Silvia Morlino

Management of pain and fatigue in the joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome, hypermobility type): Principles and proposal for a multidisciplinary approach

Joint hypermobility syndrome (JHS), or Ehlers–Danlos syndrome (EDS) hypermobility type (EDS‐HT), is a underdiagnosed heritable connective tissue disorder characterized by generalized joint hypermobility and a wide range of visceral, pelvic, neurologic, and cognitive dysfunctions. Deterioration of quality of life is mainly associated with pain and fatigue. Except for the recognized effectiveness of physiotherapy for some musculoskeletal features, there are no standardized guidelines for the assessment and treatment of pain and fatigue. In this work, a practical classification of pain presentations and factors contributing in generating painful sensations in JHS/EDS‐HT is proposed. Pain can be topographically classified in articular limb (acute/subacute and chronic), muscular limb (myofascial and fibromyalgia), neuropathic limb, back/neck, abdominal and pelvic pain, and headache. For selected forms of pain, specific predisposing characteristics are outlined. Fatigue appears as the result of multiple factors, including muscle weakness, respiratory insufficiency, unrefreshing sleep, dysautonomia, intestinal malabsorption, reactive depression/anxiety, and excessive use of analgesics. A set of lifestyle recommendations to instruct patients as well as specific investigations aimed at characterizing pain and fatigue are identified. Available treatment options are discussed in the set of a structured multidisciplinary approach based on reliable outcome tools.

Gynecologic and obstetric implications of the joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome hypermobility type) in 82 Italian patients†‡

Joint hypermobility syndrome (JHS) emerges as likely the most common clinical form of Ehlers–Danlos syndrome. Given the striking predominance of affected women, practitioners often face gynecologic and obstetric issues. However, their decisions are still based on personal experience rather than literature due to the lack of a consistent body of evidence. We collected a set of gynecologic and obstetric features in 82 post‐puberal women with JHS attending two Italian centers. Common gynecologic findings were dysmenorrhea (82.9%), meno/metrorrhagias (53.7%), irregular menses (46.3%), and dispareunia/vulvodinia (31.7%). Forty women were nulliparous and 42 had one or more pregnancy for a total of 93 diagnosed conceptions. Of them, 16.1% were spontaneous abortions, 6.5% voluntary interruptions, 10.7% preterm deliveries, and 66.7% deliveries at term. Overall outcome of proceeding pregnancies was good with no stillbirth and fetal/neonatal hypoxic/ischemic event. Non‐operative vaginal delivery was registered in 72.2%, forceps/vacuum use in 5.5% and cesarean in 22.3%. Local/total anesthesia was successfully performed in 17 pregnancies without any problem. Major post‐partum complications included abnormal scar formation after cesarean or episiotomy (46.1%), hemorrhage (19.4%), pelvic prolapses (15.3%), deep venous thrombosis (4.2%), and coccyx dislocation (1.4%). Prolapses were the most clinically relevant complication and associated with episiotomy. Gathered data were discussed for practically oriented considerations.

Towards a re-thinking of the clinical significance of generalized joint hypermobility, joint hypermobiity syndrome, and Ehlers-Danlos syndrome, hypermobility type

