Wednesday, July 22, 2015

A Clinical Description of Ehlers Danlos Syndrome Classical Type I & II

I have EDS Classical Type. They have now combined type one and two into one category which is now just called Classical Type.
Awareness is so important because of the signs that I had as a baby would have let my parents know to have me checked out and even more important, my Doctor would have known what was wrong with me.

My mother, of course having no knowledge of EDS, said that I was a very soft and floppy baby. Also, she said that I had a hard time learning how to walk and that I would kick out one leg with each step instead of just taking a normal step. These were just a very few of the things mentioned here that would have helped me in many many ways if we would have known what in the world EDS was. It would have helped me know how to protect myself during play and sports activities, it would have helped me understand why I just felt tired all the time and why I was dizzy and why my body seemed to hurt at times that my peers did not.
 
I hope that this information is helpful to those who are searching for information about EDS and also that with the links provided in the article it will help you reach deeper into the maze that is EDS in order to help get what you need to pass along awareness to others.  


http://www.ncbi.nlm.nih.gov/books/NBK1244/


Ehlers-Danlos Syndrome, Classic Type
Synonyms: Ehlers-Danlos Syndrome, Classical Type; EDS, Classic Type. Includes: Ehlers-Danlos Syndrome Type I, Ehlers-Danlos Syndrome Type II

Fransiska Malfait, MD, PhD, Richard Wenstrup, MD, and Anne De Paepe, MD, PhD.Author Information


Initial Posting: May 29, 2007; Last Update: August 18, 2011.
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Summary

Clinical characteristics.

Ehlers-Danlos syndrome (EDS), classic type is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. It includes two previously designated subtypes (EDS type I and EDS type II) that are now recognized to form a continuum of clinical findings. The skin is smooth, velvety to the touch, and hyperelastic; i.e., it extends easily and snaps back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is delayed, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Less common findings include mitral and tricuspid valve prolapse, aortic root dilatation, and spontaneous rupture of large arteries.

Diagnosis/testing.

The diagnosis of EDS, classic type is established by family history and clinical examination. Quantitative and qualitative studies of type V collagen chains are usually not useful in confirming a diagnosis. At least 50% of individuals with classic EDS have an identifiable pathogenic variant in COL5A1 or COL5A2, the genes encoding type V collagen; however, this number may be an underestimate, since no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined group.

Management.

Treatment of manifestations: Children with hypotonia and delayed motor development benefit from physiotherapy. Non-weight-bearing exercise promotes muscle strength and coordination. Anti-inflammatory drugs may alleviate joint pain. Those with hypotonia, joint instability, and chronic pain may need to adapt lifestyles accordingly. Dermal wounds are closed without tension, preferably in two layers. For other wounds, deep stitches are applied generously; cutaneous stitches are left in place twice as long as usual; and the borders of adjacent skin are carefully taped to prevent stretching of the scar. Cardiovascular problems are treated in a standard manner.

Prevention of primary manifestations: Young children with skin fragility can wear pads or bandages over the forehead, knees, and shins to avoid skin tears. Older children can wear soccer pads or ski stockings with shin padding during activities. Ascorbic acid (vitamin C) may reduce bruising.

Surveillance: Yearly echocardiogram when aortic dilatation and/or mitral valve prolapse are present.

Agents/circumstances to avoid: Acetylsalicylate; sports that strain joints.

Genetic counseling.

EDS, classic type is inherited in an autosomal dominant manner. It is estimated that approximately 50% of affected individuals have inherited the pathogenic variant from an affected parent, and approximately 50% of affected individuals have a de novo disease-causing mutation. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible for families in which the pathogenic variant has been identified in an affected family member.
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Diagnosis

Clinical Diagnosis

The diagnosis of Ehlers-Danlos syndrome (EDS), classic type is established by family history and clinical examination. Diagnostic criteria were developed by a medical advisory group in a conference (sponsored by the Ehlers-Danlos Foundation [USA] and the Ehlers-Danlos Support Group [UK]) at Villefranche in 1997 [Beighton et al 1998] (full text; pdf).

The combination of the first three major diagnostic criteria should have a highspecificity for EDS, classic type. The presence of one or more minor criteria contributes to the diagnosis of EDS, classic type but is not sufficient to establish the diagnosis.

Major diagnostic criteria for the classic type of EDS
Skin hyperextensibility. Skin hyperextensibility (see Figure 1) should be tested at a neutral site (one not subjected to mechanical forces or scarring), such as the volar surface of the forearm. It is measured by pulling up the skin until resistance is felt. In young children, hyperextensibility of the skin is difficult to assess because of abundant subcutaneous fat.
Widened atrophic scars. (see Figure 2) (a manifestation of tissue fragility)
Joint hypermobility. Joint hypermobility (see Figure 3) depends on age, gender, and family as well as ethnic backgrounds. Joint hypermobility in classic EDS is general, affecting both large and small joints, and is usually noted when a child starts to walk. It should be assessed using the Beighton scale, the most widely accepted grading system for the objective semi-quantification of joint hypermobility (see Table 1).
Positive family history


Figure 1.

Skin hyperextensibility


Figure 2.

Widened atrophic scars


Figure 3.

Passive flexion of thumbs to the forearm: manifestation of joint hypermobility

Table 1.


Beighton's Criteria for Joint Hypermobility

Joint/FindingNegativeUnilateralBilateralPassive dorsiflexion of the 5th finger >90° 0 1 2
Passive flexion of thumbs to the forearm 0 1 2
Hyperextension of the elbows beyond 10° 0 1 2
Hyperextension of the knees beyond 10° 0 1 2
Forward flexion of the trunk with knees fully extended and palms resting on the floor 0 1



A total score of ≥5 defines hypermobility.

Minor diagnostic criteria for the classic type of EDS
Smooth, velvety skin
Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees
Subcutaneous spheroids: small, cyst-like, hard shot-like nodules, freely moveable in the subcutis over the bony prominences of the legs and arms. They occur in approximately one third of affected individuals, are numerous, and feel like hard grains of rice. X-ray reveals an outer calcified layer with a translucent core. The spheroids represent subcutaneous fat globules that have lost their blood supply, becoming fibrosed and calcified.
Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pes planus)
Muscle hypotonia, delayed gross motor development
Easy bruising
Manifestations of tissue extensibility and fragility (e.g., hiatal hernia, anal prolapse in childhood, cervical insufficiency)
Surgical complications (postoperative hernias)

Testing

Electron microscopy of a skin biopsy in EDS, classic type often suggests disturbed collagen fibrillogenesis. A "cauliflower" deformity of collagen fibrils is characteristic [Hausser & Anton-Lamprecht 1994]. However, these findings are not specific for EDS and thus not diagnostic. Furthermore, ultrastructural changes, usually most pronounced in the central parts of the reticular dermis, may be missed if the skin biopsy is not full thickness.

Biochemical testing on cultured dermal fibroblasts. Collagen protein analysis is performed on cultured fibroblasts, derived from a skin biopsy in order to obtain a source of protein for electrophoretic analysis of collagen types I, III, and V. The collagens are labeled and analyzed on SDS-polyacrylamide gel electrophoresis. Abnormal proteins migrate differently on the gel when compared to control samples. Since type V collagen is synthesized by fibroblasts at low levels, alterations in electrophoretic mobility are poorly reproducible, making this an ineffective method for routine diagnostic evaluation. The test, however, helps to exclude other subtypes of EDS (e.g., the vascular, kyphoscoliotic, arthrochalasis, and dermatosparaxis types) in individuals in whom clinical differential diagnosis is difficult. Rarely, an abnormal electrophoretic pattern for type I collagen is detected due to the presence of an arginine-to-cysteine substitution inCOL1A1 coding for the proα1(I) collagen chain of type I collagen [Nuytinck et al 2000,Malfait et al 2007]

Molecular Genetic Testing

Genes. In the majority of affected families (≥50%), the pathogenic variant is identified in the genes encoding type V collagen, COL5A1 and COL5A2. However, since no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined patient group, this number may underestimate the real proportion of individuals with classic EDS harboring a pathogenic variant in one of these genes.

Evidence for locus heterogeneity. A COL1A1 pathogenic variant, p.Arg134Cys, was identified in two unrelated children with classic EDS [Nuytinck et al 2000]. The same substitution was subsequently identified in three unrelated persons with aneurysms and rupture of medium-sized arteries in young adulthood. These people also had thin and hyperextensible skin, easy bruising, and abnormal wound healing [Malfait et al 2007; Malfait and De Paepe, personal observation]. Mutation of COL1A1, however, is not a major cause of classic EDS [Malfait et al 2005].

Clinical testing
Sequence analysis. Approximately 50% of individuals with classic EDS have an identifiable pathogenic variant in COL5A1 or COL5A2. COL5A1 null alleles are detected in approximately 30%-40% of individuals with classic EDS [Malfait et al 2005].
Deletion/duplication analysis. The usefulness of such testing has not been demonstrated, as no deletions or duplications involving COL5A1 or COL5A2 as causative of classic EDS have been reported.
COL5A1 null allele test. The COL5A1 null allele test determines if the individual is heterozygous for one of several COL5A1 polymorphic exonic markers in gDNA and then establishes at the cDNA level whether both alleles are expressed. If only one of the two COL5A1 alleles is present in cDNA, it is assumed that the absent allele is null. Since this test examines both gDNA and cDNA, COL5A1null allele testing requires cultured skin fibroblasts. It does not identify pathgoenic variants within COL5A1 [Malfait et al 2005].

Table 2.


Summary of Molecular Genetic Testing Used in Ehlers-Danlos Syndrome, Classic Type

Gene 1Proportion of EDS, Classic Type Attributed to Mutation of This GeneTest MethodMutations Detected 2COL5A1 46% 3 Sequence analysis 4 Sequence variants
Deletion/duplicationanalysis 5 Exonic and whole-genedeletions/duplications 6
COL5A2 4% 3 Sequence analysis 4 Sequence variants
Deletion/duplicationanalysis 5 Exonic and whole-genedeletions/duplications 6

1.

See Table A. Genes and Databases for chromosome locus and protein name.2.

See Molecular Genetics for information on allelic variants.3.

Malfait et al [2005], Malfait & De Paepe [2005]4.

