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ABSTRACT We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We

enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and

based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in

selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers–Danlos syndrome and other unclassified forms. In seven patients,

spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and

may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable

connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities. SIMILAR CONTENT BEING VIEWED BY OTHERS THE

EHLERS–DANLOS SYNDROMES Article 30 July 2020 GIANT CELL ARTERITIS: REVIEWING THE ADVANCING DIAGNOSTICS AND MANAGEMENT Article Open access 14 February 2023 THE RELATIONSHIP BETWEEN CLINICAL

CHARACTERISTICS AND MAGNETIC RESONANCE IMAGING RESULTS OF MÉNIÈRE DISEASE: A PROSPECTIVE STUDY Article Open access 30 March 2021 INTRODUCTION Spontaneous cerebrospinal fluid (CSF) leak is an

uncommon condition usually diagnosed in patients presenting with a positional orthostatic headache, following studies confirming low CSF pressure, and/or evidence of a CSF leak on

Neuroimaging studies.1 Spontaneous CSF leaks are under-diagnosed and frequently misdiagnosed, because only the minority of patients undergo the appropriate evaluation. The exact underlying

pathogenic mechanism is unknown and an excessive fragility of the spinal dura has been suggested as a cause.2 Hereditary disorders of connective tissue (HDCT) comprise a clinically and

genetically heterogeneous group of disorders, characterized by generalized fragility of connective tissues. The prevalence of HDCT has been estimated at 1:5000; however, it may be higher, as

it is likely that some individuals with milder clinical manifestations do not come to medical attention.3 Single-gene defects in genes involved in the regulation of connective tissue

biology have been identified for some of the HDCT (such as in Marfan syndrome (OMIM# 154700), many forms of Ehlers–Danlos syndrome (EDS), etc), but in most cases the diagnosis is established

clinically.4, 5 Several case reports and small studies, published in the neurosurgical literature, suggested a link between HDCT and spontaneous CSF leaks, but the precise prevalence is not

clear.6, 7, 8, 9 Here we report the clinical and molecular findings in a cohort of 50 patients with spontaneous CSF leaks. We propose that there is a broad clinical basis for considering

spontaneous CSF leak as a clinical manifestation of HDCT, and that those patients with spontaneous CSF leaks should be screened for connective tissue and vascular abnormalities. MATERIALS

AND METHODS We enrolled a consecutive group of 50 patients, aged 12–67, referred for consultation of a spontaneous spinal CSF leak from December 2009 to September 2011. All patients were

diagnosed according to previously published diagnostic criteria for this condition that include clinical evaluation and imaging studies.1 Briefly, the diagnostic criteria consist of (a)

orthostatic headache; (b) the presence of at least one of the following: low opening pressure, sustained improvement of symptoms after epidural blood patching, demonstration of an active

spinal cerebrospinal fluid leak, cranial magnetic resonance imaging changes of intracranial hypotension; (c) no recent history of dural puncture; and (d) not attributable to another

disorder. The subjects in this cohort have not been included in previous studies. Patients were provided with oral and written information detailing the study and asking for their

participation at admission to the hospital and informed consent was obtained (CSMC IRB Protocols 0463 and 4232). Ancillary diagnostic testing, including genetic testing, echocardiography,

eye exam, and histopathological examinations of skin and dura, were obtained in selected patients, on the basis of the findings on physical examination and medical history. All patients have

been evaluated by a single medical geneticist according to the same protocol that included questions pertaining to the medical history, and clinical examination aimed on identifying skin,

musculoskeletal, cardiovascular (by echocardiogram), cranio-facial and vision abnormalities. The evaluation protocol is depicted in Table 1. SKIN AND DURA BIOPSIES Skin and dura samples were

collected in patients consented for the procedure, at the time of CSF leak repair. Freshly excised biopsies of the back skin and spinal dura were fixed, cut, and viewed with Jeol 100CX

transmission electron microscope at 80k. Digital images were collected and analyzed by an expert pathologist. RESULTS PATIENTS Of the 50 patients with spontaneous spinal CSF leaks, 38 were

women (77.6%) and 12 were men (22.4%). The mean age at presentation was 43 years (range, 12–67). PREVALENCE OF HDCT AMONG PATIENTS WITH SPONTANEOUS CSF LEAKS During the evaluation period, a

total of nine patients (all females) were diagnosed with HDCT (18%). The spectrum of disorders included Marfan syndrome (1 patient), EDS hypermobility type (four patients), EDS classic type

