ICD-10-CM ICD-10-CM

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1 Summary: There is currently one ICD-10-CM code for Ehlers-Danlos Syndrome (Q79.6). A new classification of EDS was published in March 2017, defining 13 types of EDS. Physicians providing care for and persons living with EDS request that a unique set of ICD-10-CM codes be established that assign a separate ICD-10-CM code for each of the 13 EDS types, consistent with the 2017 International Classification of EDS. Background Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by articular hypermobility, skin hyperextensibility or laxity, and tissue fragility affecting virtually every organ system: skin, ligaments, joints, bone, muscle, blood vessels and various organs. Over the past two decades, the Villefranche Nosology, with a simplified classification of EDS into 6 major types based on major and minor criteria, has been widely used as the standard for the clinical diagnosis of EDS and for clinical research on various aspects of these conditions. Two developments led to efforts to revise the nosology: the developments in clinical and molecular characterization of several new EDS variants and a growing concern about the expanded phenotype of hypermobile type EDS, the lack of genetic diagnosis for it and a general sense that the diagnostic criteria were inadequate (Bloom et al 2017). In addition, there was a need for guidelines for the management of each type of EDS which could be used by the specialist and generalist caring for the affected individuals and their families. An International Consortium on EDS, created in 2012, convened experts, performed comprehensive literature reviews and developed an updated evidence-based nosology and diagnostic criteria for each type of EDS which was released in early 2017: the 2017 International Classification of EDS. The classification and manuscripts about EDS were published in the March 2017 Part C Seminars in Medical Genetics issue of the American Journal of Medical Genetics and are all available through the Ehlers-Danlos Society ( First, the new classification recognizes EDS to be a plural, Ehlers-Danlos syndromes, multiple distinct syndromes linked by a common pathophysiologic cause (connective tissue disorder) with similar physical features. It has incorporated new information about genetics and clinical manifestations of the syndromes into 13 significant types defined by major and minor clinical criteria, as well as the genetic etiology(ies), which provides a descriptive diagnosis that the patient can identify with. Because there is substantial overlap between the EDS types and other connective tissue disorders, the type definition includes a requirement for definitive diagnosis that is confirmed by genetic testing to identify the responsible variant for all EDS types for which a gene mutation is known (which is all but hypermobile EDS)(Malfait et al 2017). January 6,

2 The 2017 clinical classification includes a pathogenetic scheme that regroups EDS types for which the proteins, coded by the causative genes, function within the same pathway, and which are likely to have shared pathogenic mechanisms, based on current knowledge, which satisfies both clinical and research needs. With the support of The Ehlers-Danlos Society, the International Consortium on EDS is committed to meet every 2 years to reevaluate and update the Classification (Malfait et al 2017). Value of the 2017 International Classification of EDS The new classification system increases the credibility associated with EDS allowing clinicians (and patients) to be clearer about the diagnosis. Because EDS is a connective tissue disorder, it affects virtually every organ and system in the body. Most patients will have a number of clinicians involved in their care: primary care, geneticists, cardiologist, dermatologists, gastroenterologists, rheumatologists, physical medicine, ophthalmologists, orthopedic, pain specialists, cardiovascular, general and OB-Gyn surgeons, psychiatrists and mental health providers and physical and occupational therapists. To realize its full value in clinical practice once the diagnosis has been made, the clinician must be able to record it in the medical record so that it is front-and-center, clearly communicated to the entire healthcare team in the short- and long-term. Knowledge of which of the 13 types is present immediately conveys important clinical information: What to anticipate considering the major and minor criteria associated with the type. It provides a pathophysiologic diagnosis that ties together what appear to be unusual symptoms and complications, e.g. easy bruising, arterial dissection, recurrent spontaneous pneumothorax and bowel rupture associated with vascular EDS (veds)(byers et al 2017). It alerts the clinician to the fact that the individual s response to treatments designed for other causes may be different because the pathophysiology is different; e.g. blood pressure management to prevent/management vascular dissection or aneurysms in the person with and without EDS. The treatment may need to be modified to accommodate manifestations associated with each type of EDS e.g. the physical rehabilitation program for POTS includes a 2 month program for those with heds to be done before the 6- month program (Shibata et al 2010). Additional precautions are needed with the use of indwelling catheters because of the risk to the integrity of vascular or organ walls (veds)(byers et al 2017) Surgical or invasive interventions must be carefully considered. The inherent tissue fragility increases the risk of tissue damage, poor healing and an increase in complications. January 6,