Examples of pathogenic variants detected by sequence analysis include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-genedeletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.5.

Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probeamplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosomesegment.6.

No deletions or duplications involving COL5A1 or COL5A2 have been reported to cause Ehlers-Danlos syndrome, classic type. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Test characteristics. See Clinical Utility Gene Card [Mayer et al 2013] for information on test characteristics including sensitivity and specificity.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing for classic EDS is complicated by the large number of exons in the coding sequences (66 inCOL5A1 and 52 in COL5A2) and the wide distribution of mutations. When a clinical diagnosis of classic EDS is suspected, we recommend the following evaluations:
Perform sequence analysis by Sanger sequencing of COL5A1 and COL5A2either on gDNA or cDNA. The authors recommend starting with sequence analysis of COL5A1 on gDNA, as most individuals with classic EDS harbor a unique pathogenic variant in this gene, leading to the introduction of a premature termination codon and nonsense-mediated decay of mRNA. When no COL5A1pathogenic variant is found, sequence analysis of COL5A2 should be performed.
Perform COL5A1 null allele test and biochemical testing. If sequence analysisof both COL5A1 and COL5A2 does not identify a causal variant in a person with the phenotype of classic EDS, the authors recommend obtaining a skin biopsy in order to perform a COL5A1 null allele test and biochemical testing.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutation of COL5A1 or COL5A2.
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Clinical Characteristics

Clinical Description

Ehlers-Danlos syndrome (EDS) is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. Previously, two subtypes, EDS type I and EDS type II, differing only in phenotypic severity, were recognized; it is now apparent that they form a continuum of clinical findings.

Skin
Cutaneous hyperextensibility is one of the cardinal features of EDS in general and of classic EDS in particular. Skin extends easily and snaps back after release (unlike lax, redundant skin, as in cutis laxa).
The skin is smooth and velvety to the touch.
The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Skin fragility may cause dehiscence of sutured incisions in skin or mucosa.
Wound healing is delayed, and stretching of scars after apparently successful primary wound healing is characteristic. Scars become wide, with a "cigarette-paper"-like or papyraceous appearance.
Other dermatologic features in classic EDS:
Molluscoid pseudotumors (see Clinical Diagnosis)
Subcutaneous spheroids (see Clinical Diagnosis)
Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing
Elastosis perforans serpiginosa: a rare skin condition of unknown etiology characterized by skin-colored to erythematous keratotic papules, some enlarging outwards in serpiginous or arcuate configurations, leaving slightly atrophic centers
Acrocyanosis: a painless disorder caused by constriction or narrowing of the small blood vessels in the skin (affecting mainly the hands) in which the affected areas turn blue and become cold and sweaty; localized swelling may also occur
Chilblains: cold injuries, characterized by a red swollen skin that is tender, hot to the touch, and may itch; can develop in less than two hours in skin exposed to cold

Tissue fragility. Manifestations of generalized tissue extensibility and fragility are observed in multiple organs:
Cervical insufficiency during pregnancy
Inguinal and umbilical hernia
Hiatal and incisional hernia
Recurrent rectal prolapse in early childhood

Joints
Complications of joint hypermobility including dislocations of the shoulder, patella, digits, hip, radius, and clavicle may occur and usually resolve spontaneously or are easily managed by the affected individual. Some individuals with classic EDS may experience chronic joint and limb pain, despite normal skeletal radiographs.
Other problems related to the joint hypermobility are joint instability, foot deformities such as congenital clubfoot or pes planus, temporomandibular joint dysfunction, joint effusions, and osteoarthritis [Hagberg et al 2004, De Coster et al 2005a, De Coster et al 2005b].

Neurologic features. Primary muscular hypotonia may occur and may cause delayed motor development, problems with ambulation, and mild motor disturbance. Fatigue and muscle cramps are relatively frequent. Rarely, CSF leak has been reported to cause postural hypotension and headache in individuals with classic EDS [Schievink et al 2004].

Easy bruising. Easy bruising is a common finding and manifests as spontaneous ecchymoses, frequently recurring in the same areas and causing a characteristic brownish discoloration of the skin, especially in exposed areas such as shins and knees. There is a tendency toward prolonged bleeding (e.g., following brushing of the teeth) in spite of a normal coagulation status.

Cardiovascular
Structural cardiac malformations are uncommon in classic EDS.
Mitral valve prolapse and, less frequently, tricuspid valve prolapse may occur. Stringent criteria should be used for the diagnosis of mitral valve prolapse.
Aortic root dilatation may be more common than previously thought [Wenstrup et al 2002]. A recent retrospective study showed that three out of 50 (6%) individuals with classic EDS had aortic dilatation at their first echocardiogram, which was performed at a median age of 16 years. However, the dilatation tended to be of little clinical consequence and the mitral valve prolapse is rarely severe. Medical or surgical intervention is rarely necessary for either [Atzinger et al 2011].
Spontaneous rupture of large arteries, along with intracranial aneurysms and arteriovenous fistulae, may occur in the rare individual with a severe form of classic EDS.

Pregnancy in a woman with classic EDS bears risk for the newborn as well as for the mother. As a whole, these complications are more frequent than in the normal population; however, it is difficult to quantitate the incidence of each complication inaffected individuals because no good studies exist:
Premature rupture of the membranes and prematurity can occur when the mother is affected, and also when the fetus is affected, especially in the most severe forms.
Because of hypotonia, breech presentation is more frequent if the baby is affectedand may lead to dislocation of the hips or shoulder of the newborn.
In affected women, tearing of the perineal skin by forceps and, after delivery, extension of episiotomy incisions and prolapse of the uterus and/or bladder may occur.

Genotype-Phenotype Correlations

The number of individuals described with pathogenic variants in COL5A1 or COL5A2 is relatively small. Although there can be some variability in severity of the phenotype, nogenotype/phenotype correlations have emerged to date. In particular, no difference in severity is noted in individuals with a COL5A1 null mutation as compared to individuals with a structural mutation or those in whom no mutation can be detected.
Mutations in COL5A1 that encode the amino-terminal region of the proα1(V) collagen chain appear to be associated with a phenotype that can differ slightly from the classic EDS phenotype.
A p.Gly530Ser substitution in the amino-terminal propeptide of the α1(V) chain may be disease-modifying when present in the heterozygous state and disease-causing in the homozygous state [Giunta & Steinmann 2000, Giunta et al 2002].
A particular splice site mutation with a complex outcome within the amino-terminal region of the proα1(V) collagen chain was recently shown to result in a classic EDS-like phenotype with only minor cutaneous involvement (absence of the characteristic atrophic scarring) but with severe kyphoscoliosis and retinal detachment [Symoens et al 2011].

Penetrance

Inter- and intrafamilial variability in the severity of the phenotype can be great.

In some families with a non-functional (i.e., null) COL5A1 allele, an affected member can have a very mild classic EDS phenotype, while other family members may have a severe phenotype [Malfait & De Paepe 2005].

Anticipation

Anticipation is not observed.

Nomenclature

As a result of the 1997 Villefranche conference on EDS [Beighton et al 1998], the former EDS type I and type II are now reclassified as EDS, classic type.

Prevalence

The prevalence of EDS type I has been estimated at 1:20,000 [Byers 2001]. However, it is likely that some individuals with milder manifestations of the disease, previously classified as EDS type II, do not come to medical attention and thus go undetected.
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Differential Diagnosis

Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation. The disorders in which clinical findings overlap with the classic type of EDS include the following:

Ehlers-Danlos syndrome, hypermobility type (EDS type III). In this form, joint hypermobility is the primary manifestation. 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, but atrophic scarring is more characteristic of the classic type of EDS. Joint hypermobility is the primary clinical manifestation. Skin abnormalities, such as variable skin hyperextensibility and smooth velvety skin, are found; but the presence of atrophic scars in individuals with joint hypermobility suggests the diagnosis of classic EDS.

The diagnosis of EDS, hypermobility type is based entirely on clinical evaluation andfamily history. In most individuals with EDS, hypermobility type, the gene in whichmutation is causative is unknown and unmapped [Malfait et al 2006a]. Haploinsufficiency of TNXB (the gene encoding tenascin X) and heterozygosity for missense mutations in TNXB have been associated with EDS, hypermobility type in a small subset of affected individuals (see Tenascin X deficiency) [Zweers et al 2003,Zweers et al 2005]. A single occurrence of a COL3A1 mutation in a family thought to have EDS, hypermobility type has been reported. Inheritance is autosomal dominant.

Tenascin X deficiency. Homozygous pathogenic variants in TNXB have been identified in individuals with an autosomal recessive EDS phenotype characterized by mild joint hypermobility, skin hyperextensibility, and easy bruising but without atrophic scarring [Schalkwijk et al 2001, Lindor & Bristow 2005]. Heterozygotes for the same pathogenic variant, especially females, appear to have an EDS hypermobility phenotype.

Familial joint hypermobility syndrome, and other syndromes in which hypermobility is found, share hypermobility of the joints with classic EDS; but the absence of skin hyperextensibility and atrophic scarring excludes the diagnosis of classic EDS.

Ehlers-Danlos syndrome, vascular type (EDS type IV) is characterized by thin, translucent skin; easy bruising; characteristic facial appearance; and arterial, intestinal, and/or uterine fragility. Affected individuals are at risk for arterial rupture, aneurysm, and/or dissection; gastrointestinal perforation or rupture; and uterine rupture during pregnancy. One fourth of individuals with EDS, vascular type experience a significant medical problem by age 20 years and more than 80% by age 40 years. The median age of death is 48 years.

The diagnosis of EDS, vascular type is based on clinical findings and confirmed by biochemical and/or molecular genetic testing. Biochemical studies in affected individuals demonstrate abnormal electrophoretic mobility and abnormal efficiency of secretion of type III procollagen by cultured dermal fibroblasts. Molecular genetic testing is used to identify pathogenic variants in COL3A1. Inheritance is autosomal dominant.

Ehlers-Danlos syndrome, progeroid form is a rare autosomal recessive disorder characterized by progeroid appearance with wrinkled facies, curly and fine hair, scanty eyebrows and eyelashes, and periodontitis, in addition to typical signs of EDS. It is caused by homozygous pathogenic variants in B4GALT7, the gene encoding beta-1,4-galactosyltransferase 7.

