. In some cases, features of Marfan syndrome can be recognized at birth, but the majority will have manifestations that emerge throughout childhood and into adulthood. Significant morbidity and mortality are associated with this syndrome, and its features are best managed using a multidisciplinary approach. This clinical report is designed to assist the pediatrician in recognizing the features of Marfan syndrome as well as caring for the individual with Marfan syndrome to maximize their health and quality of life.

The role of functional disability and social support in psychological outcomes for individuals with pediatric hypermobile ehlers-danlos syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) includes physical symptoms of chronic pain, fatigue, gastrointestinal dysfunction, and joint subluxations/dislocations. This study aims to fill a research gap regarding the psychosocial well-being in pediatric hEDS by assessing relationships between functional disability, social support, and mental health. Increased functional disability is hypothesized to be associated with increased mental health challenges, specifically anxiety and depression, and general social support is hypothesized to moderate this relationship, such that higher perceived social support will mitigate the negative psychological impacts of functional disability. Gender's influence on mental health in pediatric hEDS is also explored. Thirty-four youth with pediatric hEDS recruited from a United States Midwest multidisciplinary genetics clinic completed self-report questionnaires. Results demonstrate associations between functional disability and mental health, and social support and mental health independently; however, moderation was not found. Functional disability and social support each have a unique influence on the mental health of children with pediatric hEDS and should each receive clinical attention. Exploratory analyses into the influence of gender provide a groundwork for future studies.

Symptomatic joint hypermobility.

Joint hypermobility is relatively common and has many influences such as age, gender, training, and ethnicity among many. Joint hypermobility may be asymptomatic or symptomatic. It may also be non-syndromic or syndromic. However, "asymptomatic" joint hypermobility may result in repetitive use injury, alter biomechanics of joints at other body sites, or become symptomatic later in life. Symptomatic joint hypermobility can result from soft-tissue rheumatism (e.g. bursitis, tendonitis, etc.) or muscular tension pain due to muscular imbalance. Generalized joint hypermobility (GJH) can be easily assessed using a standardized, quick, in-office examination. Management is relatively straight forward once joint hypermobility is recognized using neuromuscular re-training. It is important to recognize that GJH may also be a feature of a heritable connective tissue disorder with other systemic findings. Therefore, assessing joint hypermobility in those with musculoskeletal complaints may lead to recognizing systemic manifestations and allow the appropriate management.

Symptom complaints and impact on functioning in youth with hypermobile Ehlers-Danlos syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS), a genetic connective tissue disorder, involves several body systems which makes symptom management and functioning difficult. The aim of this study was to understand pediatric hEDS patients' symptoms and primary complaints. Additionally, we examined the cumulative impact of symptoms on physical and psychological functioning. Thirty-four youth with hEDS were recruited from a genetics clinic and reported the hardest thing about having hEDS, their pain, fatigue, physical symptoms, functional disability, anxiety, and depression. Physical symptoms (pain and fatigue) and limitations (keeping up with friends) were reported as the most difficult parts of having hEDS. A higher number of somatic symptoms was the strongest predictor of disability, anxiety, and depression. Physical symptoms are subjectively distressing and significantly related to impairments in physical and psychological functioning. Thus, addressing these varied symptoms in treatment may yield better functioning in youth with hEDS.

Symptomatic Joint Hypermobility: The Hypermobile Type of Ehlers-Danlos Syndrome and the Hypermobility Spectrum Disorders.

Joint hypermobility may be syndromic or nonsyndromic, asymptomatic or symptomatic. However, asymptomatic joint hypermobility can cause repetitive use injury, alter biomechanics, or become symptomatic later in life. Symptomatic joint hypermobility can result from soft tissue injury or muscular strain caused by muscular imbalance. Treatment is straightforward once joint hypermobility is recognized. Generalized joint hypermobility can be assessed using a standardized in-office examination. Generalized joint hypermobility may also be a feature of a heritable connective tissue disorder with other systemic findings. Therefore, assessing joint hypermobility in the context of musculoskeletal complaints may lead to recognizing systemic manifestations and allow treatment accordingly.

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Oral and mandibular manifestations in the Ehlers-Danlos syndromes.

The Ehlers-Danlos syndromes (EDS) are hereditary disorders that affect the connective tissue and collagen structures in the body. Several types of EDS have been identified. Oral and mandibular structures, which include oral soft tissue, dentition, facial and head pain, and the functioning of the temporomandibular joint (TMJ), are variably affected in the various types of EDS. These various manifestations of EDS have been noted for many years, but newer diagnostic techniques and studies are shedding additional light on the challenges faced by EDS patients in the area of oral and mandibular disorders. Further, the impact of temporomandibular disorder (TMD) on musculoskeletal dysfunction and vice versa, make this an important feature to recognize. Oral and mandibular hypermobility of the TMJ with associated consequences of EDS are noted. These features, diagnostic parameters and treatment procedures are presented. © 2017 Wiley Periodicals, Inc.

