Ehlers-Danlos syndrome

By Marcello Cherchi, MD PhD

For patients

The phrase “Ehlers-Danlos syndrome” (EDS) refers to a group of diseases that can cause problems with joints, skin, blood vessels, the heart, the eyes and other body organs.  It may be helpful to talk with a medical genetic counselor if you or your doctor think you might have EDS.  Some EDS patients have hearing loss.  Some EDS patients may feel disequilibrium because of changes in blood pressure, an inner ear problem, or nerve problems.

For clinicians

Overview

The term “Ehlers-Danlos syndrome (EDS)” refers to a collection of diseases resulting from mutations in specific genes that encode connective tissues or specific enzymes.  These can manifest with a rather broad array of phenotypes.  Genetic testing can confirm the diagnosis.  Some patients with EDS have hearing loss of various types.  Some EDS patients may experience disequilibrium, for which plausible proximal mechanisms include orthostatic intolerance, superior semicircular canal dehiscence and peripheral neuropathy.

Introduction

The first cases of what came to be known as Ehlers-Danlos syndrome (EDS) were originally described by Danish dermatologist, Dr. Edvard Lauritz Ehlers (1863 – 1937) (Ehlers 1901) and French dermatologist, Henri-Alexandre Danlos (1844 – 1912) (Danlos 1908). The eponymous designation of “Ehlers-Danlos syndrome” appears to have been originally proposed in 1936 by the English physician, Dr. Frederick Parkes Weber (Weber 1936).

As additional cases emerged, it became apparent that there was significant phenotypic variability. With the advent of genetics, it is now understood that EDS comprises a range of distinct pathologies with different, though overlapping, clinical manifestations. The Table below summarizes the types of Ehlers-Danlos syndrome in Online Mendelian Inheritance in Man as of this writing.

Type	Other nomen­cla­ture	Inheritance pattern	OMIM disease	OMIM gene	Cytogenetic location	Gene(s)	Protein
Classical EDS, type 1	cEDS, EDS type I	AD	130000	120215	9q34.3	COL5A1	Type V collagen, alpha 1
Classical EDS, type 1	cEDS, EDS type I	AD	130000	120150	17q21.33	COL1A1 c.934C>T, p.(Arg312Cus)	Type I collagen, alpha 1
Classical EDS, type 2	cEDS, type II		130010	120190	2q32.2	COL5A2	Type 5 collagen, alpha 2
Hypermobile type EDS	clEDS, EDS type III	AD	130020	600985	6p21.3	TNXB	Tenascin XB, isoform 1
Classic-like EDS	EDS with TNXB deficiency	AR	606408	600985	6p21.3	TNXB	Tenascin XB, isoform 1
Vascular EDS	EDS type IV	AD	130050	120180	2q32.2	COL3A1	Type III collagen, alpha 1
Kypho­scoliotic EDS, type 1	EDS KSCL1, EDS type VIA	AR	225400	153454	1p36.22	• PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase)	PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase)
Kyphoscoliotic EDS, type 2	EDS type VIB	AR	614557	614505	7p14.3	FKBP14	FK506 binding protein 14
Brittle cornea syndrome, type 1	BCS1	AR	229200	612078	16q24.2	ZNF469 (zinc finger protein 469)	ZNF469 (zinc finger protein 469)
Brittle cornea syndrome, type 2	BCS2	AR	614170	614161	4q27	PRDM5	PRDM5 (PR domain-containing protein 5)
Musculo­contrac­tural EDS type 1	mcEDS, D4ST1-deficient type EDS, EDS type VIB	AR	601776	608429	15q15.1	CHST14	CHST14 (carbohydrate sulfotransferase 14)
Arthro­chalasic EDS type 1	aEDS, EDS type VIIA	AD	130060	120150	17q21.33	COL1A1	Type I collagen, alpha 1
Arthrochalasic EDS type 2	aEDS, EDS type VIIB	AD	617821	120160	7q21.3	COL1A2	Type I collagen, alpha 2
Cardiac-valvular EDS	cvEDS, EDS with COL1A2 deficiency	AR	225320	120160	7q21.3	COL1A2 (biallelic mutations that lead to COL1A2 NMD and absence of pro a2(I) collagen chains)	Type I collagen, alpha 2
Dermato­sparexis EDS	EDS type VIIC	AR	225410	604539	5q35.3	ADAMTS2	A disintegrin-like and metalloproteinase with thrombospondin type 1 motif 2
Spondylo­dysplas­tic EDS, type 1	EDS SPD1	AR	130070	604327	5q35.3	B4GALT7	Beta-1,4-galactosyltransferase 7
Spondylo­dysplas­tic EDS, type 2	EDS SPD2	AR	615349	615291	1p36.33	B3GALT6	Beta-1,3-galactosyltransferase 6
EDS, spondylo­cheiro­dysplas­tic form, type 3	SCD-EDS	AR	612350	608735	11p11.2	SLC39A13	Solute carrier family 39 (zinc transporter), member 13
Periodontal EDS	EDS PD1	AD	130080	613785	12p13.31	C1R	Complement component 1, r subcomponent
Vascular EDS	EDS VASC	AD	130050	120180	2q32.2	COL3A1	Collagen type III, alpha 1
EDS with platelet dysfunction from fibronectin abnormality	EDS type X	AD	225310	135600	2q35	FN1	Fibronectin

Table : Types of Ehlers-Danlos syndrome. AD = autosomal dominant, AR = autosomal recessive, OMIM = Online Mendelian Inheritance in Man

Genetics

Most subtypes of Ehlers-Danlos syndrome result from mutations in genes encoding proteins for connective tissue structures or for enzymes.

Pathophysiological mechanism of disease: hearing loss

Weir and colleagues studied audiometry in 141 pediatric patients diagnosed with EDS, and found some form of hearing loss in 32 (22.7%).  Of those 32 patients, the hearing loss was bilateral in 19 (59%) and unilateral in 13 (41%).  Out of 282 ears (in the 141 EDS patients), pure conductive hearing loss was found in 25 (8.5% of ears), pure sensorineural hearing loss was found in 23 (8.2% of ears), and mixed hearing loss was found in only 3 (1.4% of ears).  The authors reported that of all the EDS patients with hearing loss, 50% “received more than two diagnoses of otitis media throughout the course of their care,” and “31.4% of the cohort with hearing loss had a diagnosis of Eustachian tube dysfunction.”  There are additionally several case reports of otosclerosis in EDS patients (Miyajima, Ishimoto, Yamasoba 2007; Thomas et al. 1996).

Pathophysiological mechanism of disease: disequilibrium

As far as symptoms of disequilibrium are concerned, there are several potential mechanisms by which EDS can cause disorders of equilibrium.

The most common mechanism appears to be autonomic dysfunction, manifesting primarily as orthostatic intolerance, particularly postural orthostatic tachycardia syndrome (POTS) (Celletti et al. 2020; Celletti et al. 2017; De Wandele et al. 2014; Hakim et al. 2017; Mathias et al. 2021; Miller et al. 2020; Qarajeh et al. 2021; Roma et al. 2018; Rowe et al. 1999; Wallman, Weinberg, Hohler 2014).

Superior semicircular canal dehiscence (SSCD) has been reported in several cases of EDS, including unilateral (Chung et al. 2017) and bilateral (Preet et al. 2019; Unterberger et al. 2021).

Peripheral neuropathy of various types may also be contributory (Cazzato et al. 2016; Cook and Jordan 2021; Fernandez et al. 2022; Galan and Kousseff 1995; Igharo et al. 2023; Pascarella et al. 2016; Schady and Ochoa 1984; Voermans et al. 2006; Voermans, Knoop, van Engelen 2011).

In EDS patients with altered cervical mechanics, cervicogenic vertigo (CV) is also a reasonable consideration, though this has not been formally studied.

Clinical presentation

The clinical presentation depends on the proximal mechanism of the symptom of disequilibrium.

Physical examination

Physical examination findings will depend on the proximal mechanism of the symptom of disequilibrium.

It is reasonable for physical examination to include comparison of supine and standing pulse/pressure to seek evidence of postural orthostatic tachycardia.

Ocular motor examination

It is reasonable on infrared video oculography to assess for Valsalva-induced nystagmus which may be elicit nystagmus if superior semicircular canal dehiscence is present.

Testing: audiologic

If an EDS patient has hearing complaints it is reasonable to check audiometry.

Testing: vestibular

Consider checking audiometry, cervical vestibular evoked myogenic potentials and ocular vestibular evoked myogenic potentials to evaluate for superior semicircular canal dehiscence.

Consider checking computerized dynamic posturography for an overall quantification of balance.

Testing: other

Consider checking a tilt table test to evaluate for evidence of autonomic dysfunction.

Consider consultation with a medical geneticist regarding whether genetic testing is appropriate and, if so, which variants should be checked.

Imaging

From the otoneurological perspective, if screening tests (audiometry, cervical vestibular evoked myogenic potentials, ocular vestibular evoked myogenic potentials) are compatible with the presence superior semicircular canal dehiscence, then consider a temporal bone CT without contrast.

Treatment

Care of an EDS patient tends to be multi-disciplinary.

If a patient or their doctor suspects EDS, then consultation with a medical geneticist is sensible to determine whether genetic testing for diagnostic confirmation is appropriate.

Depending on the genetic subtype and clinical manifestations, the overall care of an EDS patient is often organized by a rheumatologist, often in consultation with other specialists, such as a dermatologist.

In EDS patients with hearing loss, referral to audiology is reasonable.

In EDS patients with superior semicircular canal dehiscence, referral to otolaryngology is reasonable. Unfortunately, EDS patients are often poor surgical candidates due to poor tissue healing and in some cases vascular complications.

In EDS patients with postural orthostatic tachycardia syndrome, referral to cardiology is reasonable.

References