Ehlers-Danlos syndrome, kyphoscoliotic form (previously known as EDS type VI) is a generalized connective tissue disorder characterized by kyphoscoliosis, joint laxity, muscle hypotonia, and, in some individuals, fragility of the ocular globe. Intelligence is normal; life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries and respiratory compromise if kyphoscoliosis is severe.

EDS, kyphoscoliotic form is caused by mutation of PLOD1, resulting in deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1). The diagnosis of EDS, kyphoscoliotic form relies on the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC, a highly sensitive and specific test. Assay of lysyl hydroxylase enzyme activity in skin fibroblasts and molecular genetic testing of PLOD1 are possible. Inheritance isautosomal recessive.

Ehlers-Danlos syndrome, arthrochalasia type (previously called type VIIA & B) is distinguished by congenital bilateral hip dislocation and severe joint hypermobility. Tissue fragility (including atrophic scars) and skin hyperextensibility are usually present; severity ranges from mild to severe. It is caused by mutation of COL1A1 or COL1A2leading to the deletion of exon 6 of the mRNA coding for the α1 chain (EDS VIIA) or the α2 chain (EDS VIIB) of type I collagen, respectively. Inheritance is autosomal dominant.

Ehlers-Danlos syndrome, dermatosparaxis type (previously called EDS type VIIC) is characterized by extreme skin fragility, laxity, and a sagging, redundant appearance. Other distinct features are delayed closure of the fontanels, characteristic facies, edema of the eyelids, blue sclerae, umbilical hernia, short fingers, and short stature. The disorder is caused by deficient activity of procollagen-N-proteinase, the enzyme that excises the N-terminal propeptide in procollagen types I, II, and III [Malfait et al 2005]. Inheritance is autosomal recessive.

Ehlers-Danlos syndrome, cardiac valvular form is characterized by joint hypermobility, skin hyperextensibility, and sometimes atrophic scarring, as well as cardiac valvular defects. Total absence of the proα2(I) chains of type I collagen as a result of homozygous or compound heterozygous pathogenic variants in COL1A2 is causative [Schwarze et al 2004, Malfait et al 2006b]. Inheritance is autosomal recessive.

Classic-like EDS with propensity for arterial rupture. One arginine-to-cysteine (Arg-to-Cys) substitution in proα1(I) chain of type I collagen (p.Arg134Cys) has been identified in a series of individuals with a condition reminiscent of classic EDS that manifests as skin hyperextensibility, easy bruising, atrophic scarring, and joint hypermobility as well as a propensity for arterial rupture in adulthood [Nuytinck et al 2000, Malfait et al 2007]. Two other proα1(I) R-to-C substitutions (p.Arg396Cys and p.Arg915Cys) were also associated with rupture of medium-sized arteries, but affectedindividuals did not have EDS-like skin features [Malfait et al 2007]. Furthermore, a pro1(I)-p.Arg888Cys substitution was reported in a family presenting an EDS/osteogenesis imperfecta overlap phenotype [Cabral et al 2007], and a proα1(I)-p.Arg836Cys substitution was shown to be associated with autosomal dominant Caffey disease[Gensure et al 2005].

Ehlers-Danlos syndrome and periventricular nodular heterotopia. Pathogenic variants in FLNA have been identified in a limited number of individuals with periventricular nodular heterotopia (a neuronal migration disorder characterized by seizures and conglomerates of neural cells around the lateral ventricles of the brain) and features of EDS [Gómez-Garre et al 2006]. See X-Linked Periventricular Heterotopia.

Ehlers-Danlos syndrome spondylocheirodyplastic form is characterized by hyperextensible thin skin, easy bruising, hypermobility of the small joints with a tendency to contractures, protuberant eyes with bluish sclerae, hands with finely wrinkled palms, atrophy of the thenar muscles, and tapering fingers. Skeletal surveys show platyspondyly with moderate short stature, osteopenia, and widened metaphyses. Mutation of SLC39A13, encoding the membrane-bound zinc transporter SLC39A13, is causative [Giunta et al 2008]. Inheritance is autosomal recessive.

The RIN2-syndrome (also known as MACS syndrome) is characterized by severe progressive scoliosis, progressive facial coarsening, gingival hypertrophy, sparse hair, and skin and joint hyperlaxity. It is caused by mutation of RIN2, the gene encoding the Ras and Rab interactor 2 that acts as a guanine nucleotide exchange factor (GEF) for the small GTPase Rab5, which is involved in early endocytosis [Basel-Vanagaite et al 2009,Syx et al 2010]. Inheritance is autosomal recessive.

Ehlers-Danlos syndrome musculocontractural type is characterized by craniofacial dysmorphism, hyperextensible thin skin, atrophic scarring, easy bruising, small joint hypermobility, hands with finely wrinkled palms and tapered fingers, congenitalcontractures of distal joints, scoliosis, progressive muscle hypotonia, and variable gastrointestinal and genitourinary involvement. The condition is caused by mutation ofCHST14, encoding dermatan 4 sulfotransferase-1, which is involved in the biosynthesis of dermatan sulfate. Inheritance is autosomal recessive [Malfait et al 2010, Miyake et al 2010].

Classic EDS shows limited overlap with other connective tissue disorders, including variants of the following; these disorders are differentiated by other distinctive clinical features:
Marfan syndrome, caused by mutation of FBN1, has a broad continuum of clinical manifestations involving the ocular, skeletal, and cardiovascular systems. Lens dislocation, seen in approximately 60%, is a hallmark feature. Myopia, retinal detachment, glaucoma, and early cataract formation are seen. Bone overgrowth leads to long extremities, pectus deformity (excavatum or carinatum), and joint laxity; scoliosis is common. Cardiovascular manifestations include dilatation of the aorta, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Marfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems. Diagnostic criteria have been established. Inheritance is autosomal dominant.
Occipital horn syndrome (OHS) (see ATP7A-Related Copper Transport Disorders) is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. There is no particular ease of bruising or fragility of the skin. Serum copper concentration and serum ceruloplasmin concentration are low. Mutation ofATP7A is causative. Inheritance is X-linked.
Hyperextensible skin should also be distinguished from that observed in the cutis laxa syndromes and in De Barsy syndrome, in which the redundant skin hangs in loose folds and only returns very slowly to its former position. In these syndromes, the skin is not fragile and wound healing is normal. The cutis laxa syndromes result from the loss or fragmentation of the elastic fiber network. They are variably associated with pulmonary, cardiac, arterial, and gastrointestinal abnormalities. Cutis laxa syndromes comprise autosomal dominant, autosomal recessive, and X-linked forms. The autosomal dominant form is caused bymutation of ELN, encoding elastin. Autosomal recessive forms of cutis laxa are associated with mutation of the genes encoding fibulin 4 and fibulin 5 (FBLN4and FBLN5), and more recently also with mutation of ATP6V0A2 and PYCR1.
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Management

For a detailed review of complications and management, see Wenstrup & Hoechstetter [2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Ehlers-Danlos syndrome (EDS), classic type, the following evaluations are recommended:
Clinical examination of the skin with assessment of skin hyperextensibility, atrophic scars and bruises, and other manifestations of classic EDS
Evaluation of joint mobility with use of the Beighton score
Evaluation for hypotonia and motor development in infants and children
A baseline echocardiogram with aortic diameter measurement for individuals under age ten years
Evaluation of clotting factors if severe easy bruising is present

Treatment of Manifestations

In children with hypotonia and delayed motor development, a physiotherapeutic program is important.

Non-weight-bearing muscular exercise, such as swimming, is useful to promote muscular development and coordination.

Individuals with muscle hypotonia and joint instability with chronic pain may have to adjust lifestyle and professional choices accordingly. Emotional support and behavioral and psychological therapy may help in developing acceptance and coping skills.

Dermal wounds should be closed without tension, preferably in two layers. Deep stitches should be applied generously. Cutaneous stitches should be left in place twice as long as usual and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar.

For recommendations on treatment of joint laxity and dislocations, see EDS, Hypermobility Type. (Note: Surgical stabilization of joints may lead to disappointing, or only temporary, improvement.)

Anti-inflammatory drugs may help with joint pain.

Long-term chronic pain may result in the need for mental health services.

Cardiovascular problems should be treated in a standard manner.

Prevention of Primary Manifestations

Very young children with pronounced skin fragility can wear protective pads or bandages over the forehead, knees, and shins in order to avoid skin tears. Older children who are active can wear soccer pads or ski stockings with shin padding during activities.

For recommendations on prevention of primary manifestations of joint laxity and dislocations, see EDS, Hypermobility Type: Management, Prevention of Primary Manifestations.

Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the primary findings of skin hyperextensibility, atrophic scarring, and joint hypermobility. In general, a dose of two grams per day is recommended for adults, with proportionally reduced doses for children; however, there is no limitation.

Prevention of Secondary Complications

For recommendations on prevention of secondary manifestations of joint laxity and dislocations, see EDS, Hypermobility Type: Management, Prevention of Secondary Complications.

Surveillance

If no abnormalities are found on echocardiogram in an adult, a follow-up echocardiogram is not necessary. (Because longitudinal data on progression of aortic dilation are not available, specific recommendations for follow-up in individuals with a normal aortic diameter are not available.)

Yearly echocardiogram is warranted if an abnormality such as aortic dilatation or mitral valve prolapse is present.

Agents/Circumstances to Avoid

The following should be avoided:
Sports with heavy joint strain (contact sports, fighting sports, football, running)
Acetylsalicylate (aspirin)

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes

Pregnancy Management

Because of the increased risk of skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder, monitoring of women throughout pregnancy and in the postpartum period is recommended.

Ascorbic acid (vitamin C) may reduce easy bruising (see Prevention of Primary Manifestations). In general, a dose of two grams per day is recommended for adults; however, no strict guidelines exist regarding recommended dose during the third trimester of pregnancy.

Monitoring of pregnant women for preterm labor is warranted during the third trimester when the risk of premature rupture of the membranes is increased.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
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Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Ehlers-Danlos syndrome (EDS), classic type is inherited in an autosomal dominantmanner.