Spontaneous ruptured dissection of the right common iliac artery in a patient with classic Ehlers-Danlos syndrome phenotype.

Unlike vascular Ehlers-Danlos syndrome (EDS), classic EDS is rarely associated with vascular manifestation. We report the case of a 39-year-old man who presented with acute abdominal pain. At the time of presentation, the patient was in hypovolemic shock, and computed tomography angiogram demonstrated common iliac artery dissection with rupture. He underwent an attempted endovascular repair that was converted to an open repair of a ruptured right common iliac artery dissection. Subsequent genetic testing revealed a substitution of arginine for cysteine in type I collagen, COL1A1 exon 14 c.934C>T mutation, consistent with a rare variant of classic EDS.

Health supervision for children with Marfan syndrome.

Marfan syndrome is a systemic, heritable connective tissue disorder that affects many different organ systems and is best managed by using a multidisciplinary approach. The guidance in this report is designed to assist the pediatrician in recognizing the features of Marfan syndrome as well as caring for the individual with this disorder.

High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders.

BACKGROUND: Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease mediated by immune hypersensitization to multiple foods and strongly associated with atopy and esophageal remodeling. OBJECTIVE: We provide clinical and molecular evidence indicating a high prevalence of EoE in patients with inherited connective tissue disorders (CTDs). METHODS: We examined the rate of EoE among patients with CTDs and subsequently analyzed esophageal mRNA transcript profiles in patients with EoE with or without CTD features. RESULTS: We report a cohort of 42 patients with EoE with a CTD-like syndrome, representing 0.8% of patients with CTDs and 1.3% of patients with EoE within our hospital-wide electronic medical record database and our EoE research registry, respectively. An 8-fold risk of EoE in patients with CTDs (relative risk, 8.1; 95% confidence limit, 5.1-12.9; χ(2)1 = 112.0; P < 10(-3)) was present compared with the general population. Esophageal transcript profiling identified a distinct subset of genes, including COL8A2, in patients with EoE and CTDs. CONCLUSION: There is a remarkable association of EoE with CTDs and evidence for a differential expression of genes involved in connective tissue repair in this cohort. Thus, we propose stratification of patients with EoE and CTDs into a subset referred to as EoE-CTD.

Performance evaluation of the next-generation sequencing approach for molecular diagnosis of hereditary hearing loss.

OBJECTIVE: To evaluate the performance of a next-generation sequencing (NGS)-based targeted resequencing genetic test, OtoSeq, to identify the sequence variants in the genes causing sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective study. SETTING: Tertiary children's hospital. SUBJECTS AND METHODS: A total of 8 individuals presenting with prelingual hearing loss were used in this study. The coding and flanking intronic regions of 24 well-studied SNHL genes were enriched using microdroplet polymerase chain reaction and sequenced on an Illumina HiSeq 2000 sequencer. The filtered high-quality sequence reads were mapped to reference sequence, and variants were detected using NextGENe software. RESULTS: A total of 1148 sequence variants were detected in 8 samples in 24 genes. Using in-house developed NGS data analysis criteria, we classified 810 (~71%) of these variants as potential true variants that include previously detected pathogenic mutations in 5 patients. To validate our strategy, we Sanger sequenced the target regions of 5 of the 24 genes, accounting for about 29.2% of all target sequence. Our results showed >99.99% concordance between NGS and Sanger sequencing in these 5 genes, resulting in an analytical sensitivity and specificity of 100% and 99.997%, respectively. We were able to successfully detect single base substitutions, small deletions, and insertions of up to 22 nucleotides. CONCLUSION: This study demonstrated that our NGS-based mutation screening strategy is highly sensitive and specific in detecting sequence variants in the SNHL genes. Therefore, we propose that this NGS-based targeted sequencing method would be an alternative to current technologies for identifying the multiple genetic causes of SNHL.

Variable expression of neurofibromatosis 1 in monozygotic twins.

Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with high penetrance but extreme variability of expression. Monozygotic (MZ) twins with NF1 who have phenotypic discordances are a useful tool in evaluating which traits are influenced by non-hereditary influences such as second hit somatic events, environmental agents, epigenetic modification, or post-zygotic mutations. We evaluated nine sets of MZ twins and one set of MZ triplets, ages 4-18 years, for NF1 features and calculated probandwise concordance (P(C)) for each feature. MZ twins were highly concordant in numbers of café-au-lait spots (P(C) = 0.89) and cutaneous neurofibromas. IQ scores were within 10 points for all twin pairs tested, and similar patterns of learning disabilities and speech disorders were observed. Twin pairs showed significant discordance for tumors, particularly plexiform neurofibromas (P(C) = 0.40) and malignant peripheral nerves sheath tumors (MPNST), as expected if post-natal second-hit events were contributing to these features. One set of twins was concordant for multiple, large paraspinal neurofibromas, suggesting that there may be more hereditary factors involved in production of paraspinal neurofibromas. Four sets were concordant for pectus deformities of the chest (P(C) = 0.80). Three sets of twins were discordant for scoliosis (P(C) = 0.40); an additional set was concordant for scoliosis but differed in presence of dystrophic features and need for surgery. Our data suggest there are additional non-hereditary factors modifying the NF1 phenotype and causing discordancies between MZ twins. Future studies may focus on differences in epigenetic changes or somatic mosaicism which have been documented for other disease genes in MZ twins.