(two patients – these presented with milder manifestations of the disease – previously classified as EDS type II, Mitis type (OMIM# 1300010)) and an unclassified HDCT in two patients. Two

out of these nine patients had a preexisting diagnosis (patient #1 with Ehlers–Danlos syndrome hypermobility type (OMIM# 130020) and patient #3 with Marfan syndrome). Patients receiving a

diagnosis of a specific connective tissue disorder have met at least the minimal diagnostic criteria according to the published Villefranche classifications,4, 5 and molecular testing has

been completed, when the genetic basis was known. Patients diagnosed with EDS hypermobility type have demonstrated generalized joint hypermobility with joint pain, and mild-skin involvement

(mainly soft skin that bruises easily), sometimes in the context of positive family history. Patients diagnosed with the classic type of EDS have demonstrated generalized joint

hypermobility, and a more severe skin involvement (mostly hyperextensible skin that bruises easily and widened scars). The diagnosis of an unclassified HDCT in two patients was established,

based on generalized skeletal, skin and vascular involvement that did not meet clinical criteria for any of the known HDCT. Overall, the observed spectrum of connective tissue abnormalities

included joint laxity and dislocations, skin fragility with easy bruising, abnormal wound healing and spontaneous subcutaneous emphysema, and cardiovascular dysfunction, including arterial

dissection, aortic root enlargement and abnormalities of the mitral and tricuspid valves. The clinical findings of these nine patients are summarized in Table 2. PREVALENCE OF BENIGN JOINT

HYPERMOBILITY SYNDROME (BJHM) AND ISOLATED FEATURES OF CTD (ICTD) AMONG PATIENTS WITH SPONTANEOUS CSF LEAKS Connective tissue signs, not consistent with a definite diagnosis, have been

observed in eight patients (16%). These patients were given a diagnosis of BJHM (OMIM# 147900), if they demonstrated joint laxity and a family history of joint hypermobility but no skin

involvement, or ICTD in patients with mild craniofacial findings but without additional significant skeletal, skin or cardiovascular manifestations or their associated complications

suggesting a generalized HDCT (Table 3). GENETIC EVALUATION Gene sequencing of _Fibrillin 1_ (_FBN1_), _Collagen 5A1+2_ (_COL5A1+2_), _Collagen 3A1_ (_COL3A1_), and _Folliculin C_ (_FLCN_)

were performed, following establishment of an initial clinical diagnosis in selected patients. _FBN1_ was sequenced in patient # 2 to exclude variants of Marfan syndrome that can present

with recurrent spontaneous pneumothoraces.10 _FLCN_ was sequenced in the same patient as mutations in this gene have been reported in some patients with recurrent spontaneous

pneumothoraces.11, 12, 13, 14 Owing to a history of spontaneous vertebral artery dissection in addition to skin and musculoskeletal findings in patient # 5, _COL3A1_ as well as _COL5A1+2_

were sequenced to exclude the vascular type of Ehlers–Danlos syndrome and a potential vascular involvement in the classic type of Ehlers–Danlos syndrome, respectively.4, 15 Both _COL5A1_ and