Risk to Family Members

Parents of a proband
It is estimated that approximately 50% of affected individuals have inherited thedisease-causing mutation from an affected parent and approximately 50% of affected individuals have a de novo disease-causing mutation.
The parents of a proband with apparent de novo mutation should be evaluated by physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain. If a disease-causing mutation has been identified in the proband, molecular genetic testing is performed in the parents.

Note: Although approximately 50% of individuals diagnosed with classic EDS have anaffected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband
The risk to sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a probandappears to be low.
Although no instances of germline mosaicism have been reported, it remains a theoretical possibility in a minority of cases.

Offspring of a proband. Each child of an individual with classic EDS has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his/her family members are at risk.

Related Genetic Counseling Issues

Prediction of phenotype. Because of intrafamilial clinical variability, it is not possible to predict the phenotype in family members who have inherited a disease-causing mutation.

Considerations in families with apparent de novo mutation. When neither parent of aproband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that mutation occurred de novo in the proband; however, the frequency of parental mosaicism is unknown. Additional explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal diagnosis for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for the gene of interest or custom prenatal testing.

Requests for prenatal testing for conditions which (like classic EDS) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.
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Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
Association Francaise des Syndrome d'Ehlers Danlos
34 rue Léon Joulin
Turns 37 000
France
Email: contact@afsed.com
www.afsed.com
Ehlers-Danlos National Foundation
1760 Old Meadow Road
Suite 500
McLean VA 22102
Phone: 703-506-2892
Email: ednfstaff@ednf.org
www.ednf.org
Ehlers-Danlos Support Group
PO Box 337
Aldershot Surrey GU12 6WZ
United Kingdom
Phone: 01252 690940
Email: director@ehlers-danlos.org
www.ehlers-danlos.org
National Library of Medicine Genetics Home Reference
Ehlers-Danlos syndrome
Medline Plus
Ehler-Danlos Syndrome
National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)
Phone: 800-334-8571 ext 24640
Email: gentac-registry@rti.org
GenTAC
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Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.


Ehlers-Danlos Syndrome, Classic Type: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
COL5A1 9q34​.3 Collagen alpha-1(V) chain Ehlers-Danlos Syndrome Variant Database (COL5A1) COL5A1
COL5A2 2q32​.2 Collagen alpha-2(V) chain Ehlers-Danlos Syndrome Variant Database (COL5A2) COL5A2



Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.


OMIM Entries for Ehlers-Danlos Syndrome, Classic Type (View All in OMIM)

120190 COLLAGEN, TYPE V, ALPHA-2; COL5A2
120215 COLLAGEN, TYPE V, ALPHA-1; COL5A1
130000 EHLERS-DANLOS SYNDROME, CLASSIC TYPE
130010 none found


COL5A1

Gene structure. The COL5A1 cDNA comprises 66 exons distributed over more than 150 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Several types of mutations have been identified in bothCOL5A1 and COL5A2:
The most common types of molecular defect lead to haploinsufficiency forCOL5A1 mRNA. In approximately 40% of individuals with classic EDS, nonsense or frameshift mutations are responsible for a non-functional COL5A1allele [Schwarze et al 2000, Wenstrup et al 2000, Schwarze et al 2001, Malfait et al 2005]. Nonsense, frameshift, or splice-site mutations that introduce a premature termination codon are usually responsible for this non-functionalCOL5A1 allele. A variety of mechanisms lead to nonsense-mediated decay of themutation-bearing mRNA or to failure of the chains to associate. The predicted consequence is synthesis of approximately half the amount of normal type V collagen.
Structural mutations in COL5A1, which exert a dominant-negative effect, have been demonstrated in approximately ten to 15 individuals with classic EDS. In a small proportion of individuals, a mutation affects the structural integrity of type V collagen, resulting in the production of a functionally defective type V collagen protein (dominant-negative mutation). These structural mutations are most commonly splice-site mutations that result in exon skipping [Burrows et al 1998,Malfait et al 2005] and a few point mutations that result in the substitution for glycine in the triple-helical region of the collagen molecule [Giunta & Steinmann 2000, Malfait et al 2005]. A unique point mutation in COL5A1 that changes a highly conserved cysteine residue to a serine in the C-terminal propeptide of the α1(V) collagen chain has also been identified (p.Cys1639Ser) (NM_000093.3:c.4916G>C). In contrast to other disorders characterized by mutation of the fibrillar collagen genes, remarkably few pathogenic variants resulting from the substitution of a glycine by a bulkier amino acid have been found.
A p.Gly530Ser (NM_000093.3: c.1588G>A) substitution in the amino-terminal propeptide of the α1(V) chain may be disease-modifying when present in the heterozygous state and disease-causing in the homozygous state [Giunta & Steinmann 2000, Giunta et al 2002].

Normal gene product. Collagen α1 (V) chain (type V collagen chains). Type V collagen is a quantitatively minor fibrillar collagen that is widely distributed in a variety of tissues. It is present mainly as [α1(V)]2 α2(V) heterotrimers in skin, bone, and tendon. It forms heterotypic fibrils with type I collagen and regulates the diameter of those fibrils, presumably through its very large amino-terminal propeptide. Recent data indicate that type V collagen controls collagen fibril assembly in several tissues [Wenstrup et al 2004].

Abnormal gene product. Missense mutations in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity; i.e., the mutant forms can interfere with the utilization of the normal protein derived from the normal allele. Diminished amounts, caused by premature termination of codons in COL5A1 or mRNA product, may alter normal collagen fibrillogenesis.

COL5A2

Gene structure. The COL5A2 cDNA comprises 51 exons distributed over 67 kb. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Structural mutations in COL5A2 have been demonstrated in few individuals with classic EDS. These structural mutations are most commonly splice-site mutations that result in exon skipping [Michalickova et al 1998, Malfait et al 2005] and one point mutation that results in a substitution for glycine in the triple helical region of the collagen molecule [Richards et al 1998].

Normal gene product. Collagen α2(V) chains (type V collagen chains). Type V collagen is a quantitatively minor fibrillar collagen that is widely distributed in a variety of tissues. It is present mainly as [α1(V)]2, α2(V) heterotrimers in skin, bone, and tendon. It forms heterotypic fibrils with type I collagen and regulates the diameter of those fibrils, presumably through its very large amino-terminal propeptide.

Abnormal gene product. Missense mutations in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity; that is, the mutant forms can interfere with the utilization of the normal protein derived from the normal allele.
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References

Published Guidelines/Consensus Statements
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Available online. 1998. Accessed 4-3-15. [PubMed]