In this Issue of the American Journal of Medical Genetics Part A, Remvig et al. [2014] report the results of a Delphi study aimed at measuring the level of agreement among clinicians in assessing patients with generalized joint hypermobility (JHM), joint hypermobility syndrome (JHS), and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) according to theBeighton score [Beighton et al., 1973], Brighton [Grahame et al., 2000] and Villefranche criteria [Beighton et al., 1998], respectively. In linewith the need for an international consensus onmethods for measuring JHM and on more accurate tools for classifying patients with the overlapping JHS and EDS-HT (i.e., JHS/EDS-HT) recently claimed by various authors [Tinkle et al., 2009; Remvig et al., 2011], the study by Remvig et al. [2014] fails to identify an agreement in the methods used to assess and recognize these conditions among 15 practitioners (various disciplines) from different European countries. For decades, JHMhas been considered a benign trait without any or with minimal clinical significance, except, perhaps, during the planning of orthopedic interventions in order to improve the shortterm outcome of surgery. Thanks to the increasing attention posed on JHM as a marker for the wide category of heritable connective tissue disorders (HCTDs), the subgroup of individuals with nonspecific phenotypes, heterogeneously termed as (“symptomatic”) generalized JHM, (“benign”) JHS, EDS-HT, or JHS/EDS-HT, is becoming a model for studying the subtle, but long-lasting and potentially progressive consequences of congenital derangement of this ubiquitous tissue on humans’ variability. In recent years, a new generation of researchers throughout the world is invested in exploring connections between JHM and chronic dysfunctions in practically all major systems and organs. This natural (r)evolution of knowledge imposes a new approach to think and manage JHM as a biomarker and JHS/EDS-HT as a recognizable clinical entity which is waiting for a more rigorous definition. During the last 4 years, we had the opportunity to evaluate and partly manage an increasing number of patients with various HCTDs and, in particular, the “so-called” JHS/EDS-HT spectrum. By sequential application of the various available diagnostic tools/ criteria on dozens of patients at different ages and belonging to the clinical categories of generalized (either observational or historical) JHM, JHS and EDS-HT, we are astonished by the extreme overlap between these three phenotypic groups. The fact that these three conditions are likely, at least in some pedigrees, the changing patterns of the samebiological (etiological? genetic?) entity emerges from intraindividual (i.e., categorical transitions at different ages in the same patient) and intrafamilial (i.e., pedigree members with different diagnoses at the same observational window) considerations. As a consequence, the need for identifying more accurate clinical tools to distinguish between individuals with congenital laxity of the connective tissue and proneness to the associated dysfunctions/disabilities, and those presenting phenocopies due to other acquired/heritablemechanisms is urgent for both clinical and research purposes. On a clinical perspective, practitioners and patients require handy, accurate, and validated tools to carry out a clinical diagnosis regardless of known variables (e.g., age, sex, ethnicity, habits, articular, and extra-articular clinical variability) for classificatory, therapeutic, and prognostic aims. On a research perspective, Beighton score and Brighton/Villefranche criteria are dichotomous tools which do not take into account the above mentioned variability. How can we assess a 15-year-old boy with recurrent joint dislocations (shoulders, elbows), symptoms of orthostatic intolerance, irritable bowel syndrome, overt lack of coordination, but Beighton score 0/9, only sporadic joint pain and completely normal skin? In this case, what is the significance of Beighton score 6/9, soft/ translucent skin and chronic limb pain in the mother, and generalized JHM and developmental coordination disorder in his younger sister? Are the Brighton and Villefranche criteria sufficient to carry out the diagnosis in the propositus and trace the underlying heritable/genetic trait in this family? What do we lose by not

Late diagnosis of lateral meningocele syndrome in a 55-year-old woman with symptoms of joint instability and chronic musculoskeletal pain

Lateral meningocele syndrome (LMS) is a rare hereditary connective tissue disorder characterized by pan‐spinal meningoceles, specific facial dysmorphism, skeletal and soft tissue abnormalities, and hypotonia and/or muscle weakness. LMS has been observed in eleven patients with two instances of vertical transmission, and seven sporadic cases with an age at diagnosis ranging from 25 months to 33 years. We report on a further observation of LMS in a 55‐year‐old woman presenting with a long history of joint instability, chronic musculoskeletal pain, and iatrogenic bladder and anorectal dysfunction due to irreversible nerve damage after surgical excision of a meningeal cyst. Her clinical characteristics are compared with those of previously reported patients, as well as two further cases originally diagnosed with Hajdu–Cheney and Ehlers–Danlos syndromes, but displaying typical features of LMS.

A 22-Week-Old Fetus with Nager Syndrome and Congenital Diaphragmatic Hernia due to a Novel SF3B4 Mutation

Nager syndrome, or acrofacial dysostosis type 1 (AFD1), is a rare multiple malformation syndrome characterized by hypoplasia of first and second branchial arches derivatives and appendicular anomalies with variable involvement of the radial/axial ray. In 2012, AFD1 has been associated with dominant mutations in SF3B4. We report a 22-week-old fetus with AFD1 associated with diaphragmatic hernia due to a previously unreported SF3B4 mutation (c.35-2A>G). Defective diaphragmatic development is a rare manifestation in AFD1 as it is described in only 2 previous cases, with molecular confirmation in 1 of them. Our molecular finding adds a novel pathogenic splicing variant to the SF3B4 mutational spectrum and contributes to defining its prenatal/fetal phenotype.

Refining patterns of joint hypermobility, habitus, and orthopedic traits in joint hypermobility syndrome and Ehlers–Danlos syndrome, hypermobility type

Joint hypermobility syndrome (JHS) and Ehlers–Danlos syndrome, hypermobility type (EDS–HT) are two overlapping heritable disorders (JHS/EDS–HT) recognized by separated sets of diagnostic criteria and still lack a confirmatory test. This descriptive research was aimed at better characterizing the clinical phenotype of JHS/EDS–HT with focus on available diagnostic criteria, and in order to propose novel features and assessment strategies. One hundred and eighty‐nine (163 females, 26 males; age: 2–73 years) patients from two Italian reference centers were investigated for Beighton score, range of motion in 21 additional joints, rate and sites of dislocations and sprains, recurrent soft‐tissue injuries, tendon and muscle ruptures, body mass index, arm span/height ratio, wrist and thumb signs, and 12 additional orthopedic features. Rough rates were compared by age, sex, and handedness with a series of parametric and non‐parametric tools. Multiple correspondence analysis was carried out for possible co‐segregations of features. Beighton score and hypermobility at other joints were influenced by age at diagnosis. Rate and sites of joint instability complications did not vary according to age at diagnosis except for soft‐tissue injuries. No major difference was registered by sex and dominant versus non‐dominant body side. At multiple correspondence analysis, selected features tend to co‐segregate in a dichotomous distribution. Dolichostenomelia and arachnodactyly segregated independently. This study pointed out a more protean musculoskeletal phenotype than previously considered according to available diagnostic criteria for JHS/EDS–HT. Our findings corroborated the need for a re‐thinking of JHS/EDS–HT on clinical grounds in order to find better therapeutic and research strategies.

Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.

Filamin A is an X‐linked, ubiquitous actin‐binding protein whose mutations are associated to multiple disorders with limited genotype–phenotype correlations. While gain‐of‐function mutations cause various bone dysplasias, loss‐of‐function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X‐linked cardiac valvular dystrophy (XCVD). The term “Ehlers–Danlos syndrome (EDS) with periventricular heterotopias” has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X‐linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829‐1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N‐terminus rod 1 domain of filamin A. Our findings expand the male‐specific phenotype of FLNA mutations that now includes classical‐like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype–phenotype correlations within this spectrum.

Spectrum of mucocutaneous, ocular and facial features and delineation of novel presentations in 62 classical Ehlers-Danlos syndrome patients

Classical Ehlers‐Danlos syndrome (cEDS) is characterized by marked cutaneous involvement, according to the Villefranche nosology and its 2017 revision. However, the diagnostic flow‐chart that prompts molecular testing is still based on experts’ opinion rather than systematic published data. Here we report on 62 molecularly characterized cEDS patients with focus on skin, mucosal, facial, and articular manifestations. The major and minor Villefranche criteria, additional 11 mucocutaneous signs and 15 facial dysmorphic traits were ascertained and feature rates compared by sex and age. In our cohort, we did not observe any mandatory clinical sign. Skin hyperextensibility plus atrophic scars was the most frequent combination, whereas generalized joint hypermobility according to the Beighton score decreased with age. Skin was more commonly hyperextensible on elbows, neck, and knees. The sites more frequently affected by abnormal atrophic scarring were knees, face (especially forehead), pretibial area, and elbows. Facial dysmorphism commonly affected midface/orbital areas with epicanthal folds and infraorbital creases more commonly observed in young patients. Our findings suggest that the combination of ≥1 eye dysmorphism and facial/forehead scars may support the diagnosis in children. Minor acquired traits, such as molluscoid pseudotumors, subcutaneous spheroids, and signs of premature skin aging are equally useful in adults.

Posterior column ataxia with retinitis pigmentosa coexisting with sensory‐autonomic neuropathy and leukemia due to the homozygous p.Pro221Ser FLVCR1 mutation

FLVCR1 encodes for a ubiquitous heme exporter, whose recessive mutations cause posterior column ataxia with retinitis pigmentosa (PCARP). Recently, FLVCR1 recessive mutations were also found in two sporadic children with hereditary sensory‐autonomic neuropathy (HSAN). We report the unique case of a 33‐year‐old Italian woman with a combination of typical PCARP, sensory‐autonomic neuropathy with sensory loss to all modalities and multiple autonomic dysfuctions, and acute lymphocytic leukemia. Molecular analysis demonstrated homozygosity for the previously identified FLVCR1 p.Pro221Ser variation. The same variation, in combination with a frameshift mutation, was previously identified in an Italian child with HSAN. Functional studies carried out on patient‐derived lymphoblastoid cell lines showed decreased FLVCR1a transcript, increased reactive oxygen species, excessive intracellular heme accumulation, and increased number of Annexin V positive cells. This indicates that the homozygous p.Pro221Ser FLVCR1 variation compromises the ability of FLVCR1a to export heme leading to enhanced susceptibility to programmed cell death. Our study demonstrates the existence of a phenotypic continuum among the discrete disorders previously linked to FLVCR1 mutations, and suggests that the related alteration of heme metabolism may lead to the degeneration of specific neuronal cell populations.

The "old theme" of variability versus transitory phenotypes in thanatophoric dysplasia type 1: two 19-week-old fetuses with ("San Diego" variant) and without ragged metaphyses due to the same FGFR3 mutation.

Conflict of interest: none. Correspondence to: Marco Castori, M.D., Ph.D., Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense 87, Rome 00152, Italy. E-mail: mcastori@scamilloforlanini.rm.it Article first published online in Wiley Online Library (wileyonlinelibrary.com): 16 August 2013 DOI 10.1002/ajmg.a.36131 TO THE EDITOR: