Skin Biopsy


Prof. Daniel MANICOURT
Dr. Stephane DAENS

Ehlers-Danlos Syndrome (EDS) is a heterogeneous group of genetic connective tissue disorders characterized by joint hyperlaxity, skin hyperextensibility and tissue fragility. The new 2017 New York classification recognizes 13 types and defines new clinical criteria for the hypermobile type (SEDh) which constitutes the major part of the syndrome (80 to 90% of cases). In the natural history of SEDh, 3 phases are described: the hypermobility phase (Beighton score > 6/9 or if the score is lower, hyperlaxity of other joints not tested by Beighton is taken into account) in the early years of life, the pain phase (which explains the misdiagnosis of fibromyalgia) which begins between the 2nd and 4th decade of life and the rigidity phase observed in the elderly and in a few rare adults. From the fifties onwards, the Beighton score can decrease to 3/9 in the SEDh and to establish the existence of joint hyperlaxity, the 5-question Grahame questionnaire is used. The use of the 62-item Somatosensory Diagnostic Scale (Harmonet) is also an aid to diagnosis.

The skin biopsy is designed to look for abnormalities of connective tissue components including collagen in the dermis. Since collagen is present in tendons and in the skin, abnormalities of collagen in tendons are also observed in the skin. For this reason, skin biopsy is of interest in Ehlers-Danlos Syndrome, especially since it is easy to perform and not very traumatic for patients.

Skin biopsy can be performed for 2 purposes:

1/ for a culture of fibroblasts to search for genetic mutations. In this case, it will be negative in the hypermobile Ehlers-Danlos syndrome (HDS) whose genetic mutations are currently unknown. Therefore, biopsy for genetic research in SEDh is not contributory.

2/ for a morphological study of the connective tissue. There are 3 examinations that are done in this case:

a/ histology (light microscopy) sometimes shows abnormalities, such as elastopathy, which allows the diagnosis of SED to be suspected

b/ immunohistology: the anti-FXIIIa antibody marks the presence of type I dermal dendrocytes (DD-1). The decrease in the number of DD-1s is in favour of a SED, because the DD-1s decrease in number as soon as skin tension deviates from a certain norm.

c/ the ultrastructural study (transmission electron microscopy) is the most important examination. It allows the visualization of collagen abnormalities by the presence of variability in the diameter of the fibrils, irregularity of the inter-fibrillar spaces and flower-shaped fibrils (photo 1). Since the number of flower-shaped fibrils may be minimal, careful examination of the sections is necessary. Other modifications can also be observed: those of the elastic fibres, deposits of granulo-filamentous material...


Photo 1: Collagen changes in the SEDh (flower-shaped fibrils (>), variable fibril diameter and irregularity of inter-fibril spaces)

The diagnosis of SEDs, as in all pathologies, must always be based on the clinic. With the exception of the dermatosparaxial SED, cutaneous ultrastructural modifications have a high sensitivity but low specificity in the SED; nevertheless, all of these modifications are reproducible in each of the different types of SED and allow the diagnosis to be confirmed and classified. It is therefore important that the sections are read by an experienced examiner who is familiar with all the changes induced by the different types of SEDs.

The morphological changes described in the SEDh may also be observed in some "healthy" family members of a patient with SEDh. However, when these individuals are properly examined, they have joint hyperlaxity that is asymptomatic or associated with certain signs defined by the New York criteria for SEDh or a Beighton score of less than 5 or 6/9 and are therefore classified as Hypermobility Spectrum Disorder (HSD). However, there is a continuum between asymptomatic hyperlaxity, HSD and SEDh. Some patients may develop other symptoms over the course of their lives and their diagnosis may change from HSD to SEDh.

In the SEDh, where genetic mutations are not known, skin biopsy for a morphological study is a valuable aid to diagnosis, as it is the only way to confirm the diagnosis, as the other tests (Rx, MRI...) are all negative until the joints are destroyed or neurological complications appear. The earlier the diagnosis is made, the sooner preventive and therapeutic devices can be put in place, thus preserving the patient's quality of life and also limiting medical costs.



Document: "How to perform a skin biopsy (Paris May 2018)"

Article on the electron microscopy appearance of tendons