Literature Cited
Atzinger CL, Meyer RA, Khoury PR, Gao Z, Tinkle BT. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome. J Pediatr. 2011 May;158(5):826–830.e1. [PubMed]
Basel-Vanagaite L, Sarig O, Hershkovitz D, Fuchs-Telem D, Rapaport D, Gat A, Isman G, Shirazi I, Shohat M, Enk CD, Birk E, Kohlhase J, Matysiak-Scholze U, Maya I, Knopf C, Peffekoven A, Hennies HC, Bergman R, Horowitz M, Ishida-Yamamoto A, Sprecher E. RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome. Am J Hum Genet. 2009;85:254–63.[PMC free article] [PubMed]
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet.1998;77:31–7. [PubMed]
Burrows NP, Nicholls AC, Richards AJ, Luccarini C, Harrison JB, Yates JR, Pope FM. A point mutation in an intronic branch site results in aberrant splicing of COL5A1 and in Ehlers-Danlos syndrome type II in two British families. Am J Hum Genet. 1998;63:390–8. [PMC free article] [PubMed]
Byers PH. Disorders of collagen biosynthesis and structure. In: Scriver, Beaudet, Sly, Valle, eds. The Metabolic and Molecular Bases of Inherited Disease. 2 ed. Edinburgh, UK: Churchill Livingstone; 2001:1065-81.
Cabral WA, Makareeva E, Letocha AD, Scribanu N, Fertala A, Steplewski A, Keene DR, Persikov AV, Leikin S, Marini JC. Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. Hum Mutat. 2007;28:396–405.[PubMed]
De Coster PJ, Martens LC, De Paepe A. Oral health in prevalent types of Ehlers-Danlos syndromes. J Oral Pathol Med. 2005a;34:298–307. [PubMed]
De Coster PJ, Van den Berghe LI, Martens LC. Generalized joint hypermobility and temporomandibular disorders: inherited connective tissue disease as a model with maximum expression. J Orofac Pain. 2005b;19:47–57. [PubMed]
Gensure RC, Mäkitie O, Barclay C, Chan C, Depalma SR, Bastepe M, Abuzahra H, Couper R, Mundlos S, Sillence D, Ala Kokko L, Seidman JG, Cole WG, Jüppner H. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest.2005;115:1250–7. [PMC free article] [PubMed]
Giunta C, Elçioglu NH, Albrecht B, Eich G, Chambaz C, Janecke AR, Yeowell H, Weis M, Eyre DR, Kraenzlin M, Steinmann B. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet.2008;82:1290–305. [PMC free article] [PubMed]
Giunta C, Nuytinck L, Raghunath M, Hausser I, De Paepe A, Steinmann B. Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome. Am J Med Genet. 2002;109:284–90. [PubMed]
Giunta C, Steinmann B. Compound heterozygosity for a disease-causing G1489E [correction of G1489D] and disease-modifying G530S substitution in COL5A1 of a patient with the classical type of Ehlers-Danlos syndrome: an explanation of intrafamilial variability? Am J Med Genet. 2000;90:72–9. [PubMed]
Gómez-Garre P, Seijo M, Gutiérrez-Delicado E, Castro del Río M, de la Torre C, Gómez-Abad C, Morales-Corraliza J, Puig M, Serratosa JM. Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. J Med Genet. 2006;43:232–7. [PMC free article] [PubMed]
Hagberg C, Berglund B, Korpe L, Andersson-Norinder J. Ehlers-Danlos Syndrome (EDS) focusing on oral symptoms: a questionnaire study. Orthod Craniofac Res. 2004;7:178–85. [PubMed]
Hausser I, Anton-Lamprecht I. Differential ultrastructural aberrations of collagen fibrils in Ehlers-Danlos syndrome types I-IV as a means of diagnostics and classification. Hum Genet. 1994;93:394–407. [PubMed]
Lindor NM, Bristow J. Tenascin-X deficiency in autosomal recessive Ehlers-Danlos syndrome. Am J Med Genet A. 2005;135:75–80. [PubMed]
Malfait F, Coucke P, Symoens S, Loeys B, Nuytinck L, De Paepe A. The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients. Hum Mutat.2005;25:28–37. [PubMed]
Malfait F, De Paepe A. Molecular genetics in classic Ehlers-Danlos syndrome.Am J Med Genet C Semin Med Genet. 2005;139C:17–23. [PubMed]
Malfait F, Hakim AJ, De Paepe A, Grahame R. The genetic basis of joint hypermobility syndromes. Rheumatology. 2006a;45:502–7. [PubMed]
Malfait F, Symoens S, Coucke P, Nunes L, De Almeida S, De Paepe A. Total absence of the alpha2(I) chain of collagen type I is a rare cause of Ehlers-Danlos Syndrome hyermobility type. J Med Genet. 2006b;43:e36. [PMC free article] [PubMed]
Malfait F, Symoens S, De Backer J, Hermanns-Lê T, Sakalihasan N, Lapière CM, Coucke P, De Paepe A. Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat. 2007;28:387–95. [PubMed]
Malfait F, Syx D, Vlummens P, Symoens S, Nampoothiri S, Hermanns-Lê T, Van Laer L, De Paepe A. Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum Mutat. 2010;31:1233–9. [PubMed]
Mayer K, Kennerknecht I, Steinmann B. Clinical utility gene card for: Ehlers-Danlos syndrome types I-VII and variants - update 2012. Eur J Hum Genet.2013;21 [PMC free article] [PubMed] [Cross Ref]
Michalickova K, Susic M, Willing MC, Wenstrup RJ, Cole WG. Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce Ehlers-Danlos syndrome type I. Hum Mol Genet. 1998;7:249–55. [PubMed]
Miyake N, Kosho T, Mizumoto S, Furuichi T, Hatamochi A, Nagashima Y, Arai E, Takahashi K, Kawamura R, Wakui K, Takahashi J, Kato H, Yasui H, Ishida T, Ohashi H, Nishimura G, Shiina M, Saitsu H, Tsurusaki Y, Doi H, Fukushima Y, Ikegawa S, Yamada S, Sugahara K, Matsumoto N. Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum Mutat. 2010;31:966–74.[PubMed]
Nuytinck L, Freund M, Lagae L, Pierard GE, Hermanns-Le T, De Paepe A. Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. Am J Hum Genet. 2000;66:1398–402. [PMC free article] [PubMed]
Richards AJ, Martin S, Nicholls AC, Harrison JB, Pope FM, Burrows NP. A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II. J Med Genet. 1998;35:846–8. [PMC free article] [PubMed]
Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, van Haren B, Miller WL, Bristow J. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001;345:1167–75.[PubMed]
Schievink WI, Gordon OK, Tourje J. Connective tissue disorders with spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery. 2004;54:65–70. [PubMed]
Schwarze U, Atkinson M, Hoffman GG, Greenspan DS, Byers PH. Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II). Am J Hum Genet. 2000;66:1757–65. [PMC free article] [PubMed]
Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, Byers PH. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet. 2004;74:917–30. [PMC free article] [PubMed]
Schwarze U, Schievink WI, Petty E, Jaff MR, Babovic-Vuksanovic D, Cherry KJ, Pepin M, Byers PH. Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV. Am J Hum Genet. 2001;69:989–1001. [PMC free article] [PubMed]
Symoens S, Malfait F, Vlummens P, Hermanns-Lê T, Syx D, De Paepe A. A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement. PLoS One. 2011;6:e20121.[PMC free article] [PubMed]
Syx D, Malfait F, Van Laer L, Hellemans J, Hermanns-Lê T, Willaert A, Benmansour A, De Paepe A, Verloes A. The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2). Hum Genet. 2010;128:79–88. [PubMed]
Wenstrup RJ, Hoechstetter LB. Ehlers-Danlos syndromes. In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 2 ed. New York, NY: John Wiley & Sons; 2004:211-24.
Wenstrup RJ, Florer JB, Brunskill EW, Bell SM, Chervoneva I, Birk DE. Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem.2004;279:53331–7. [PubMed]
Wenstrup RJ, Florer JB, Willing MC, Giunta C, Steinmann B, Young F, Susic M, Cole WG. COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet. 2000;66:1766–76. [PMC free article] [PubMed]
Wenstrup RJ, Meyer RA, Lyle JS, Hoechstetter L, Rose PS, Levy HP, Francomano CA. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med. 2002;4:112–7. [PubMed]
Zweers MC, Bristow J, Steijlen PM, Dean WB, Hamel BC, Otero M, Kucharekova M, Boezeman JB, Schalkwijk J. Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet. 2003;73:214–7. [PMC free article] [PubMed]
Zweers MC, Dean WB, van Kuppevelt TH, Bristow J, Schalkwijk J. Elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome patients with tenascin-X mutations. Clin Genet. 2005;67:330–4. [PubMed]
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Chapter Notes

Sunday, March 29, 2015

Low Blood Volume In Postural Orthostatic Tachycardia Syndrome (POTS)

It has been theorized that patients with Postural Orthostatic Tachycardia Syndrome (POTS) have a lower blood volume than people without POTS. First of all what is POTS?

Well, basically POTS is like this. When a person stands up their blood flows to their heart and brain and then down to their waist and feet. In someone with POTS when the person stands the blood flows to the feet first and then by the time the body knows this the heart has stared working really hard to get the blood to flow up to the heart and bairn. By that time the POTS patient is dizzy and out of breath and sweating. This is the one disorder that makes my life so very very hard. I can deal with the pain of Ehlers Danlos Syndrome and R.A. and Lupus and the many other disorders that cause pain but the POTS is so life altering for me that it has not only destroyed my dreams but it has stolen my dignity from me as I am just unable to take care of myself.

 

I would like to add to this extreme sweating, being out of breath, cooling down to the point of my skin becoming white and clammy and then freezing which no amount of blankets or heat will warm you up, and extreme fatigue. I'm sure there are other symptoms that happen but these mentioned in the picture and what I added happen every single time I take a shower!!! It is just awful! 


























I am going to provide the links of different blogs that will explain POTS and the way it can control the body and an article about a study of patients with POTS and how it is proven that there is a lower blood volume in these people. It is important to know this because the outcome of blood test never show what is wrong with the POTS patient because the wrong values are been used since most POTS patients don't have the same amount of blood as non POTS people. For instance, (This is not an exact way to do this, plus it involves math and math and I are by no means friends so please take this as only a what if.) if you have two bottles of water, one being 100% full and one being 80% full to get the same outcome of a test of the two from the 100% full bottle say 4 TBSP would need to be drawn and from the 80% full bottle say 5 TBSP would need to be drawn to get the same results of the outcome. If this is not done then the results of the test for the 80% full bottle would be about 20% higher than the actual result causing the POTS patients needs to be overlooked causing the patient to remain weak, tired and sick not being allowed to get the necessary medication, saline IV, vitamins and any other products that would help the POTS patient have a more productive life. Another way this could be done is to take the outcome of the POTS patients blood test and multiply it by .8 or to adjust the scale or range of normal blood levels for a test you would take both side of the scale and multiply by 1.25. to give you a better idea of where the POTS patient falls in the blood test ranges. Again, this is not an exact way to do this because the POTS patient, unless they are tested to see how much blood volume they have, will not have the correct numbers to multiply with. It cannot be assumed that all POTS patient have the same lower level of blood volume, nor does every POTS patient have a lower level of blood volume than non POTS people.  

So how much blood is in the human body? http://wonderopolis.org/wonder/how-much-blood-is-in-your-body/
Blood is composed of cells and plasma. The cells include red blood cells, white blood cells and platelets.
The red blood cells carry oxygen from the lungs and give blood its red color. The white blood cells fight infections. The platelets help form clots to stop bleeding in case of a cut.
All these cells float in the liquid plasma, which is mostly water. Plasma also contains nutrients, electrolytes, hormones and protein antibodies to fight infection.
The amount of blood in a human body varies, depending on factors such as age, sex, overall health and even where a person lives. For example, men tend to have more blood than women of comparable size and weight.
Interestingly, people who live at high altitudes may have up to two liters of extra blood compared to those who live at lower altitudes. Because the air at higher altitudes has less oxygen, people who live at high altitudes need extra blood to deliver the right amount of oxygen to their lungs.
Scientists estimate the volume of blood in a human body to be approximately 7 percent of body weight. An average adult body with a weight of 150 to 180 pounds will contain approximately 4.7 to 5.5 liters (1.2 to 1.5 gallons) of blood. An average child with a body weight of 80 pounds will have approximately half the amount of blood as an adult.
Blood carries out many critical functions in the body. It transports nutrients and oxygen to the body’s cells. It also takes away waste from those cells. Blood also moves hormones and chemicals around the body.
You might be surprised to learn that blood also plays a special role in regulating body temperature. When your body heats up, blood helps keep the temperature steady by transferring extra heat to the skin, where it can be released from the body.
As part of the immune system, blood also helps fight disease. If you scrape your knee at the park, the platelets in blood begin to clot to help stop the bleeding. This self-repair function prevents further blood loss, which could be fatal in cases of massive bleeding.


This link I am providing is a link to explain what POTS is.

http://edstoday.org/eds-awareness/associated-disorders
Postural Orthostatic Tachycardia Syndrome (POTS)

“One of the most debilitating complications of Ehler-Danlos Syndrome EDS is a type of dysautonomia called Postural Orthostatic Tachycardia Syndrome or POTS. Dysautonomia is the result of our autonomic nervous system ceasing to function properly. Our autonomic nervous system regulates functions that our body does automatically such as digestion, breathing, heart rate, blood pressure, body temperature, blood sugar regulation, hormonal/endocrine imbalances and our sleep cycle.” 
~Dr. Diana Driscoll~

This link is to a blog that explains a little about low blood volumes in POTS patients and what life is like with this condition. http://potsgrrl.blogspot.com/p/in-support-of-iv-saline-therapy-for.html

Lastly I am adding an article about the testing of POTS patients that explain the testing done to determine that POTS patients have a lower blood volume than people without POTS. I hope that you are able to understand more about this condition and to learn enough about it to know that it doesn't strike only patients with Ehlers Danlos Syndrome and although many people that get POTS can be cured from it, in Ehlers Danlos Syndrome there is no cure or fix for it. It remains a very disabling disorder that is hard to explain to friends and family or to get them to believe that the POTS patients can be extremely ill as a result of it. 