_COL5A2_ were normal in patients # 4 and 8 who were diagnosed with classic EDS (<50% of patients with classic EDS have an identifiable mutation in this gene). The diagnosis of

hypermobility EDS is established clinically and the genetic basis is unknown with the exception of very rare TNXB mutations in a small subset of patients. Therefore, genetic testing has not

been further pursued in patients 1, 6, 7, and 9. SKIN HISTOPATHOLOGY Electron microscopy examination of skin biopsies from 28 patients and dura biopsies from 7 patients revealed inconsistent

findings with five samples (3 patients with HDCT and 2 with spontaneous CSF leaks but no connective tissue abnormalities) demonstrating significant pathological changes in the distribution,

diameter and striation pattern of collagen and elastic fibers. All others appeared normal with minimally, non-specific changes. These results essentially exclude skin histopathology as

being an efficient clinical tool to support a diagnosis of spontaneous CSF leak in patients with an underlying HDCT. DISCUSSION The main finding of our study was the high frequency of

connective tissue abnormalities in patients with spontaneous CSF leaks. In addition, the spectrum of connective tissue abnormalities was broader than previously described, and ranges from

rather benign hypermobility syndrome to life-threatening disorders with variable combinations of vascular, cardiac, skin and joint-related symptoms and signs. This may dictate future

surveillance and management guidelines for those patients. Overall, we found that the neurological presentation, the findings on imaging studies, and the histopathological findings, cannot

distinguish between patients with and without an underlying HDCT. An additional observation in this cohort is that the immediate outcome (ie, resolution of symptoms assessed following

surgical procedure and before discharge) seems to be similar among patients with and without an underlying HDCT. Thus, until a long-term follow-up on this cohort will be available, the same

management protocol should generally be applied to both groups. This protocol includes several modalities such as an epidural blood patch, followed by a percutaneous placement of fibrin glue

or surgical repair of the leak in more resistant, recurrent cases. The prevalence of HDCT in patient with spontaneous CSF leaks has been rarely estimated. Most reported studies described

either single or limited number of patients, thus increasing the risk of publication bias.6, 7, 8, 9 A review of the medical records of 58 patients with spontaneous CSF leaks found nine

patients (seven females and two males) who exhibited some clinical features of a connective tissue disorder.16 The limitations of this study are that detailed descriptions of the patients

and methods of evaluation are not available. A recent prospective study has attempted to overcome these limitations by enrolling a cohort of consecutive Taiwanese patients presented with

spontaneous CSF leaks and matched controls that were evaluated for connective tissue signs of Marfan syndrome and the hypermobility type of Ehlers–Danlos syndrome.7 None of the patients in

this cohort received a diagnosis of a HDCT, while there was a tendency toward a high frequency of skin findings in both groups. Yet, this study was limited by several factors. First, the

clinical evaluation protocol was not strict enough to include the key features on medical history and clinical examination that can be associated with HDCT, possibly biasing the reported

incidence. Second, the authors focused on the rather peripheral skeletal findings associated with Marfan syndrome, but overlooked other important manifestations, including the major

diagnostic criteria (family history, lens dislocation, aortic dilatation) that were defined in the revised nosology, which might have produced false-negative results of Marfan syndrome.

Third, ancillary studies such as echocardiograms and genetic studies were not included; these studies are sometimes key in the diagnosis of several HDCT. The recognition of HDCT in patients

with spontaneous CSF leaks may be important mainly because of the potential vascular (and other connective tissue) fragility that is associated with them. Although limited by the size of

this cohort, it would appear that the data shown here present a case for screening individuals with spontaneous CSF leaks for connective tissue and vascular complications. Descriptions of

patients with connective tissue disorders do not report an association with spontaneous CSF leaks, suggesting that it is not a common complication of this group of disorders.17 However, the

precise incidence of which is unknown, as headache is a common complaint among patients with HDCT, and only a minority of affected individuals have undergone appropriate examination. The

recognized HDCT that we diagnosed in this cohort are two subtypes of EDS and Marfan syndrome. The hypermobility type of EDS is the most common subtype of EDS and a common cause of chronic,

undiagnosed pain syndrome. Clinical manifestations include painful and chronic joint instability and dislocations leading to degenerative joint disease at a young age.18 The genetic basis of