Joint hypermobility syndrome: A common clinical disorder associated with migraine in women.

Preliminary studies suggested that headache disorders are more common in patients with joint hypermobility syndrome (JHS). The objectives of this study were to determine if the prevalence, frequency, and disability of migraine differ between female patients with JHS and a control population. Twenty-eight patients with JHS and 232 controls participated in the case-cohort study. Participants underwent a structured verbal interview and were assigned a diagnosis of migraine based on criteria of the International Classification of Headache Disorders, 2nd Edition. The primary outcome measures were the prevalence, frequency, and headache-related disability of migraine. Logistic regression was used for the prevalence analysis and Poisson regression for the frequency and disability analyses. Results indicated that the prevalence of migraine was 75% in JHS patients and 43% in controls. The adjusted odds ratio for the prevalence of migraine was 3.19 (95% CI 1.24, 8.21] in JHS patients. The rate ratios for migraine frequency and headache-related disability were 1.67 (95% CI 1.01, 2.76) and 2.99 (95% CI 1.66, 5.38), respectively, for JHS patients. Our study suggests that JHS is a clinical disorder strongly associated with an increased prevalence, frequency, and disability of migraine in females.

Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome.

OBJECTIVES: To delineate the prevalence of cardiac findings in hypermobile and classic Ehlers-Danlos syndrome and provide longitudinal analysis of aortic root growth. STUDY DESIGN: A retrospective chart review was conducted, and data were analyzed for cross-sectional prevalence of aortic dilation and valvular anomalies. The clinical implications of aortic root growth were determined by assessment of progression of aortic root measurements over time and clinical symptoms. RESULTS: Patients whose first echocardiogram was obtained in late childhood or adulthood were less likely to have aortic dilation (P < .002) than those whose first echocardiogram was obtained in early childhood. Longitudinally, seven individuals had dilated aortas before age 14, and only one individual continued to show dilation after age 14 (P = .0143). No patient with a normal aortic root in childhood had development of dilation in adulthood. Fifteen of the 252 patients (6.0%) had mitral valve prolapse (MVP), although only one patient (0.4%) had MVP that was mild to moderate. CONCLUSIONS: Although aortic root size and MVP are increased in patients with these types of Ehlers-Danlos syndrome, they tend to be of little clinical consequence. Echocardiography may still be warranted as part of cardiovascular assessment, but decreased frequency of screening is recommended especially in symptom-free adults.

Sleep-related respiratory abnormalities and arousal pattern in achondroplasia during early infancy.

OBJECTIVE: To assess sleep-disordered breathing (SDB), sleep architecture, and arousal pattern in infants with achondroplasia and to evaluate the relationship between foramen magnum size and the severity of SDB. STUDY DESIGN: A retrospective review of polysomnographic recordings and medical records was performed in infants with achondroplasia and in aged-matched control subjects. All studies were re-scored with the emphasis on respiratory events, sleep state, and arousals. In addition, the neuroimaging study of the brain (magnetic resonance imaging) was reviewed to evaluate foramen magnum diameters and to assess their relationship to SDB. RESULTS: Twenty-four infants met the criteria for entry into analysis, 12 infants with achondroplasia (A) and 12 control infants (C). There was no significant difference in age or sex. Infants with achondroplasia had a significant increase in total respiratory disturbance index (RDI; A, 13.9 +/- 10.8 versus C, 2.0 +/- 0.9; P < .05). However, there was no significant difference in percentages of active sleep, quiet sleep, or sleep efficiency. Analysis of arousals demonstrated that infants with achondroplasia had a significant decrease in both spontaneous arousal index (A, 10.5 +/- 3.5/hr versus C, 18.6 +/- 2.7; P < .0001) and respiratory arousals (A, 10.3% +/- 6.3% versus C, 27.5 +/- 9.5%; P < .0001). Evaluation of foramen magnum dimensions demonstrated smaller foramen magnum size, but there were no significant correlations between anteroposterior or transverse diameters and RDI. CONCLUSION: Infants with achondroplasia have significant SDB during early infancy. SDB in infants with achondroplasia is not associated with alteration in sleep architecture, possibly because of attenuation of the arousal response. We speculate that the concomitant increased apneic events and decreased arousal response will lead to vulnerability in these infants and may underlie the pathophysiologic mechanism of sudden unexpected death in this population.