Too see the References please visit the article at 
http://circ.ahajournals.org/content/111/13/1574.full

Arrhythmia/Electrophysiology

Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome

Satish R. Raj, MD;
Italo Biaggioni, MD;
Paula C. Yamhure, RN;
Bonnie K. Black, RN, NP;
Sachin Y. Paranjape, BS;
Daniel W. Byrne, MS;
David Robertson, MD

+Author Affiliations
From the Divisions of Clinical Pharmacology (S.R.R., I.B., D.R.) and Cardiovascular Medicine (P.C.Y., B.K.B., S.Y.P.), Departments of Medicine, Pharmacology (S.R.R., I.B., D.R.), Biostatistics (D.W.B.), and Neurology (D.R.), Vanderbilt University, Nashville, Tenn.
Reprint requests to Satish R. Raj, MD, AA3228 Medical Center North, Vanderbilt University, 1161 21st Ave S, Nashville, TN 37232-2195. E-mail satish.raj@vanderbilt.edu
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Abstract

Background— Patients with postural tachycardia syndrome (POTS) experience considerable disability, but in most, the pathophysiology remains obscure. Plasma volume disturbances have been implicated in some patients. We prospectively tested the hypothesis that patients with POTS are hypovolemic compared with healthy controls and explored the role of plasma renin activity and aldosterone in the regulation of plasma volume.

Methods and Results— Patients with POTS (n=15) and healthy controls (n=14) underwent investigation. Heart rate (HR), blood pressure (BP), plasma renin activity, and aldosterone were measured with patients both supine and upright. Blood volumes were measured with 131I-labeled albumin and hematocrit. Patients with POTS had a higher orthostatic increase in HR than controls (51±18 versus 16±10 bpm, P<0.001). Patients with POTS had a greater deficit in plasma volume (334±187 versus 10±250 mL,P<0.001), red blood cell volume (356±128 versus 218±140 mL,P=0.010), and total blood volume (689±270 versus 228±353 mL,P<0.001) than controls. Despite the lower plasma volume in patients with POTS, there was not a compensatory increase in plasma renin activity (0.79±0.58 versus 0.79±0.74 ng · mL−1 · h−1, P=0.996). There was a paradoxically low level of aldosterone in the patients with POTS (190±140 pmol/L versus 380±230 pmol/L;P=0.017).

Conclusions— Patients with POTS have paradoxically unchanged plasma renin activity and low aldosterone given their marked reduction in plasma volume. These patients also have a significant red blood cell volume deficit, which is regulated by the renal hormone erythropoietin. These abnormalities suggest that the kidney may play a key role in the pathophysiology of POTS.Key Words:
tachycardia
renin
nervous system, autonomic
blood volumealdosterone

Received September 26, 2004; revision received December 14, 2004; accepted December 21, 2004.

Postural tachycardia syndrome (POTS) is the most common disorder among patients seen at several centers specializing in diseases of the autonomic nervous system. It affects an estimated 500 000 people in the United States alone.1 POTS (excessive increase in heart rate [>30 bpm] on standing, associated with orthostatic symptoms in the absence of orthostatic hypotension) can produce substantial disability among otherwise healthy people.

The pathophysiology of POTS is poorly understood. Many of these patients have elevated levels of plasma norepinephrine, particularly when upright.2 Subgroups of patients have a primary hyperadrenergic state,3 whereas others have partial dysautonomia that affects the lower limbs.4–7 The role of blood volume in the pathogenesis of POTS is unclear. Some investigators have found that patients with POTS have deficits in their plasma volumes8,9and that some patients improve after acute10 or chronic9 plasma volume expansion. Conversely, other investigative groups have reported normal plasma volumes in patients with POTS.11,12

The renin-angiotensin-aldosterone system plays a key role in the neurohormonal regulation of plasma volume in humans.13 In response to hypovolemia, plasma renin activity and angiotensin II would be expected to increase to promote blood volume expansion. Angiotensin II promotes sodium and water retention, both directly by stimulating sodium reabsorption in the proximal tubules14 and indirectly by stimulating aldosterone secretion.15The mineralocorticoid aldosterone governs sodium transport at several sites in the kidney. Jacob et al8 have reported that some patients with POTS have low plasma renin activity despite a low plasma volume, which suggests that a perturbation in the renin-angiotensin-aldosterone axis might have a role in the pathophysiology of POTS.

In this prospective, controlled study, we tested the hypothesis that patients with POTS have a deficit in plasma volume. We also explored the regulation of plasma volume by renin and aldosterone.
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Methods
Subjects
Patients referred to the Vanderbilt University Autonomic Dysfunction Center with POTS between October 2002 and November 2003 were candidates for inclusion in this study. Patients met the current criteria for POTS.16 Briefly, patients developed symptoms of orthostatic intolerance accompanied by a heart rate rise ≥30 bpm (or a rate that exceeds 120 bpm) that occurred within the first 10 minutes of standing or head-up tilt, without any evidence of orthostatic hypotension (a fall in blood pressure of >20/10 mm Hg). Patients had at least a 6-month history of symptoms, in the absence of another chronic debilitating disorder or prolonged bed rest, and were at least 18 years of age. Healthy control subjects (who did not meet criteria for POTS, and were at least 18 years of age) underwent all of the same protocol elements. Patients and controls were free of medications that could impair autonomic tone17 and were not taking fludrocortisone for at least 5 days before testing. The Vanderbilt University Investigational Review Board approved this study, and written informed consent was obtained from each subject before the study began.

Protocol
Study investigations were performed at the Elliot V. Newman Clinical Research Center at Vanderbilt University. For 3 days before testing, subjects consumed a diet that contained 150 mEq of sodium per day and 70 mEq of potassium per day. The diet was free of caffeine-containing beverages.

Supine and Upright Posture Study
Heart rate, blood pressure, aldosterone, plasma renin activity, and plasma norepinephrine and epinephrine were assessed after overnight rest with subjects in the supine position and again after subjects had been standing for up to 30 minutes (as tolerated). The standing test was performed to assess the hemodynamic and biochemical responses to increased central hypovolemia (accentuated by the gravitational stress). For catecholamine measurements, blood was collected in plastic syringes and immediately transferred to chilled vacuum tubes with EGTA and reduced glutathione (Amersham International PLC) and immediately put on ice. The plasma was separated by refrigerated centrifugation at −4°C and stored at −70°C until the assay. Concentrations of norepinephrine and epinephrine were measured by batch alumina extraction, followed by high-performance liquid chromatography for separation with electrochemical detection and quantification.8 Plasma renin enzymatic activity was assayed by conversion of angiotensinogen to angiotensin I by a radioimmunoassay technique (antibodies from IgG Corporation)18and reported in nanograms of angiotensin I per milliliter per hour. Blood for aldosterone was collected in chilled vacuum tubes without preservative, and the serum was extracted and sent to the laboratory on ice. Serum aldosterone was measured by radioimmunoassay (DPC Coat-a-Count, Diagnostic Products Corp). The aldosterone-to-plasma renin activity ratio was calculated with the conventional units for aldosterone (ng/dL; 1 ng/dL=27.7 pmol/L) and plasma renin activity (ng · mL−1 · h−1) and reported without units.

Blood Volume Assessment
Plasma volume was determined by the indicator dye-dilution technique. In the morning after an overnight fast, patients were placed in a supine position for a minimum of 60 minutes before collection of the baseline sample. A 20-gauge intravenous catheter was placed in an antecubital vein, and blood samples could be obtained without stasis. A baseline venous sample of 5 mL was collected before injection of the tracer. With a prefilled 1-mL syringe, up to 25 μCi of 131I-labeled human serum albumin (Volumex, Iso-Tex Diagnostics Inc) was injected into the antecubital vein and flushed with 30 mL of normal saline. Starting at 12 minutes after injection, 5 mL of venous blood was collected at 6-minute intervals until 30 minutes after injection (5 samples, including baseline sample). Hematocrit was measured in duplicate from each sample after 10-minute centrifugation at 11 500 rpm on an International Equipment Co microcapillary centrifuge and read on an International Equipment Co microcapillary tube reader. Plasma radioactivity was measured in duplicate and averaged (for each sample and a reference standard) with an automated counter (BVA-100 Blood Volume Analyzer, DAXOR Corporation). A least-squares regression of the volume of distribution at each time point was automatically performed to determine the volume of distribution at the time of injection. Plasma volume was determined as the volume of distribution of albumin.

Total blood volume was calculated from measured plasma volume and microcapillary venous antecubital hematocrit corrected for the plasma-packing ratio (0.99),19 the ratio of mean body hematocrit to peripheral (measured) hematocrit (0.91),20 and the effects of heparin within the sampling syringe (0.97).21

Red blood cell volume was calculated as the difference between total blood volume and plasma volume. This DAXOR method of red blood cell volume assessment was recently found to correlate well with the traditional 51Cr red blood cell-labeling method (Pearson correlation R=0.96), with a mean difference between the techniques of 0.9% (personal communication with Dr Howard Dworkin, William Beaumont Hospital, Royal Oak, Mich).

Ideal plasma and total blood volume was determined on the basis of the height, weight, and gender of the individual subject.22Individual “deficits” in plasma volume, red blood cell volume, and total blood volume were calculated as the ideal minus measured volume (in milliliters), or this difference divided by the ideal volume (percentage).

Plasma Volume Shift With Upright Tilt
All studies occurred between 10 AM and noon in a quiet, dimly lit room at a comfortable ambient temperature (21°C to 24°C). An antecubital venous catheter was inserted (if not already in situ and functioning) for blood sampling at least 15 minutes before the beginning of the test, with the patient supine. Subjects were tilted head-up to 60° for 30 minutes or until the subject experienced presyncope that required test termination.

Blood was drawn at baseline and then at 5, 10, 15, 20, and 30 minutes of tilt for measurement of hematocrit in quadruplicate (see Blood Volume Assessment section for details of hematocrit assessment). Relative changes in hematocrit from baseline were used to calculate the change in plasma volume with upright tilt. The percentage change in plasma volume (ΔPV%)=100×[(HctBaseline−HctTime)/HctTime]× [1/(1−HctBaseline)], with the absolute change in plasma volume (ΔPV)=ΔPV%×measured plasma volume (where HctBaseline is hematocrit before tilt, and HctTime is hematocrit at a given time after tilt).23 ΔPVEnd and ΔPV%End were defined as the ΔPV at the time of the last measured hematocrit before tilt termination. ΔPVEnd was used in place of the individual late time points to minimize the confounding effect of late data dropout due to premature tilt termination. A negative value reflects a shift in plasma volume out of the vascular space.

Gender Analysis
POTS is a disorder that affects women more often than men. In addition to an overall analysis that included all subjects, a separate analysis was performed that included only female subjects. This was to ensure that the results were not skewed by the small number of men.

Statistical Analysis and Sample Size Calculations
Our primary end point was the plasma volume deficit (measured plasma volume minus ideal plasma volume). The null hypothesis was that the plasma volume deficit would not be statistically different between patients with POTS and control subjects. We calculated the size of our required sample after determining that a 7.5% deficit in plasma volume in patients with POTS would be clinically significant. We did not expect the control subjects to have a plasma volume deficit. Assuming a pooled SD of 5% (giving an effect size of 1.5), a sample size of 13 subjects in each group would give 95% power to detect a statistically significant difference with a Student t test with a 2-sided significance level of 0.05.24Differences between groups were analyzed with the Student t test. The Mann-Whitney U test was also used to confirm the results obtained from the Student t test, and the significance of the reported parameters was not different between the 2 tests. Categorical variables were analyzed with the Fisher exact test. Values are reported as means and SDs unless otherwise noted. Probability values of <0.05 were considered statistically significant, and all tests were 2 sided. Statistical analyses were performed with SPSS for Windows (version 12.0, SPSS). Sample size calculations were performed with nQuery Advisor (version 5.0). Prism for Windows 4 (version 4.02, GraphPad Software Inc.) was used for graphical presentation.
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Results

Baseline Information
We enrolled 15 patients with POTS and 14 controls. The baseline characteristics are enumerated in Table 1. There was no significant difference in baseline characteristics between patients with POTS and control subjects for the overall group or when just the female subjects were considered.
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TABLE 1. Baseline Information

Supine and Upright Posture Study

As seen in Figure 1A, patients with POTS had a higher heart rate than control subjects both when supine (77±12 versus 64±12 bpm, P=0.008) and when standing upright for up to 30 minutes (128±18 versus 80±11 bpm, P<0.001). As would be expected on the basis of the diagnostic criteria for POTS, patients with POTS had a significantly greater increase in heart rate (51±18 bpm) on assuming the upright position than did the control subjects (16±10 bpm, P<0.001). The supine systolic blood pressure was similar between the 2 groups (POTS versus control, 111±14 versus 114±13 mm Hg; P=0.525; Figure 1B). Both groups experienced a small increase in systolic blood pressure that was not statistically significant on standing, with no difference between groups (POTS versus control, 123±20 versus 115±14 mm Hg; P=0.244). Neither the diastolic blood pressures while supine (POTS 67±8 mm Hg; control 70±9 mm Hg; P=0.321) or standing (POTS 79±14 mm Hg; control 77±10 mm Hg; P=0.636) nor the mean blood pressures while supine (POTS 81±9 mm Hg; control 85±10 mm Hg;P=0.367) or standing (POTS 94±15 mm Hg; control 90±10 mm Hg; P=0.417) were different between the 2 groups.

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Figure 1. Hemodynamic parameters and catecholamines: supine and upright. Supine and upright values for heart rate (A), systolic blood pressure (BP; B), venous plasma norepinephrine (C), and venous plasma epinephrine (D) for patients with POTS and control subjects. Error bars represent SE. Probability values are from between-group comparison with Studentt test.

Plasma catecholamines were drawn with subjects in both the supine and upright positions. The supine plasma norepinephrine (Figure 1C) values appeared to be slightly higher in patients with POTS (1.37±0.62 nmol/L) than in the control subjects (0.98±0.45 nmol/L), but this difference was not statistically significant (P=0.073). In response to standing, plasma norepinephrine increased significantly more in patients with POTS (>3-fold increase in norepinephrine) than in the control subjects (>2-fold increase in norepinephrine; P=0.002). Patients with POTS had a significantly higher upright plasma norepinephrine than did the control subjects (4.76±2.37 versus 2.44±0.89 nmol/L, P=0.002). In contrast to norepinephrine values, plasma epinephrine values were not different between the 2 groups in either the supine or the upright positions (Figure 1D), nor was the increase in epinephrine from supine to upright position significantly different between the groups (P=0.350).

Renin and Aldosterone
After 3 days of the study’s fixed dietary salt intake, there was no difference in plasma renin activity (Figure 2A) between the patients with POTS and the control groups in the supine position (0.79±0.58 versus 0.79±0.74 ng · mL−1 · h−1, P=0.996). In contrast to the standing plasma norepinephrine values, there was no difference in standing plasma renin activity between patients with POTS and control subjects (2.03±1.26 versus 2.08±2.05 ng · mL−1 · h−1; P=0.944). The supine serum aldosterone (Figure 2B) was significantly lower in patients with POTS (190±140 pmol/L) than in control subjects (380±230 pmol/L; P=0.017). Serum aldosterone increased in both groups on standing. The upright serum aldosterone was significantly lower in patients with POTS (480±290 pmol/L) than in control subjects (810±370 pmol/L;P=0.019). The supine aldosterone-plasma renin activity ratio, a measure of the relationship between these 2 parameters, was significantly lower in patients with POTS (0.93±0.65) than in control subjects (3.19±3.29; P=0.047; Figure 2C).

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Figure 2. Renin and aldosterone. Supine and upright values for plasma renin activity (A) and serum aldosterone (B) for patients with POTS and control subjects. C, Aldosterone to renin ratio (in conventional units) in supine position, as measure of mismatch between renin activity and aldosterone response, for patients with POTS and control subjects. Ratio of aldosterone to plasma renin activity was calculated with conventional units for aldosterone (ng/dL; 1 ng/dL=27.7 pmol/L) and plasma renin activity (ng · mL−1 · h−1) and reported without units. Error bars represent SE. Probability values are from between-group comparison with Student t test.

Supine and Upright Posture Study in Females
The hemodynamic and biochemical responses of the female subjects to supine and standing posture are shown in the figure in the online-only Data Supplement. The results were qualitatively similar to those seen in the overall group analysis. In the standing position, female patients with POTS had a significantly higher heart rate (P<0.001), a significantly higher plasma norepinephrine level (P=0.025), and a significantly lower aldosterone level (P=0.038) than control subjects. There were no differences between the groups while standing for blood pressure, plasma epinephrine, or plasma renin activity. In the setting of the smaller sample size in this subgroup analysis, none of the supine hemodynamic and biochemical parameters were significantly different between groups.

Blood Volumes
As shown in Table 2, plasma volume was significantly lower in patients with POTS (2348±438 mL) than in control subjects (2823±480 mL, P=0.010), whereas ideal plasma volumes were not significantly different. Calculating the plasma volume deficit controls for individual variations in ideal plasma volumes based on size and gender. Patients with POTS had a plasma volume deficit of 334±187 mL, which represented 12.8±7.6% of their ideal plasma volume, whereas control subjects had no deficit (10±250 mL [0.8±8.8%]). Figure 3A illustrates both this highly significant difference and the variability in plasma volume deficits within the 2 groups. The plasma volume of 1 patient with POTS actually exceeded expectations. Conversely, 3 patients with POTS had a plasma volume deficit of >20%, with a plasma volume deficit as high as 27% in 1 patient with POTS.
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TABLE 2. Blood Volumes


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Figure 3. Blood volumes. Individual and mean values are presented for plasma volume (PV) deficit (A) as percentage (individual deficit=[ideal plasma volume−measured plasma volume]/ideal plasma volume) for control subjects and patients with POTS. Negative value for deficit implies excess in plasma volume. Probability values are from between-group comparison with Student t test. Similar figures are presented for red blood cell volume deficit (B) and total blood volume (TBV) deficit (C). D through F, Data when only female subjects were included.

The measured red blood cell volume was also lower by a mean of >300 mL in patients with POTS than in control subjects (Table 2). Control subjects experienced a modest deficit in red blood cell volume. In contrast, patients with POTS had a mean deficit in red blood cell volume of >350 mL, which represented a 22.7% deficit from the expected red blood cell volume (Figure 3B). The difference between the 2 groups was highly significant (P=0.003). Supine hematocrit values were not different between patients with POTS and control subjects (37.8±2.4% versus 38.0±3.0%,P=0.812), which reflects the parallel decrease in both plasma volume and red blood cell volume in patients with POTS.

The total blood volume followed the same pattern as the plasma volume and red blood cell volume components. The measured total blood volume was significantly lower in patients with POTS than in control subjects (P=0.010; Table 2). Even after we corrected for individual differences in ideal total blood volume, patients with POTS still had a significantly larger relative deficit in total blood volume (16.5±6.8% versus 5.6±7.8%, P<0.001; Figure 3C). This works out to a mean absolute total blood volume deficit of 460 mL compared with the control subjects.

Blood volumes for the female subjects are shown in Figures 3D through 3F and in Table 2. Concordant with the overall group, each of the 3 measured blood volume deficits was greater for patients with POTS than for control groups.

Plasma Volume Shifts With Upright Tilt
Plasma volume shifts with upright tilt were calculated both early during the tilt (5 minutes [ΔPV%5 minutes]) and near the end of tilt (ΔPV%End) as a percentage of the baseline plasma volume. Neither the mean ΔPV%5 minutes (−11.7±3.2% versus −10.4±3.5%,P=0.298) nor the mean ΔPV%End (−16.6±4.7% versus −15.3±4.6%,P=0.463) was different in patients with POTS compared with control subjects. As can be seen in Figure 4, there was significant heterogeneity in the maximal plasma volume shift with upright tilt in both groups.