EDS hypermobility type is unknown in most cases; therefore, the diagnosis of this type is based entirely on clinical evaluation that includes musculoskeletal and skin findings and sometimes

positive family history, but the absence of fragility of other soft tissues.4 The classic type of EDS is characterized by joint hypermobility, similar to the one observed in the

hypermobility type, but a much more extensive skin involvement (skin hyperextensibility, abnormal wound healing and scar formation), as well as fragility of other connective tissues in some

cases (large arteries, cervical insufficiency during pregnancy, recurrent hernias, rectal prolapse etc).4, 19 The diagnosis of EDS classic type is established clinically, although up to 50%

of individuals have a mutation in _COL5A1_ or _COL5A2_, the genes encoding type V collagen. Therefore, a positive genetic testing supports the diagnosis, whereas a negative test cannot rule

it out. In addition, although cauliflower deformity of skin collagen fibrils is a characteristic of classic EDS, it is not specific or diagnostic, especially in milder cases, such as the

patients described here. The clinical manifestations of Marfan syndrome are highly variable and can involve the ocular, skeletal, skin, cardiovascular, and pulmonary systems. Mutations in

_FBN1_ have been detected in ∼95% of affected patient although the diagnosis can usually be established clinically.5, 20 CSF leaks from dural sac have been reported in Marfan syndrome.21

There were several limitations to the current study. First, there is an unequal distribution of gender in this study (38 females _vs_ 12 males). It is not known whether females have a higher

incidence of CSF leaks itself, or symptoms arising from it, or whether this is due to sampling bias. As HDCT, and especially EDS hypermobility type, are more prevalent in symptomatic

females,22 this gender bias must be taken into account when trying to generalize the sample data to the general group of patients with CSF leaks. Second, selection bias should be considered

in this study. As all the recruited patients were referred, they might have a different disease spectrum, because many patients with spontaneous CSF leaks recover spontaneously without

seeking a referral. Therefore, the study results cannot be generalized to all patients with spontaneous CSF leaks. Future studies including long-term follow-up on this cohort are needed to

understand the impact of an underlying HDCT on the natural history and management of patients with spontaneous CSF leaks. In conclusion, although clinicians need to be aware of the cardiac,

vascular and connective tissue manifestations associated with HDCT, the association of spontaneous CSF leaks with these abnormalities may be an additional clinical manifestation in the

spectrum of generalized connective tissue fragility. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of HDCT, and that individuals

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mechanisms and perspectives. _Am J Med Genet A_ 2010; 152: 2406–2408. Article  Google Scholar  Download references ACKNOWLEDGEMENTS Dr Rimoin appreciated support from the Steven Spielberg

Pediatric Research Center, the NIH/NICHD Program Project Grant (HD36657), the Medical Genetics NIH/NIGMS Training Program Grant (5-T32-GM08243), and the Cedars-Sinai General Clinical

Research Center Grant (M01-RR00425) for samples collected under CSMC IRB Protocols 0463 and 4232. AUTHOR INFORMATION Author notes * David L Rimoin: Deceased. AUTHORS AND AFFILIATIONS *

Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA Eyal Reinstein, Mitchel Pariani & David L Rimoin * Department of Pathology, Cedars-Sinai Medical Center, Los

Angeles, CA, USA Serguei Bannykh * Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA Wouter I Schievink Authors * Eyal Reinstein View author publications You can

also search for this author inPubMed Google Scholar * Mitchel Pariani View author publications You can also search for this author inPubMed Google Scholar * Serguei Bannykh View author

publications You can also search for this author inPubMed Google Scholar * David L Rimoin View author publications You can also search for this author inPubMed Google Scholar * Wouter I

Schievink View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Eyal Reinstein. ETHICS DECLARATIONS COMPETING INTERESTS

The authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Reinstein, E., Pariani, M., Bannykh, S. _et al._ Connective

tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study. _Eur J Hum Genet_ 21, 386–390 (2013). https://doi.org/10.1038/ejhg.2012.191 Download

citation * Received: 27 March 2012 * Revised: 10 July 2012 * Accepted: 20 July 2012 * Published: 29 August 2012 * Issue Date: April 2013 * DOI: https://doi.org/10.1038/ejhg.2012.191 SHARE

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clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * hereditary disorders of connective tissue * spontaneous cerebrospinal fluid leak * positional

headache screening