3 EDS is not often recognized nor understood by the majority of clinicians which has a negative impact on patient care. The creation of a classification system based on clinical criteria, genetics, and pathophysiology increases the credibility of the diagnosis within the medical community and should help the clinician and family in understanding the clinical symptoms and plan appropriate treatment. It also helps the patient/family explain to others some of the symptoms: e.g. clumsiness and frequent falls in children, the tendency for easy bruising which has been sufficient to raise questions of abuse (Byers et al 2017). For children, the specific type diagnosis can help explain the difficulties children experience which affect their self-esteem and social functioning clumsiness, frequent falls, and fatigue (Engelbert et al 2017). It assists the family working with the school and daycare to plan appropriate preventive interventions, such as adjusting physical demands (e.g. carrying books to and from school) and identifying physical education activities that are appropriate and safe for the child with EDS. Knowledge of the type of EDS assists the physical and occupational therapist in designing interventions and patient education needed for EDS, e.g. to protect joints, improve proprioception, reduce neuropathy/impingements and adapt activities of daily living as well as additional precautions needed related to the specific type of EDS. Special precautions with the types impacting the vascular system would include educating the patient about avoiding Valsalva maneuvers in those with veds and the others that impact the vascular system. With a separately identifiable ICD-10-CM code, general and type-specific international registries will be able to better define the natural history, clinical experience and epidemiology of EDS. Modern-day access to registry databases and population studies will facilitate more rapid learning about the clinical aspects of each type of EDS, moving the scientific knowledge from anecdotal reporting of associations to epidemiological evidence. Specific ICD-10 diagnosis codes for each type will ease the process of identifying a homogenous population of potential candidates for participation in research studies as new diagnosis and treatments become available. There are two other ways that a more specific ICD-10-CM code for each type will be of value to the patient and the clinician. Regardless of the type experienced, EDS is a lifelong progressive condition that has a major impact on the lives and daily function of most living with EDS. There are few clinical studies addressing the impact on the patients function and quality of life, as reflected in patient-centered outcomes research. The role of fitness, exercise and rehabilitation in the functional ability and quality of life is needed for many of the types, e.g. classical EDS (ceds) and hypermobile EDS (heds) (Bowen et al 2017). This information is valuable not only to the scientific community to define gaps in care and research needed to address the impact on the individual s life, it has positive value to the individual to better understand their type of EDS and its implications for their life and future, including decisions about the future including having children. January 6,

4 Being able to differentiate the type of EDS present has additional value with respect to healthcare utilization and costs. People with EDS have multiple problems and potentially have a higher use of healthcare services. Treatment focuses on management of symptoms and prevention of complications, e.g. dislocations, joint damage, vascular or organ ruptures. Medical management includes physical rehabilitation, physical and occupational therapy to address prevention and adaptation for daily activities, pain management modalities, orthotics and splinting, and mental health support to improve coping. Specific type diagnosis and coding in the medical record allows for more accurate analysis of the healthcare utilization and costs associated with the different types. This will facilitate clinical utility analysis to assess the impact of new treatments designed specifically for EDS. As these are heritable connective tissue conditions, there are no known treatments to reverse the underlying pathology. There are limited medical treatments for the manifestations associated with the different types. Management of blood pressure is one of the few recommendations for medical management but the current drug options are generic and not specific for the pathophysiology associated with EDS. Treatments targeted for almost all of the EDS types will be classified as orphan drugs which means that it will be is especially important to be able to link the targeted therapy with the specific EDS type for research purposes, inclusion in clinical formularies and medical coverage policies developed by public and private payers and to monitor long-term outcomes. There are a number of types for which specific ICD-10-CM coding would be beneficial. The need for an ICD-10 code that identifies the subset of EDS is of particular importance for those types that have a high rate of vascular involvement with a propensity to dissection and rupture: Vascular EDS (veds), Classical EDS (ceds), and Kyphoscoliotic EDS (keds) (Malfait et al 2017). ICD-10-CM codes for these three types would help identify patients for much needed large scale studies on vascular risk and cardiac features to aid in management of those with these three EDS types. In addition to radiologic monitoring of the vascular system, e.g. abdominal aorta, aortic and mitral valves, management includes aggressive medical management of blood pressure. Maintaining a normal or low blood pressure and preventing surges in blood pressure (hoping to minimize the likelihood of arterial dissection or rupture) is one of the few medical interventions available. This is especially important in vascular EDS (veds) which often first presents with life-threatening arterial dissections and ruptures, as well as intestinal and uterine ruptures resulting in an average mortality of 51 years (Byers et al 2017). Management recommendations to avoid repeat ruptures include a protocol of permissive hypotension using traditional medications and avoidance of inotropic agents. For these types, clear and quick identification of both the presence of EDS but also the type by the patient (if they are able) and in the medical record should alert the emergency staff of the urgency of presentations that could represent a rupture or spontaneous arterial dissection or organ rupture requiring immediate medical and potentially surgical attention by surgeons familiar with the surgical challenges of EDS with its inherent vessel friability and high rate of complications and mortality. Research January 6,