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Figure 4. Plasma volume shift with upright tilt. Individual and mean shifts in plasma volume (PV Shift), as percentage of baseline plasma volume, in response to upright tilt are presented for control subjects and patients with POTS. Negative value represents shift of plasma volume from intravascular to extravascular space. Mean differences were not statistically significant between groups. Max indicates maximum.

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Discussion

This study sought to assess both blood volume and the role of the renin-angiotensin-aldosterone system in the regulation of blood volume in POTS. The main findings from this prospective study were that compared with control subjects, patients with POTS (1) have a significant deficit of plasma volume, (2) have a significantly lower level of serum aldosterone, (3) have an inappropriately low level of plasma renin activity given the degree of hypovolemia that they exhibit, and (4) have a significant deficit of red blood cell volume in the setting of an elevated standing heart rate and plasma norepinephrine.

Plasma Volume
Patients with POTS had a lower basal plasma volume (Table 2) than the control subjects. Accurate plasma volume assessments can be affected by several environmental, dietary, and patient-related factors.25 These variables may in part explain the mixed results obtained by other investigators who have tried to assess plasma volume in patients with POTS.8,9,11,12 Several measures were undertaken in the present study to ensure that the plasma volume was measured accurately. Study subjects were withdrawn from all medications that might alter the plasma volume (such as fludrocortisone) for at least 5 days before the study. They consumed a controlled sodium diet for at least 3 days before assessment, because sodium intake can alter activation of the renin-angiotensin-aldosterone axis and subsequently alter plasma volume. Finally, all plasma volume assessments were performed in the same temperature-controlled room on the research unit after the subjects had been supine for at least 1 hour. Other factors that can physiologically alter plasma volume include the subject’s size and gender.21,22 To correct for individual variations in subject size, we calculated the expected plasma volume for each subject based on his or her size and gender and subtracted the measured plasma volume to arrive at the individual’s actual plasma volume deficit, as shown in Figure 3A. Patients with POTS had a mean plasma volume deficit of almost 350 mL, whereas control subjects had no such deficit. The deficit of 13% in patients with POTS constitutes a moderate to severe hypovolemia. This reduction in effective circulating volume could trigger a cascade of perturbations associated with POTS. In the supine position, this hypovolemia may cause only modest or nonsignificant changes in heart rate and plasma norepinephrine. In the upright position, in the setting of gravitational blood pooling, the additional reduced volume could decrease the cardiac output and cause a reflex increase in sympathetic nerve activity. The result would be an increase in the upright plasma norepinephrine levels and an increase in standing heart rate, as seen in patients with POTS (Table 1).

Renin-Aldosterone Paradox
The renin-angiotensin-aldosterone system plays an important role in the regulation of plasma volume.13 Hypovolemia, acting via reduced renal blood flow and possible cardiorenal mechanisms,26,27 would be expected to increase plasma renin activity, which should augment levels of angiotensin II and subsequently lead to increased levels of aldosterone. Angiotensin II promotes renal sodium retention both directly, through receptors in the renal proximal tubule,14 and indirectly, by stimulating the secretion of the mineralocorticoid aldosterone.15Through this augmented sodium retention, the renin-angiotensin-aldosterone axis should restore extracellular fluid volume (Figure 5A).

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Figure 5. Aldosterone paradox in POTS. A, Under normal circumstances, low plasma volume is sensed in kidney (and in heart and aorta) and stimulates increase in plasma renin activity (renin), angiotensin II (A-II), and aldosterone (ALDO). Increase in plasma renin activity and aldosterone promotes salt and water retention, which leads to increase in extracellular fluid volume and plasma volume. B, In POTS, there is failure to sense and appropriately respond to low plasma volume. There is no appropriate increase in plasma renin activity, angiotensin-II, and aldosterone given the hypovolemia. Because plasma renin activity and aldosterone are not increased, salt and water retention is not increased, and plasma volume is not increased.

Plasma renin activity was similar in patients with POTS and control subjects, whereas supine and upright levels of aldosterone were significantly lower in patients with POTS (Figure 2). Given their degree of hypovolemia, however, one would expect both plasma renin activity and aldosterone levels to be significantly higher in the POTS group than in controls. Both the plasma renin activity and, to a greater extent, aldosterone levels were inappropriately low given the hypovolemic status of the patients with POTS. We have termed this dysregulation of plasma renin activity and aldosterone in POTS the “renin-aldosterone paradox” (Figure 5B).

Aldosterone secretion is controlled at many levels: it is stimulated by angiotensin II, potassium, and hyponatremia, and acutely by the adrenocorticotropic hormone; it is inhibited by dopamine and atrial natriuretic factor (ANF).28 Electrolyte abnormalities are not likely to explain the low aldosterone as the sodium and potassium levels were similar in the POTS group and controls (Table 1). Although we cannot exclude the possibility that there are abnormalities in ANF or increases in adrenal dopamine concentrations that could contribute to the low aldosterone state, the most likely explanation for the renin-aldosterone paradox is an inappropriately low level of angiotensin II.

The cause of the inappropriately low levels of plasma renin activity and aldosterone in POTS is not clear. Low-flow states across the juxtaglomerular apparatus (as is seen in renal artery stenosis) are known to increase plasma renin activity. It is possible that the opposite effect somehow occurs in POTS, presumably by impaired vascular function. Other possibilities include problems with the sensor mechanisms at the level of the macula densa, or in the transmission of this signal to the juxtaglomerular apparatus, or in the response of the juxtaglomerular apparatus.13 It is also possible that patients with POTS have a low blood vessel “capacitance” that in turn limits the blood volume. Such a phenomenon has been proposed to exist in patients with pheochromocytoma, who have low blood volume.29,30 Plasma volume and total blood volume increase in response to treatment with an α-adrenergic antagonist.31

Red Blood Cell Volume
In addition to deficits in plasma volume patients with POTS also had a significant reduction in red blood cell volume (Figure 3B andTable 2). This finding would not have been apparent on cursory assessment. Hematocrit levels were not different between the 2 groups (Table 1). Because there was a parallel reduction in the 2 largest components of blood volume (plasma volume and red blood cell volume), the percentage of the blood column that was due to the red blood cells appeared to be normal. Thus, we required a formal radioisotope dilution assessment of blood volumes to document the red blood cell volume deficit.

This red blood cell volume deficit has been observed previously in patients with POTS.11,12 The pathogenesis of this deficit, however, is not known. The renal hormone erythropoietin is the primary agonist for red blood cell production in the bone marrow.32–34 It is possible that a deficit in erythropoietin production might play a pathophysiological role in POTS, although this is not yet clear.

There are several pieces of evidence that point to an important role for angiotensin II and the renin-angiotensin-aldosterone axis in the regulation of erythropoietin production. First, in healthy subjects, infusions of angiotensin II caused serum erythropoietin levels to increase significantly, but this stimulation of erythropoietin was blocked when the subjects were premedicated with losartan, an angiotensin receptor blocker.35,36 Second, plasma renin activity is higher among hemodialysis patients who do not require exogenous erythropoietin to maintain a hematocrit of 30% (which suggests adequate endogenous erythropoietin) than in those patients who require exogenous erythropoietin.37 Third, plasma ultrafiltration induced a doubling of plasma renin activity, which was accompanied by a 69% rise in serum erythropoietin over 4 hours.37 This increase in erythropoietin was abolished with the use of an ACE inhibitor. Finally, some patients develop a persistently elevated hematocrit after renal transplant.38Inactivation of the renin-angiotensin-aldosterone system by an ACE inhibitor or an angiotensin receptor blocker can correct this polycythemia,39,40 and conversely, withdrawal of the ACE inhibitor has been associated with “rebound” polycythemia.38 Taken together, these pieces of evidence suggest that the paradoxically low renin activity seen in patients with POTS could be the cause of the low red blood cell volume through a direct hormonal effect.

Another possible explanation for the low red blood cell volume seen in POTS is that it is a direct result of the low plasma volume. The kidney may function as the key organ involved in the regulation of hematocrit, because it controls both plasma volume (through salt regulation) and red blood cell volume (through erythropoietin).41 To maintain an appropriate hematocrit (the hematocrit was similar between patients with POTS and controls), the red blood cell volume may be adjusted downward through a physiologically reduced level of erythropoietin to match the deficit in plasma volume.

Erythropoietin replacement, by itself, is not likely to restore normal physiological function in patients with POTS. Hoeldtke et al12studied 8 patients with POTS and found 6 of those patients to have a low red blood cell volume. Treatment with open-label erythropoietin improved the red blood cell volume but did not increase the plasma volume. The orthostatic tachycardia was corrected in only 1 of their patients, although 3 patients subjectively reported feeling better.

Study Limitations
We have found that plasma renin activity and aldosterone are not appropriately regulated in patients with POTS. The low aldosterone-renin ratio seen in POTS suggests a mismatch between these 2 hormones. One limitation of the present study was that levels of angiotensin II, a biochemical link between renin and aldosterone, were not measured directly. Other potential regulators of aldosterone secretion (dopamine and ANF) and salt and water regulation (such as antidiuretic hormone, serum osmolality, and B-type natriuretic peptide) may also provide useful insights into the renin-aldosterone paradox seen in POTS. Future studies will include an assessment of these markers.
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Conclusions

In summary, we have found that patients with POTS have a reduction in plasma volume. They have inappropriately low levels of renin and low levels of aldosterone, 2 hormones that promote sodium retention and increase plasma volume and are regulated by the kidneys. These patients also have a significantly low volume of red blood cells. Red blood cell production is primarily stimulated by erythropoietin, a hormone that is released by the kidney. Taken together, these findings suggest that abnormalities in the kidney might be critical in the pathophysiology of POTS.
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Acknowledgments

This study was supported in part by National Institutes of Health grants 2P01 HL56693 and M01 RR00095 (General Clinical Research Center) from the National Institutes of Health. Dr Raj is a Vanderbilt Clinical Research Scholar, supported by a K12 grant from the National Institutes of Health. The DAXOR Corporation (New York, NY) kindly donated the equipment and supplies needed for the blood volume assessment.