5 on and access to new drugs designed to control blood pressure in the person with veds will benefit from consistency between the clinical type diagnosis and the ICD-10-CM coding. It s hoped the research will clarify whether and under what circumstances there is benefit from treatment with the one systematic investigation of efficacy of a drug for treatment of blood pressure in veds (Byers et al 2017). Similarly, identification of other types of EDS would have clinical management implications from prevention to management including contraindications. For example, several types include bone pathology: Arthrochalasia EDS (aeds), Classical EDS (ceds), Dermatosparaxis EDS (deds), Spondylodysplastic EDS (speds), and Kyphoscoliotic EDS (keds). This may be seen as bone dysplasia or osteoporosis with relative high fracture risk. Another example involves the eyes. High myopia is common in some types placing them at risk for retinal detachment whereas others may have cornea or scleral anomalies. These include thinned corneas causing keratoconus or keratoglobus with contraindications to corneal re-shaping surgery to correct vision and scleral rupture. Preventive management in these cases include avoiding certain activities that increase eye pressure, no direct contact sports, and education regarding the first signs of a retinal detachment to seek emergent therapy to prevent total blindness. Specific ICD-10-CM diagnosis coding will also benefit those with hypermobile EDS (heds) which is believed to be the most common genetic connective tissue disorder. It is the only type for which an identified distinctive cause (genetic variant) has not been identified. heds is known to evolve over time from a hypermobility phase, progressing to more widespread and progressively worsening of musculoskeletal pain, exacerbation of fatigue and then a stiffness phase presenting only in a few. In addition to the musculoskeletal/joint problems already included in the criteria defining heds, there are a number of symptoms and conditions that are associated heds: fatigue, chronic pain, sleep disturbance, GI motility/dysmotility and pain, urinary incontinence, neurologic symptoms, autonomic dysfunction (orthostatic instability, postural orthostatic tachycardia syndrome) as well as anxiety and depression (Bulbena et al 2017; Chopra et al 2017; Ericson and Wolman 2017; Fikree et al 2017; Hakim 2017a; Hakim et al 2017b; Henderson et al 2017; Mitakides and Tinkle 2017). However, the evidence was not sufficient to prove they are the result of heds in order to add them to the diagnostic criteria. With the larger databases (managed care, private and public insurance claims and pharmacy claims) now available for research, understanding the link between these associated conditions and heds will be greatly facilitated when the specific type diagnosis is made and reported in the medical record (and registries) with a matching ICD-10-CM code. Not only will this help focus on advances and define the needs for further research, it will facilitate development of treatments based on etiology. In summary, the expansion of the ICD-10-CM coding for EDS to specify the type diagnosed will allow: Clarity of diagnosis for patient and clinician with improved ability for education, guidance on future prognosis and life-planning, and anticipatory management of existing and associated manifestations, January 6,

6 More accurate diagnosis coding in the EHR record for short- and long-term communication to the healthcare team as well as for use in clinical research, healthcare resource utilization and for payer analysis of utilization and coverage, Registry participation and the ability to define homogenous groups of patients by type, Better understanding of the natural history and epidemiology of EDS and the types with increased diagnostic accuracy, ease of data collections, and understanding of prevalence, incidence etc., More accurate cost analysis - economic burden analysis by type of EDS, Easier identification of a homogenous set of potential candidates for research studies and allow quicker access by patients to new therapies, and Impact analysis of the EDS type on daily function, work, and quality of life to facilitate patient-centered measures of care. Current ICD-10-CM codes for EDS There is currently only one ICD-10-CM code for Q79.6 Ehlers-Danlos Syndrome and 2 other related codes which would be appropriate for use with individuals whose musculoskeletal/connective tissue problems are not due to EDS [M35.7 Hypermobility Syndrome (Familial ligamentous laxity) M24.2 (M24.20-M24.28) Disorder of the ligament (ligamentous laxity)]. The clinical reality, as demonstrated by the 2017 Classification, is that EDS is not a single syndrome with a single set of manifestations; it has 13 defined types. The use of a single ICD-10-CM diagnosis code to report the variation in presentation associated with the 13 types is not sufficient for a number of reasons: The guidelines for coding recommend each of the manifestations of the syndrome as a separate code under the primary diagnosis code. Using this methodology is cumbersome, time consuming, and less specific when known types have been identified which include the common manifestations and would eliminate the need to separately report manifestations. Many clinicians have limited knowledge about EDS beyond problems associated with joint hypermobility. Dermatologists and plastic surgeons may be more aware of skin manifestations because they are associated with poor wound healing and scarring as well as hematologists for easy bruising and extensive hematoma formation. Most are less familiar with the problems associated with tissue fragility and the association of EDS with the other common manifestations that may present with the different types. The pathophysiologic link between the diagnosis of EDS and the separately coded manifestation may not be made. January 6,

7 Like Marfan syndrome which has separate codes to report cardiovascular, ocular and skeletal manifestations (ICD-10-CM Q87.4-Q87.43), maintaining a connection between the primary diagnosis (EDS) and the manifestation (e.g. joint dislocation, bruising, and aneurysm rupture or arterial dissection) is critical clinically. Problem lists generated for the patient and summaries use a limited number of diagnosis codes. As medical encounters accumulate, the connection between the manifestations and EDS can be lost if we are relying on the reporting of separate codes for each. Often, the EDS diagnosis gets omitted. The use of one ICD-10-CM code to report a heterogeneous group of patients who will require very different clinical services and have different combinations of symptoms, manifestations and complications diminishes its clinical usefulness, as well its use in clinical, population health and epidemiologic research. It does not facilitate identification of patients with specific types who may be eligible for research studies. It has limited and potentially negative impact when it s used as part of coverage and payment policies by commercial and public payers to identify appropriate use of services and treatment for EDS. Therefore, in order to support current improvement in the classification and diagnosis of EDS types and its positive impact on patient care and to remain consistent with the international consensus, we propose that the ICD-10-CM coding for EDS be expanded to delineate the 13 types of EDS in accordance with nosology provided in the 2017 International Classification of EDS. DISTINCT DIAGNOSIS The types of EDS each have a distinct and unique clinicopathologic profile. Classical type: Marked joint hypermobility, skin laxity and fragility are characteristic of this type of EDS. Skin is fragile and tears or bruises easily, joint dislocation and scoliosis are common, as are sprains and strains from the joint instability. Some have predisposition to bone fragility fractures and arterial ruptures. Classical-like type: Joint hypermobility, hyperelastic skin and fragile skin, yet lacks the multiple atrophied scars in the skin that are often seen in classic EDS. Cardiac-valvular type: Presents with severe heart valve disease requiring valve replacement surgery. May also involve variable skin hyperextensibility, atrophic scarring, and joint hypermobility as seen in classic EDS. Vascular type: Rare but potential fatal disorder that is known to cause arterial aneurysms, dissections and ruptures; rupture of bowels or uterus and reduced January 6,

8 lifespan. Even minor trauma can lead to extensive bruising and skin tears. Easy bruising is most often noticed in childhood, often accompanied by visibility of blood vessels through translucent skin. Hypermobile type: Believed to be the most common genetic connective tissue disorder. Joint hypermobility is the major manifestation of this form of EDS and subluxations/dislocations are frequent. There are a range of conditions that can accompany heds which are not specific enough to be included in the criteria for diagnosis: sleep disturbance, fatigue, pain, postural orthostatic tachycardia, functional gastrointestinal disorders, dysautonomia, anxiety, and depression. Arthrochalasia type: Patients are short, severely affected by joint laxity and dislocations and also have skin laxity and hypotonia. Dermatosparaxis type: Skin is soft and doughy with sagging and folding with severe bruisability. Kyphoscoliosis type: Fragile globe of the eyes, significant skin and joint laxity and severe curvature of the spine are typical. Brittle Cornea type: Thin fragile cornea with an increased risk for spontaneous corneal rupture, and too often, blindness and severe vision loss. Those affected also have joint laxity and hearing loss. Spondylodysplastic type: Can be one of the most severe and disabling forms of EDS and produces short stature and mild intellectual disability in addition to bone (i.e. skeletal) dysplasia. Musculocontractural type: Distinctive head and facial features; multiple deformed and rigid joints at birth; progressive spinal and foot deformities; and eye and urinary tract issues. Myopathic type: Muscle weakness that present in infancy or childhood and is associated with proximal large joint rigidity and distal joint hypermobility. Muscle weakness tends to get better with age until young adulthood. Periodontal type: Early-onset inflammation of the tissue around teeth, with extensive gum destruction and loss of teeth starting in childhood or adolescence. Below is a proposed modification of the ICD-10-CM codes for EDS. January 6,

9 REFERENCES: Bloom, L., Byers, P., Francomano, C., Tinkle, B., Malfait, F., & on behalf of the Steering Committee of The International Consortium on the Ehlers-Danlos Syndromes. (2017). The international consortium on the Ehlers Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Bowen, J. M., Sobey, G. J., Burrows, N. P., Colombi, M., Lavallee, M. E., Malfait, F., & Francomano, C. A. (2017). Ehlers Danlos syndrome, classical type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Brady, A. F., Demirdas, S., Fournel-Gigleux, S., Ghali, N., Giunta, C., Kapferer-Seebacher, I., Malfait, F. (2017). The Ehlers Danlos syndromes, rare types. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Byers, P. H., Belmont, J., Black, J., De Backer, J., Frank, M., Jeunemaitre, X., Wheeldon, N. (2017). Diagnosis, natural history, and management in vascular Ehlers Danlos syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Bulbena et al pp Bulbena, A., Baeza-Velasco, C., Bulbena-Cabré, A., Pailhez, G., Critchley, H., Chopra, P., Porges, S. (2017). Psychiatric and psychological aspects in the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Chopra et al pp ; Chopra, P., Tinkle, B., Hamonet, C., Brock, I., Gompel, A., Bulbena, A., & Francomano, C. (2017). Pain management in the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Engelbert, R. H. H., Juul-Kristensen, B., Pacey, V., de Wandele, I., Smeenk, S., Woinarosky, N., Simmonds, J. V. (2017). The evidence-based rationale for physical therapy treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Ericson and Wolman pp ; Ericson, W. B., & Wolman, R. (2017). Orthopaedic management of the Ehlers Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Fikree et al pp ; Fikree, A., Chelimsky, G., Collins, H., Kovacic, K., & Aziz, Q. (2017). Gastrointestinal involvement in the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Hakim, A., De Wandele, I., O Callaghan, C., Pocinki, A., & Rowe, P. (2017a). Chronic fatigue in Ehlers-Danlos syndrome-hypermobile type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Hakim, A., O Callaghan, C., De Wandele, I., Stiles, L., Pocinki, A., & Rowe, P. (2017b). Cardiovascular autonomic dysfunction in Ehlers-Danlos syndrome-hypermobile type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Henderson pp ; Henderson, F. C., Austin, C., Benzel, E., Bolognese, P., Ellenbogen, R., Francomano, C. A., Voermans, N. C. (2017). Neurological and spinal manifestations of the January 6,

10 Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Malfait, F., Francomano, C., Byers, P., Belmont, J., Berglund, B., Black, J., Tinkle, B. (2017). The 2017 international classification of the Ehlers Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Mitakides and Tinkle pp ; Mitakides, J., & Tinkle, B. T. (2017). Oral and mandibular manifestations in the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), Tinkle, B., Castori, M., Berglund, B., Cohen, H., Grahame, R., Kazkaz, H., & Levy, H. (2017). Hypermobile Ehlers Danlos syndrome (a.k.a. Ehlers Danlos syndrome Type III and Ehlers Danlos syndrome hypermobility type): Clinical description and natural history. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), OPTION: A 4 digit sub-classification code for each of the 13 types that is consistent with the 2017 International Classification of the Ehlers-Danlos Syndromes (Malfait et al, AJMG Part C: 2017 pp8-26 available at TABULAR MODIFICATION Q79.6 Ehlers-Danlos syndromes Classical EDS (ceds) Skin hyperextensibility and atrophic scarring; and generalized joint hypermobility 9 minor criteria: Smooth velvety skin; molluscoid pseudotumours; subcutaneous spheroids/spherules; complications of joint hypermobility; muscle hyptonia, delayed gross motor development; easy bruising; manifestations of tissue extensibility and fragility; surgical complications, positive family history Autosomal dominant Genetic basis: Major: COL5A1, COL5A2, COL1A Classical-like EDS (cleds) Skin hyperextensibility with velvety skin texture and absence of atrophic scarring; Generalized joint hypermobility with or without recurrent dislocations; and Easily bruised skin or spontaneous ecchymoses January 6,

11 7 minor criteria: Autosomal recessive Genetic basis: TNXB Cardiac-valvular EDS (cveds) Severe progressive cardiac-valvular problems; Skin hyperextensibility, atrophic scars, thin skin, easy bruising; and joint hypermobility 4 minor criteria: Autosomal recessive Genetic basis: COL1A Vascular EDS (veds) Family history of veds with documented causative variant in COL3A1; Arterial rupture at a young age; Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology; Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears; and Carotid-cavernous sinus fistula formation in the absence of trauma 12 minor criteria; Autosomal dominant. Genetic basis: COL3A1; COL1A Hypermobile EDS (heds) Generalized joint hypermobility (GJH); AND 2 or more of the following must be present: o Systemic manifestations of a more generalized connective tissue January 6,

12 disorder o Positive family history o Musculoskeletal complications AND All these prerequisites must be met o Absence of unusual skin fragility o Exclusion of other heritable and acquired connective tissue disorders including autoimmune rheumatologic conditions, and o Exclusion of alternative diagnosis that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. Autosomal dominant Genetic basis: Diagnosis remains clinical Arthrochalasia EDS (aeds) Congenital bilateral hip dislocation; Severe generalized joint hypermobility (GJH), with multiple dislocations/subluxations; and Skin hyperextensibility 5 minor criteria. Autosomal dominant Genetic basis: COL1A1 or COL1A Dermatosparaxis EDS (deds) Extreme skin fragility with congenital or postnatal skin tears Characteristic craniofacial features, which are evident at birth or early infancy, or evolve later in childhood Redundant, almost lax skin, with excessive skin folds at the wrists and ankles Increased palmar wrinkling Severe bruisability with a risk of subcutaneous hematomas and hemorrhage Umbilical hernia Postnatal growth retardation Short limbs, hand and feet Perinatal complications due to connective tissue fragility 11 minor criteria: January 6,

13 Autosomal recessive. Genetic basis: ADAMTS Kyphoscoliotic EDS (keds) Congenital muscle hypotonia; Congenital or early onset kyphoscoliosis (progressive or non-progressive); and GJH with dislocations/subluxations (shoulders, hips and knees in particular) 10 minor criteria, as well as gene-specific minor criteria: A final diagnosis requires laboratory and molecular testing. Autosomal recessive Genetic basis: PLOD or FKBP14 mutations Brittle Cornea Syndrome (BCS) Thin cornea, with or without rupture; Early onset progressive keratoconus; Early onset progressive keratoglobus; and Blue sclerae 14 minor criteria. Autosomal recessive Genetic basis: ZNF469 or PRDM Spondylodysplastic EDS (speds) Short stature (progressive in childhood); Muscle hypotonia (ranging from severe congenital to mild later-onset; and Bowing of limbs 5 minor criteria: A final diagnosis requires molecular testing plus gene-specific criteria. Autosomal recessive Genetic basis: B3GALT6, B4GALT7, SLC39A13 January 6,

14 Musculocontractural EDS (mceds) Congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot); Characteristic craniofacial features, which are evident at birth or in early infancy; and Characteristic cutaneous features including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling. 15 minor criteria: Autosomal recessive Genetic basis: CHST Myopathic EDS (meds) Congenital muscle hypotonia, and/or muscle atrophy, that improves with age; Proximal joint contractures (knee, hip and elbow); and Hypermobility of distal joints 4 minor criteria: Autosomal recessive and autosomal dominant Genetic basis: COL12A Periodontal EDS (peds) Severe and intractable periodontitis of early onset (childhood or adolescence); Lack of attached gingiva; Pretibial plaques; and Family history of a first-degree relative who meets clinical criteria. 8 minor criteria: A final diagnosis requires molecular testing Autosomal recessive Genetic basis: C1R or C1S January 6,